Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Management of Community-Acquired Pneumonia in the Era of Pneumococcal Resistance

Management of Community-Acquired Pneumonia in the Era of Pneumococcal Resistance ObjectiveTo provide recommendations for the management of community-acquired pneumonia and the surveillance of drug-resistant Streptococcus pneumoniae(DRSP).MethodsWe addressed the following questions: (1) Should pneumococcal resistance to β-lactam antimicrobial agents influence pneumonia treatment? (2) What are suitable empirical antimicrobial regimens for outpatient treatment of community-acquired pneumonia in the DRSP era? (3) What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era? and (4) How should clinical laboratories report antibiotic susceptibility patterns for, S pneumoniaeand what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest? Experts in the management of pneumonia and the DRSP Therapeutic Working Group, which includes clinicians, academicians, and public health practitioners, met at the Centers for Disease Control and Prevention in March 1998 to discuss the management of pneumonia in the era of DRSP. Published and unpublished data were summarized from the scientific literature and experience of participants. After group presentations and review of background materials, subgroup chairs prepared draft responses, which were discussed as a group.ConclusionsWhen implicated in cases of pneumonia, S pneumoniaeshould be considered susceptible if penicillin minimum inhibitory concentration (MIC) is no greater than 1 µg/mL, of intermediate susceptibility if MIC is 2 µg/mL, and resistant if MIC is no less than 4 µg/mL. For outpatient treatment of community-acquired pneumonia, suitable empirical oral antimicrobial agents include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral β-lactam with good activity against pneumococci (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). Suitable empirical antimicrobial regimens for inpatient pneumonia include an intravenous β-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S pneumoniaecan also be used to treat adults with community-acquired pneumonia. To limit the emergence of fluoroquinolone-resistant strains, the new fluoroquinolones should be limited to adults (1) for whom one of the above regimens has already failed, (2) who are allergic to alternative agents, or (3) who have a documented infection with highly drug-resistant pneumococci (eg, penicillin MIC ≥4 µg/mL). Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by DRSP.SINCE THE first description of a Streptococcus pneumoniaeisolate with diminished susceptibility to penicillin in 1967,resistance to penicillin and other antimicrobial agents among S pneumoniaeisolates has been increasing.Population-based active surveillance data from 7 geographic areas in the United States in 1997 showed that 21% of invasive pneumococcal isolates were not fully susceptible to penicillin (minimum inhibitory concentration [MIC] ≥0.1 µg/mL), 12% had penicillin MIC of no less than 2 µg/mL, and 7% had penicillin MIC of no less than 4 µg/mL.Surveillance data collected from 27 institutions in the United States from February through June 1997 revealed that 28% of respiratory tract isolates of S pneumoniaehad penicillin MIC of no less than 0.1 µg/mL and 16% had penicillin MIC of no less than 2 µg/mL.Streptococcus pneumoniaeis the most commonly identified cause of community-acquired pneumonia, accounting for 9% to 55% of cases of community-acquired pneumonia among patients requiring hospitalization.Nevertheless, the clinical impact of pneumonia caused by drug-resistant S pneumoniae(DRSP) is in debate. Much of the confusion and controversy concerning this issue is related to problems with the designation of pneumococcal resistance to penicillin. The National Committee for Clinical Laboratory Standards currently categorizes pneumococcal isolates as penicillin susceptible if MIC is no greater than 0.06 µg/mL, of intermediate susceptibility if MIC is 0.1 to 1.0 µg/mL, and resistant if MIC is no less than 2.0 µg/mL.Although these categories may have clinical relevance for some agents used to treat otitis media and meningitis, they are not appropriate for guiding treatment of pneumonia. An increased rate of treatment failure has been documented among children with acute otitis media caused by nonsusceptible S pneumoniae(penicillin MIC ≥0.1 µg/mL) treated with selected oral cephalosporins; treatment failures also have been reported among children and adults with meningitis caused by nonsusceptible strains treated with penicillin or third-generation cephalosporins.In contrast, some comparative studies of pneumococcal pneumonia among children and adults indicate that pneumococcal resistance does not have a deleterious impact on treatment outcome.However, recently published studiesand case reportssuggest that pneumococcal resistance may have an impact on mortality and other outcome measures in pneumonia.Although the association between penicillin resistance and clinical outcome has been uncertain until recently, resistance has been shown to influence which antimicrobial agents clinicians choose for treatment of pneumococcal pneumonia. In fact, the choice of antibiotic by clinicians may be influenced more by the MIC interpretation (ie, susceptible, intermediate, or resistant) than by the status of the patient or by evaluation of outcome data available in the literature.Thus, modifying the MIC break points so that more pneumococcal pneumonia isolates are reported appropriately as susceptible may improve care and also lead to a decrease in the use of broad-spectrum antimicrobial therapy in favor of more narrow-spectrum therapy.The Drug-Resistant Streptococcus pneumoniaeTherapeutic Working Group (DRSPTWG), consisting of clinicians, academicians, and public health practitioners, was convened by the Centers for Disease Control and Prevention, Atlanta, Ga, in March 1998 to attempt to resolve these and other issues regarding the clinical impact of DRSP on pneumococcal pneumonia and to develop recommendations for the treatment of pneumonia when DRSP is a possibility. The focus of these recommendations is on community-acquired pneumonia among immunocompetent patients. Subgroups of the DRSPTWG drafted responses to 4 specific questions, which were then discussed by the entire group. The conclusions of these subgroups are presented below.DISCUSSION GROUP CONCLUSIONSQuestion 1Should pneumococcal resistance to β-lactams influence community-acquired pneumonia treatment?Evidence now indicates that patients hospitalized for pneumococcal pneumonia caused by strains currently defined as having intermediate susceptibility to penicillin (MIC=0.1-1.0 µg/mL) respond well to treatment with adequate intravenous doses of β-lactams (eg, 4 million to 15 million units per day of penicillin G for adults and 100,000 to 300,000 U/kg per day for children older than 1 month in 4 to 6 divided doses; or 2-12 g of ampicillin sodium daily for adults or 100-300 mg/kg per day for children older than 1 month in 4 to 6 divided doses). Comparative studies of adults and children have reported that infection with penicillin-nonsusceptible pneumococci (MIC ≥0.1 µg/mL) does not influence the outcome of pneumonia treatment.Most of these patients were infected by pneumococci that had penicillin MICs in the intermediate range. There are conflicting data on the outcome after treatment of pneumonia caused by pneumococcal strains with penicillin MICs in the resistant range (≥2 µg/mL).Despite some reports of poor outcome among patients infected with intermediate-susceptibility strains,most available evidence indicates that standard treatment with a β-lactam antimicrobial agent is effective against pneumococcal pneumonia caused by strains with penicillin MIC of no greater than 1 µg/mL. Two of the reports of treatment failures did not include comparison groups,and a third did not adjust for possible confounders, such as severity of illness at the time of admission.Therefore, it was unclear if drug resistance caused poor response. Subsequent studies comparing patients infected by penicillin-susceptible strains with patients infected by intermediate-susceptibility strains provide strong evidence that no increased mortality or treatment failure is associated with strains currently defined as having intermediate susceptibility to penicillin.Few of these studies, however, were able to adjust for important confounders. These studies, if analyzed together, include more than 240 patients with pneumococcal pneumonia caused by intermediate-susceptibility strains, and therefore would be able to detect a 5% to 10% increase in clinical treatment failures.In addition, pharmacokinetic and pharmacodynamic considerations suggest that β-lactam therapy would be effective against pneumococcal strains with intermediate susceptibility to penicillin. The duration of time that serum or tissue levels exceed the MIC is the crucial pharmacodynamic factor correlated with the therapeutic efficacy of β-lactams against pneumococci, and the presence of free-drug concentrations above the MIC for at least 40% to 50% of the dosing interval is the critical determinant.If the goal of therapy is to achieve serum concentrations higher than the MIC for more than 40% of the dosing interval, 8 million to 15 million units of penicillin G daily in 4 to 6 divided doses may effectively treat adults with pneumonia caused by S pneumoniaestrains with MIC of no greater than 4 µg/mL.In children, somewhat higher dosages, ranging from 100,000 to 300,000 U/kg per day in 4 to 6 divided doses, have been commonly used and similarly produce effective serum concentrations.This predicted efficacy reflects the higher likelihood that the drug will accumulate in well-perfused alveoli in concentrations approximating those in the bloodstream than it will in middle ear fluid in otitis media, which acts as a closed-space infection, or in cerebrospinal fluid in meningitis, in which the blood-brain barrier intervenes. Also based on these considerations, intravenous penicillin might not be expected to have an effect on pneumococcal strains with penicillin MIC of no less than 8 µg/mL.Some evidence suggests that there is increased risk of mortalityor complicationsat penicillin MIC of 2 to 4 µg/mL, whereas other evidence indicates that there is no increased clinical failure at this level of resistance.In these reports, approximately 100 of the pneumonia cases were caused by strains currently categorized as resistant to penicillin, and nearly all resistant isolates had penicillin MIC of 2 to 4 µg/mL. The increase in mortality seen in one studywas confined to patients with pneumococcal isolates with penicillin MIC of no less than 4 µg/mL. Importantly, the increased mortality in this large study was confined to deaths occurring after the fourth day of hospitalization, consistent with the previous observation that early hospital mortality is not influenced by antibiotic treatment.None of the other studies comparing outcomes of pneumococcal pneumonia caused by penicillin-susceptible and penicillin-resistant strains included analyses confined to this subgroup.These data (Figure 1) suggest that most pneumonia caused by isolates defined as not fully susceptible to penicillin should respond well to treatment with a β-lactam antibiotic using optimal dosing, although treatment failures may occur at higher levels of resistance. Therefore, we believe that the susceptibility categories for S pneumoniae, when implicated as the cause of pneumonia, should be redefined. Pneumococcal strains currently defined as having intermediate susceptiblity to penicillin should be considered susceptible in the case of pneumonia. Some data indicate that strains with penicillin MIC of 2 µg/mL could also be considered susceptible if treated daily with penicillin G, 100,000 to 300,000 U/kg (or with ampicillin sodium or cefotaxime sodium, 100 mg/kg).Data are insufficient to support the use of β-lactams against strains with penicillin MIC of no less than 4 µg/mL. We recommend that the susceptibility categories for cases of pneumonia be changed so that S pneumoniaeisolates with penicillin MIC of no greater than 1 µg/mL be classified as susceptible; isolates with MIC of 2 µg/mL, intermediate; and isolates with MICs of no less than 4 µg/mL, resistant. Patients with pneumococcal pneumonia caused by strains with penicillin MIC of no greater than 1 µg/mL would therefore be treated appropriately with optimal dosage of intravenous penicillin G and selected other oral and parenteral β-lactams.The relationship between pneumococcal resistance and treatment outcomes for patients with pneumonia. Horizontal lines indicate the current National Committee for Clinical Laboratory Standards (NCCLS) break points.Good evidence exists that for Streptococcus pneumoniaestrains with penicillin minimum inhibitory concentration (MIC) of up to 1 µg/mL, resistance does not increase the likelihood of treatment failures.For strains with penicillin MICs of 2 and 4 µg/mL, some evidence indicates no increase in pneumonia treatment failures,whereas other evidence indicates increased mortalityor complications.Too few patients with pneumonia and pneumococcal isolates with penicillin MICs of no less than 8 µg/mL have been studied to draw appropriate conclusions, but pharmacodynamic considerations indicate theoretical reasons for concern.Asterisk indicates no significant difference in outcome between patients infected with strains of intermediate penicillin susceptibility vs penicillin-sensitive strains; S, susceptible; I, intermediate; and R, resistant.Question 2What are suitable empirical antimicrobial regimens for treatment of outpatient community-acquired pneumonia in the DRSP era?Empirical antibiotic treatment for outpatients with pneumonia should always be active against S pneumoniaebecause this organism is one of the most commonly identified causes of bacterial pneumonia, and because it causes more severe disease than other commonly identified pathogens. When possible, chest radiography should be performed to substantiate the diagnosis of pneumonia, and an etiologic diagnosis should be attempted (ie, sputum Gram stain should be performed and routine culture should be considered, recognizing that the sensitivity and specificity of these tests vary widely for different pathogens and that they will not detect atypical agents) for all persons with suspected pneumonia. As discussed above, pneumococci with penicillin MIC of no greater than 2 µg/mL should respond to β-lactam therapy. Population-based active surveillance data from 7 geographic areas in the United States in 1997 showed that 7% of invasive S pneumoniaeisolates in the United States had penicillin MIC of greater than 2 µg/mL.The relative importance of S pneumoniaeas a cause of outpatient community-acquired pneumonia is difficult to define because diagnostic tests are not performed on many outpatients, and when tests are performed, they often do not include the collection of sputum specimens. However, a review of the literature indicates that S pneumoniaeaccounts for 2% to 27% of cases of community-acquired pneumonia among persons treated on an ambulatory basis.We therefore estimate that 0.14% (7% of 2%) to 1.9% (7% of 27%) of outpatients with bacterial pneumonia have pneumococcal infections with levels of resistance high enough to warrant consideration of alternative treatment.Table 1shows the relative efficacy of commonly used antimicrobial agents for treating pneumococcal pneumonia, categorized by penicillin MIC. Recommendations for the empirical treatment of outpatient pneumonia are summarized in Table 2. Because pneumonia that is treated on an outpatient basis is generally not immediately life-threatening, and because S pneumoniaeisolates with penicillin MICs of no less than 4 µg/mL are uncommon, activity against highly penicillin-resistant pneumococci is not necessary for an initial regimen. Suitable empirical regimens for first-line therapy include a macrolide (eg, erythromycin, clarithromycin, or azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral β-lactam with good antipneumococcal activity (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). We favor the use of a macrolide or doxycycline because their broad coverage of atypical pathogens (particularly Mycoplasma pneumoniae) offsets their decreased efficacy against pneumococci. In addition, macrolides are the current recommendation of the American Thoracic Society for uncomplicated pneumonia in adults without comorbid features,and macrolides and doxycycline are among the agents recommended by the Infectious Diseases Society of America.However, macrolides are not usually recommended for empirical therapy in children younger than 5 years, because the broad spectrum of coverage of atypical agents generally is not believed to be important for this age group. An alternative regimen for selected adult patients is a fluoroquinolone with antipneumococcal activity (eg, grepafloxacin, levofloxacin, or sparfloxacin). The use of sparfloxacin may be limited because of concerns of phototoxicity. Because of new data showing an association with serious liver damage, the Food and Drug Administration issued a public health advisory recommending that trovafloxacin be used only for patients with serious and life- or limb-threatening infections who receive initial treatment in an inpatient health care facility and for whom physicians believe that the benefit of the agent outweighs its potential risk. For children younger than 5 years, in whom atypical agents are uncommon and in whom doxycycline and fluoroquinolones should be avoided, β-lactams may be the best choice. Detailed descriptions of the diagnostic evaluation and duration of therapy for community-acquired pneumonia can be found in the guidelines published by the Infectious Diseases Society of Americaand in those published by the American Thoracic Society.Table 1. Commonly Used Antimicrobial Agents for Treating Pneumonia*AgentPenicillin MIC, ug/mL†≤0.06 (Susceptible)0.12-1 (Intermediate)Resistant24≥8PenicillinsPenicillin V++++−−−Penicillin G++++++++±−Ampicillin sodium (oral)+++++±−−Ampicillin (parenteral)++++++++±−Amoxicillin++++++−−Piperacillin sodium++++++−−Ticarcillin+++−−−CephalosporinsCefotaxime sodium++++++++±−Ceftriaxone sodium++++++++±−Cefepime hydrochloride++++++±−Cefuroxime axetil (parenteral)++++++−−Cefuroxime (oral)+++++±−−Ceftizoxime+++++−−−Cefprozil+++++−−−Cefpodoxime proxetil+++++−−−Ceftazidime++++−−−Cefaclor+++−−−−Cefixime+++−−−−Fluoroquinolones‡New (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)+++++++++++++Ofloxacin (or ciprofloxacin hydrochloride)++++++±−MacrolidesAzithromycin++++±−−Clarithromycin++++±−−Erythromycin++++±−−OthersVancomycin hydrochloride++++++++++++++Clindamycin++++++++−Imipenem (or meropenem)++++++±−−Doxycycline (or tetracycline)++++++−−Chloramphenicol++++++±−−Trimethoprim-sulfamethoxazole++±−−−*MIC indicates minimum inhibitory concentration; +++, estimated percentage of pneumococci in MIC category covered by agent is at least 90%, good evidence of clinical efficacy; ++, estimated percentage of pneumococci in MIC category covered by agent is at least 75%, probable clinical efficacy; +, estimated percentage of pneumococci in MIC category covered by agent is at least 50%, possible clinical efficacy; ±, estimated percentage of pneumococci in MIC category covered by agent is at least 40% and/or little evidence of clinical efficacy; and −, estimated percentage of pneumococci in MIC category covered by agent is less than 40% and/or no evidence of clinical efficacy. Ratings estimate clinical efficacy and in vitro susceptibility in pneumococcal pneumonia.†Susceptibility (susceptible, intermediate, or resistant) is defined by National Committee for Clinical Laboratory Standards.‡These agents should be reserved as second-line agents because of concerns about emerging resistance and they are not approved by the Food and Drug Administration (FDA) for use in children younger than 18 years. Their relative antipneumococcal activity differs slightly, with that of trovafloxacin equal or superior to that of grepafloxacin, which equals that of sparfloxacin, which is superior to that of levofloxacin.The use of sparfloxacin may need to be limited because of concerns of phototoxicity. Because of new data showing an association with serious liver damage, the FDA issued a public health advisory recommending that trovafloxacin be used only for patients with serious and life- or limb-threatening infections who receive initial treatment in an inpatient health care facility and for whom physicians believe that the benefit of the agent outweighs potential risk.Table 2. Recommended Empiric Regimens for Treating Community-Acquired Pneumonia*Empiric TreatmentPenicillin MIC, ug/mLComments≤0.060.12-124≥8OutpatientsMacrolide (erythromycin, clarithromycin, or azithromycin)++++±−−Covers atypical pathogens (Mycoplasmaspecies, Chlamydiaspecies, and Legionellaspecies)Doxycycline (or tetracycline)++++++−−Covers atypical pathogens; not FDA-approved for children younger than 8 yOral ß-lactam (cefuroxime axetil, amoxicillin, or amoxicillin-clavulanate potassium)++++++−−Does not cover atypical pathogens; alternatively, cefpodoxime or cefprozil may be usedFluoroquinolone (grepafloxacin, levofloxacin, or sparfloxacin)†+++++++++++++Not first-line treatment because of concerns about emerging resistance; not FDA approved for use in children; covers atypical pathogensHospitalized (Nonintensive Care Unit) PatientsParenteral ß-lactam (cefuroxime, cefotaxime sodium, ceftriaxone sodium, or ampicillin sodium–sulbactam sodium) plus macrolide (erythromycin, clarithromycin, or azithromycin)++++++++±−Cefotaxime and ceftriaxone have superior activity against resistant pneumococci in comparison with ampicillin-sulbactam and with cefuroximeFluoroquinolone (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)†+++++++++++++See previous comments about fluoroquinolonesIntubated or Intensive Care Unit Patients‡Intravenous ß-lactam (ceftriaxone or cefotaxime sodium) plus intravenous macrolide (erythromycin or azithromycin)++++++++±−Ceftriaxone or cefotaxime are preferred over other ß-lactams because of their superior activity against resistant pneumococci; clarithromycin has no intravenous formulationIntravenous ß-lactam (ceftriaxone or cefotaxime) plus fluoroquinolone (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)†++++++++++++Ceftriaxone or cefotaxime are preferred over other ß-lactams; see previous comments about fluoroquinolonesFluoroquinolone (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)†++++++++++See previous comments about fluoroquinolones; efficacy of monotherapy for critically ill persons with pneumococcal pneumonia has not been established*FDA indicates Food and Drug Administration. Other abbreviations are given in the first footnote to Table 1. Ratings estimate clinical efficacy and in vitro susceptibility among persons with pneumococcal pneumonia. In-depth information on empiric treatment of pneumonia is given by the Infectious Diseases Society of Americaand the American Thoracic Society guidelines.†The relative antipneumococcal activity of these agents differs slightly, with that of trovafloxacin equal or superior to that of grepafloxacin, which equals that of sparfloxacin, which is superior to that of levofloxacin.The use of sparfloxacin may need to be limited because of concerns of phototoxicity. Because of new data showing an association with serious liver damage, the FDA issued a public health advisory recommending that trovafloxacin be used only for patients with serious and life- or limb-threatening infections who receive initial treatment in an inpatient health care facility and for whom physicians believe that the benefit of the agent outweighs its potential risk.‡Vancomycin hydrochloride may be indicated for the treatment of selected critically ill children with community-acquired pneumonia for whom coverage of drug-resistant Streptococcus pneumoniaemust be ensured.Macrolides do not provide optimal coverage of penicillin-resistant pneumococci, because macrolide resistance is common among such strains (approximately 60%)and because macrolide resistance is often high when present.Although evidence of the clinical impact of macrolide resistance is limited, a study showed that treatment with erythromycin failed for 2 of 3 patients hospitalized with community-acquired pneumonia caused by macrolide-resistant S pneumoniaestrains; evidence from patients with other pneumococcal syndromes indicates that macrolide resistance is likely to have a clinical impact when present.Existing data are insufficient to determine whether macrolides can be used effectively against macrolide-resistant pneumococcal strains in which lower-level resistance results from increased drug efflux (mefE-encoded resistance), with resulting MIC of 1 to 32 µg/mL.Adequate concentrations of macrolides may be able to overcome this resistance. However, when macrolide resistance is caused by a ribosomal methylase encoded by ermAM, with resulting MIC generally of no less than 64 µg/mL,resistance presumably cannot be overcome by increasing the dosage.Several studies and surveillance data suggest that some newly available fluoroquinolones are efficacious for the treatment of pneumonia caused by S pneumoniae, including penicillin-resistant strains.We will consider these agents as a group, although some evidence indicates that their antipneumococcal activity differs slightly (ie, antipneumoccocal activity of trovafloxacin equals or is superior to that of grepafloxacin; grepafloxacin and sparfloxacin have equal activity; and antipneumoccocal activity of sparfloxacin is superior to that of levofloxacin),trovafloxacin should not be used for outpatient community-acquired pneumonia because of data showing an association between the use of this agent and hepatotoxic effects. Also, concerns about phototoxic effects resulting from the use of sparfloxacin may limit the use of this agent. In one study, microbiologic eradication from sputum was reported among all 30 patients with pneumococcal pneumonia treated with oral levofloxacin.In a study of in vitro susceptibility of S pneumoniaeclinical isolates to levofloxacin, none of 180 isolates (including 60 isolates with intermediate susceptibility to penicillin and 60 penicillin-resistant isolates) was resistant to this agent.A surveillance study of antimicrobial resistance in respiratory tract pathogens found levofloxacin was active against 97% of 9190 pneumococcal isolates and found no cross-resistance with penicillin, amoxicillin-clavulanate, ceftriaxone sodium, cefuroxime, or clarithromycin.However, a recent report found an increased incidence of ciprofloxacin hydrochloride resistance among penicillin-resistant pneumococcal isolates.We do not advocate the use of newer fluoroquinolones for first-line treatment because of their very broad spectrum of activity, because of concerns that resistance among pneumococci will rapidly emerge after widespread use of this class of antimicrobial agents, and because their activity against pneumococci with high penicillin resistance (MIC ≥4 µg/mL) makes it important that they be reserved for selected patients with community-acquired pneumonia. Such patients include adults for whom one of the first-line regimens has already failed, who are allergic to alternative agents, or who have a documented infection with highly drug-resistant pneumococci (ie, penicillin MIC ≥4 µg/mL). Use of fluoroquinolones has been shown to result in increased resistance in S pneumoniaein vitro,and population-based surveillance in the United States has shown a statistically significant increase in ofloxacin resistance among pneumococcal isolates between January 1, 1995, and December 31, 1997 (unpublished data, Active Bacterial Core Surveillance, Centers for Disease Control and Prevention). Furthermore, fluoroquinolone use may result in resistance among gram-negative organisms as well.The following β-lactams are not recommended because of poor in vitro activity against strains of S pneumoniaewith penicillin MIC of greater than 1 µg/mL: penicillin V potassium, all of the first-generation cephalosporins, cefaclor, cefixime, ceftibuten, and loracarbef.Trovafloxacin is not recommended for the treatment of outpatients with community-acquired pneumonia because of new data showing an association between the use of this agent and serious liver injury. Rifampin should not be used as single-agent therapy because resistance rapidly emerges when this drug is used alone.A combination of trimethoprim and sulfamethoxazole is not recommended because of high rates of resistance (18% to 26%) among invasive isolatesand evidence that it is less effective than amoxicillin for the management of pneumonia in children, independent of susceptibility results.Question 3What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era?The inpatient management of community-acquired pneumonia should be based largely on the severity of illness at the time of admission. An etiologic diagnosis should be attempted for all patients by means of Gram stains, cultures, and other tests as appropriate.No simple empirical regimen can cover all potential pathogens. Therefore, for moderately ill patients, defined as those who are hospitalized but who do not require admission to an intensive care unit, initial antimicrobial treatment should target the suspected etiologic agents and may omit coverage of rare pathogens (including highly resistant pneumococci, ie, with penicillin MIC ≥4 µg/mL). However, for critically ill patients, defined as those who are intubated or in an intensive care unit, treatment should provide more comprehensive coverage.For moderately ill persons, initial treatment should include a parenteral β-lactam, such as cefuroxime, ceftriaxone, cefotaxime, or a combination of ampicillin sodium and sulbactam sodium, and a macrolide, such as erythromycin, azithromycin, or clarithromycin, as outlined in Table 2. An attractive alternative for adults is a fluoroquinolone with improved activity against S pneumoniae. Although such fluoroquinolones may be active against isolates of S pneumoniaethat are highly resistant to β-lactams,they should be reserved for selected patients, as previously discussed.For critically ill persons, empirical treatment should cover the agents most likely to cause severe disease, as outlined in Table 2. First-line therapy in this situation should include an intravenous β-lactam, such as ceftriaxone or cefotaxime, and an intravenous macrolide, such as erythromycin or azithromycin. Alternatively, intravenous ceftriaxone or cefotaxime and a fluoroquinolone with antipneumococcal activity may be used for critically ill adults. A fluoroquinolone with improved activity against S pneumoniaemay be used alone for adults, but caution should be exercised, because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients with pneumococcal pneumonia has not been determined. Critically ill patients, as defined above, have been excluded from most trials of fluoroquinolones for community-acquired pneumonia.Drugs that are not appropriate for treating hospitalized patients with pneumococcal pneumonia in the era of DRSP include first-generation cephalosporins and ceftazidime, ceftizoxime, and ticarcillin because of the high rate of resistance to these agents among penicillin-resistant pneumococci.Vancomycin hydrochloride has remained uniformly active against pneumococci, but ample evidence shows that overuse of vancomycin has led to resistance among other pathogens.To date, a few isolates of Staphylococcus aureuswith reduced susceptibility to vancomycin (MIC=8 µg/mL) have been discovered.Although isolates highly resistant to penicillin (MIC ≥4 µg/mL) are increasingly common, the availability of new agents means that an antimicrobial agent other than vancomycin with demonstrated in vitro activity against most isolates is generally available for patients with pneumonia. In addition, the clinical efficacy of vancomycin for the treatment of critically ill patients with pneumococcal pneumonia has not been well documented. Therefore, vancomycin should not be used routinely for the treatment of adults with pneumococcal pneumonia. However, vancomycin should be included in the initial antimicrobial regimen for any person with suspected bacterial meningitis. In addition, because fluoroquinolones are not currently approved for treatment of children, treatment with vancomycin may be appropriate for selected critically ill children with community-acquired pneumonia, in whom coverage of DRSP must be ensured (using the criteria for fluoroquinolone use in adults). Vancomycin therapy, if included in an empirical treatment regimen, should be promptly discontinued if a subsequently isolated etiologic agent does not require treatment with the drug.Question 4How should clinical laboratories report antibiotic susceptibility patterns for S pneumoniae, and what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest?The current categories for defining susceptibility concentrations (ie, susceptible, intermediate, and resistant) are not clinically useful for the treatment of patients with pneumococcal pneumonia and should be modified, as discussed above. The DRSPTWG recommends that penicillin break points be shifted upward for isolates that cause pneumonia (but not meningitis and otitis media) to make the break points more clinically meaningful and to assist clinicians in treatment decisions. For categorization of these isolates, we recommend defining penicillin susceptibility as an MIC of no greater than 1 µg/mL, intermediate susceptibility as an MIC of 2 µg/mL, and resistance as an MIC of no less than 4 µg/mL. This recommendation will require changes in the way laboratories report and clinicians interpret susceptibility results, because susceptibility break points will differ according to the clinical syndrome being treated.Laboratories should report MICs and susceptibility categories for penicillin and for extended-spectrum cephalosporins for all pneumococcal isolates from appropriately collected sputum, from other lower respiratory tract specimens, from blood, and from all other sterile sites. Non–β-lactam susceptibility results may be reported to physicians by category (ie, susceptible, intermediate, or resistant), based on disk diffusion testing, or by category and MIC, based on MIC testing of appropriately collected respiratory and other relevant pneumococcal isolates.The drugs that should be included in surveillance studies depend on whether the surveillance system under consideration is a local, hospital laboratory–based system or a large reference laboratory. The DRSPTWG identified 6 antimicrobial agents that should be included in surveillance by all local laboratories: penicillin, cefotaxime (or ceftriaxone), erythromycin, doxycycline (or tetracycline), clindamycin, and fluoroquinolones with antipneumococcal activity. The DRSPTWG identified 2 other agents that could also be included, depending on available resources and on the interests of the clinicians in the area: trimethoprim-sulfamethoxazole and vancomycin.The list for large reference laboratories was designed to be comprehensive. The agents identified as important to include on this list are penicillin, amoxicillin, ceftriaxone (or cefotaxime), cefuroxime, cefpodoxime proxetil (or cefprozil), erythromycin, clindamycin, fluoroquinolones with antipneumococcal activity, vancomycin, trimethoprim-sulfamethoxazole, doxycycline (or tetracycline), and meropenem. Surveillance on the local, regional, national, and even international level should be encouraged. When possible, active surveillance and population studies should be performed. To derive the maximum benefit from a surveillance system, clinicians need to be fully aware of the population studied by that system. The population should be clearly defined not only before the initiation of surveillance but also when the results are reported, because S pneumoniaesusceptibility can vary widely by demographic factors such as age, race, and geographic area. Final surveillance reports should list MICs or zone diameter values in addition to susceptibility categories. Laboratories conducting surveillance should use approved methodsand should state these methods in their annual reports.SUMMARY AND RECOMMENDATIONSIn response to increasing rates of resistance among pneumococcal isolates, particularly among highly resistant strains, the DRSPTWG makes the following recommendations:For pneumococcal isolates causing pneumonia, penicillin susceptibility categories should be shifted upward so that the susceptible category includes all isolates with MIC of no greater than 1 µg/mL, the intermediate category includes isolates with MIC of 2 µg/mL, and the resistant category includes isolates with MIC of no less than 4 µg/mL.Suitable empirical antimicrobial regimens for outpatients with community-acquired pneumonia include a macrolide (eg, erythromycin, clarithromycin, or azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral β-lactam with good antipneumococcal activity (eg, cefuroxime, amoxicillin, or amoxicillin-clavulanate). An oral fluoroquinolone with improved activity against S pneumoniaealso may be used for the treatment of adults for whom one of these regimens has already failed, who are allergic to alternative agents, or who have a documented infection with highly drug-resistant pneumococci (ie, penicillin MIC ≥4 µg/mL). For children younger than 5 years in whom atypical agents are uncommon and for whom doxycycline and fluoroquinolones should be avoided, β-lactams may be the best choice.A suitable empirical antimicrobial regimen for moderately ill patients hospitalized for pneumonia includes a parenteral β-lactam such as cefuroxime, cefotaxime, ceftriaxone, or ampicillin-sulbactam, and a macrolide, such as erythromycin, azithromycin, or clarithromycin. An alternative for adults is a fluoroquinolone with antipneumococcal activity. However, these drugs should be reserved for selected patients.A suitable empirical antimicrobial regimen for critically ill persons hospitalized for pneumonia includes an intravenous β-lactam, such as cefotaxime or ceftriaxone, and an intravenous macrolide, such as erythromycin or azithromycin. Alternatively, intravenous ceftriaxone or cefotaxime and a fluoroquinolone with improved activity against S pneumoniaemay be used for critically ill adults. A fluoroquinolone with improved antipneumococcal activity may be used alone, but caution should be exercised because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients with pneumococcal pneumonia has not been determined.Vancomycin is not routinely indicated for treatment of community-acquired pneumonia or of pneumonia caused by DRSP. However, vancomycin should be included in the initial antimicrobial regimen for any person with suspected bacterial meningitis. In addition, treatment with vancomycin may be appropriate for selected critically ill children with community-acquired pneumonia. Vancomycin therapy, if included in an empirical treatment regimen, should be promptly discontinued if a subsequently isolated etiologic agent does not require treatment with the drug.Laboratories should report MICs for penicillin and for extended-spectrum cephalosporins for all pneumococcal isolates from appropriately collected specimens. Antimicrobial agents that should be included in surveillance by all local laboratories are penicillin, cefotaxime (or ceftriaxone), erythromycin, doxycycline (or tetracycline), clindamycin, and fluoroquinolones with antipneumococcal activity. In addition to these, reference laboratories should survey amoxicillin, cefuroxime, cefpodoxime (or cefprozil), clindamycin, vancomycin, trimethoprim-sulfamethoxazole, and meropenem.DHansmanMMBullenA resistant pneumococcus [letter].Lancet.1967;2:264-265.JSSpikaRRFacklamBDPlikaytisMJOxtobyAntimicrobial resistance of Streptococcus pneumoniaein the United States, 1979-1987.J Infect Dis.1991;163:1273-1278.RFBreimanJCButlerFCTenoverJAElliottRRFacklamEmergence of drug-resistant pneumococcal infections in the United States.JAMA.1994;271:1831-1835.CThornsberrySDBrownYCYeeSKBouchillonJKMarlerTRichIncreasing penicillin resistance in Streptococcus pneumoniaein the US: effect on susceptibility to oral cephalosporins.Infect Med.1993;10(suppl D):S15-S24.CGWhitneyNBarrettMFarleyIncreasing prevalence of drug-resistant Streptococcus pneumoniae(DRSP): implications for therapy for pneumonia.In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 51.GVDoernMAPfallerKKuglerJFreemanRNJonesPrevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniaein North America: 1997 results from the SENTRY Antimicrobial Surveillance Program.Clin Infect Dis.1998;27:764-770.TJMarrieHDurantLYatesCommunity-acquired pneumonia requiring hospitalization: 5-year prospective study.Rev Infect Dis.1989;11:586-599.GDFangMFineJOrloffNew and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases.Medicine (Baltimore).1990;69:307-316.MTKauppinenEHervaPKujalaMLeinonenPSaikkuHSyrjalaThe etiology of community-acquired pneumonia among hospitalized patients during a Chlamydia pneumoniaeepidemic in Finland.J Infect Dis.1996;172:1330-1335.BJMarstonJFPlouffeTMFileIncidence of community-acquired pneumonia requiring hospitalization.Arch Intern Med.1997;157:1709-1718.TJMarrieCommunity-acquired pneumonia: epidemiology, etiology, treatment.Infect Dis Clin North Am.1998;12:723-740.National Committee for Clinical Laboratory StandardsPerformance Standards for Antimicrobial Susceptibility Tests (M 100-S8).Villanova, Pa: National Committee for Clinical Laboratory Standards; 1998. Vol 18.RDaganOAbramsonELeibovitzImpaired bacteriologic response to oral cephalosporins in acute otitis media caused by intermediate resistance to penicillin.Pediatr Infect Dis J.1996;15:980-985.RDaganOAbramsonELeibovitzBacteriologic response to oral cephalosporins: are established susceptibility breakpoints appropriate in the case of acute otitis media?J Infect Dis.1997;176:1253-1259.IRFriedlandKPKlugmanFailure of chloramphenicol in penicillin-resistant pneumococcal meningitis.Lancet.1992;339:405-408.CCJohnTreatment failure with use of a third-generation cephalosporin for penicillin-resistant pneumococcal meningitis: case report and review.Clin Infect Dis.1994;18:188-193.MJCatalanJMFernandezAVazquezEVde SeijasASuarezJCde QuirosFailure of cefotaxime in the treatment of meningitis due to relatively resistant Streptococcus pneumoniae.Clin Infect Dis.1994;18:766-769.KPKlugmanIRFriedlandJSBradleyBactericidal activity against cephalosporin-resistant Streptococcus pneumoniaein cerebrospinal fluid of children with acute bacterial meningitis.Antimicrob Agents Chemother.1995;39:1988-1992.KOClevelandMGThrelkeldFCTenoverRJLeggiadroDrug-resistant pneumococcal meningitis in an American adult [letter].Clin Infect Dis.1995;20:1572-1573.RPallaresJLinaresMVadilloResistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.N Engl J Med.1995;333:474-480.IRFriedlandComparison of the response to antimicrobial therapy of penicillin-resistant and penicillin-susceptible pneumococcal disease.Pediatr Infect Dis.1995;14:885-890.DFeikinASchuchatMKolczakMortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997.Am J Public Health.2000;90:223-229.GSTurretSBlumBAFazalJEJustmanEETelzakPenicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high HIV seroprevalence.Clin Infect Dis.1999;29:321-327.SCBuckinghamSPBrownVHJoaquinBreakthrough bacteremia and meningitis during treatment parenterally with cephalosporins for pneumococcal pneumonia.J Pediatr.1998;132:174-176.SFDowellTSmithKLeversedgeJSnitzerPneumonia treatment failure associated with highly resistant pneumococci.Clin Infect Dis.1999;29:462-463.DBJerniganSFDowellLALiedtkeLJStrausbaughInfectious Diseases Society of America Emerging Infections Network (EIN)Factors influencing antibiotic selection for community-acquired pneumonia (CAP).In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 683.IRFriedlandKPKlugmanAntibiotic-resistant pneumococcal disease in South African children.AJDC.1992;146:920-923.EChoiHLeeClinical outcome of invasive infections by penicillin-resistant Streptococcus pneumoniaein Korean children.Clin Infect Dis.1998;26:1346-1354.SLDeeksRPalacioRRuinskyRisk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae.Pediatrics.1999;103:409-413.CFeldmanJMKallenbachSDMillerJRThorburnHJKoornhofCommunity-acquired pneumonia due to penicillin-resistant pneumococci.N Engl J Med.1985;313:615-617.HSachoKPKlugmanHJKoornhofCommunity-acquired pneumonia in an adult due to a multiply-resistant pneumococcus [letter].J Infect.1987;14:188-189.RPallaresFGudiolJLinaresRisk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.N Engl J Med.1987;317:18-22.WACraigPharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.Clin Infect Dis.1998;26:1-12.CSBryanRTalwaniMSStinsonPenicillin dosing for pneumococcal pneumonia.Chest.1997;112:1657-1664.JPHieberJDNelsonA pharmacologic evaluation of penicillin in children with purulent meningitis.N Engl J Med.1977;297:410-413.American Academy of Pediatrics Committee on Infectious DiseasesTherapy for children with invasive pneumococcal infections.Pediatrics.1997;99:289-299.KPKlugmanThe clinical relevance of antibiotic resistance in the management of pneumococcal pneumonia.Infect Dis Clin Pract.1998;7:180-184.RAustrianJGoldPneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia.Ann Intern Med.1964;60:759-776.EBerntssonTLagergardOStrannegardBTrollforsEtiology of community-acquired pneumonia in outpatients.Eur J Clin Microbiol.1986;5:446-447.DBLangilleLYatesTJMarrieSerological investigation of pneumonia as it presents to the physician's office.Can J Infect Dis.1993;4:328.BO'DohertyDADutchmanRPettitAMaroliRandomized, double-blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia.J Antimicrob Chemother.1997;40(suppl A):73-81.LWubbelLMunizAAhmedEtiology and treatment of community-acquired pneumonia in ambulatory children.Pediatr Infect Dis J.1999;18:98-104.GVDoernMAPfallerMEErwinABBrueggemannRNJonesThe prevalence of fluoroquinolone resistance among clinically significant respiratory tract isolates of Streptococcus pneumoniaein the United States and Canada: 1997 results from the SENTRY Antimicrobial Surveillance Program.Diagn Microbiol Infect Dis.1998;32:313-316.JHJorgensenLMWeigelMJFerraroJMSwensonFCTenoverActivities of newer fluoroquinolones against Streptococcus pneumoniaeclinical isolates including those with mutations in the gyrA, parC, and parE loci.Antimicrob Agents Chemother.1999;43:329-334.JGBartlettRFBreimanLAMandellTMFileCommunity-acquired pneumonia in adults: guidelines for management.Clin Infect Dis.1998;26:811-838.MSNiedermanJBBassGDCampbellGuidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy.Am Rev Respir Dis.1993;148:1418-1426.PPGleasonWNKapoorRAStoneMedical outcomes and antimicrobial costs with the use of the American Thoracic Society guidelines for outpatients with community-acquired pneumonia.JAMA.1997;278:32-39.LMEdnieMAVisalliMRJacobsPCAppelbaumComparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci.Antimicrob Agents Chemother.1996;40:1950-1952.JHoffmanMSCetronMMFarleyThe prevalence of drug-resistant Streptococcus pneumoniaein Atlanta.N Engl J Med.1995;333:481-486.GVDoernABrueggemannHPHolley JrAMRauchAntimicrobial resistance of Streptococcus pneumoniaerecovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.Antimicrob Agents Chemother.1996;40:1208-1213.JSutcliffeATait-KamradtLWondrackStreptococcus pneumoniaeand Streptococcus pyogenesresistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system.Antimicrob Agents Chemother.1996;40:1817-1824.JCCraftGNotarioRHomDShortridgeRKFlammCan erythromycin-resistant Streptococcus pneumoniaebe treated with a macrolide?In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 264.MAubierHLodeGGialdroni-GrassiSparfloxacin for the treatment of community-acquired pneumonia: a pooled data analysis of two studies.J Antimicrob Chemother.1996;77(suppl A):73-82.MAJacksonVFBurryLCOlsonSEDuthieGLKearnsBreakthrough sepsis in macrolide-resistant pneumococcal infection.Pediatr Infect Dis.1996;15:1049-1051.RDaganLPiglanskyPYagupskyDMFlissALeibermanELeibovitzBacteriologic response in acute otitis media: comparison between azithromycin, cefaclor and amoxicillin.In: Programs and Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sep 28-Oct 1, 1997; Toronto, Ontario, Canada.Washington, DC: American Society for Microbiology; 1997. Abstract K-103.BWeisblumErythromycin resistance by ribosome modification.Antimicrob Agents Chemother.1995;39:577-585.LKMcDougalFCTenoverLNLeeDetection of TN917-like sequences within a TN916-like conjugative transposon (TN3872) in erythromycin-resistant isolates of Streptococcus pneumoniae.Antimicrob Agents Chemother.1998;42:2312-2318.TMFileJSegretiLDunbarA multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia.Antimicrob Agents Chemother.1997;41:1965-1972.KPKlugmanTCapperABryskierIn vitro susceptibility of penicillin-resistant Streptococcus pneumoniaeto levofloxacin, selection of resistant mutants, and time-kill synergy studies of levofloxacin combined with vancomycin, teicoplanin, fusidic acid, and rifampin.Antimicrob Agents Chemother.1996;40:2802-2804.CThornsberryPOgilvieJKahnYMaurizSurveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae,and Moraxella catarrhalisin the United States in 1996-1997 respiratory season: The Laboratory Investigator Group.Diagn Microbiol Infect Dis.1997;29:249-257.CEGoldsmithJEMoorePGMurphyJEAmblerIncreased incidence of ciprofloxacin resistance in penicillin-resistant pneumococci in Northern Ireland.J Antimicrob Chemother.1998;41:420-421.TDaviesGPankuchBDewasseMJacobsPAppelbaumIn vitro development of resistance to five quinolones and amoxicillin/clavulanate in Streptococcus pneumoniae.In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 227.DMCappellettyMJRybakBactericidal activities of cefprozil, penicillin, cefaclor, cefixime, and loracarbef against penicillin-susceptible and -resistant Streptococcus pneumoniaein an in vitro pharmacodynamic infection model.Antimicrob Agents Chemother.1996;40:1148-1152.JVerhaegenLVerbistIn-vitro activity of 21 β-lactam antibiotics against penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae.J Antimicrob Chemother.1998;41:381-385.KMCitronJRMayRifamycin antibiotics in chronic purulent bronchitis.Lancet.1969;2:982-983.KPKlugmanPneumococcal resistance to antibiotics.Clin Microbiol Rev.1990;3:171-196.WlStrausASQaziZKundiNKNomaniBSchwartzPakistan Co-trimoxazole Study GroupAntimicrobial resistance and clinical effectiveness of co-trimoxazole versus amoxycillin for pneumonia among children in Pakistan: randomised controlled trial.Lancet.1998;352:270-274.JFPlouffeMTHerbertTMFileOfloxacin versus standard therapy in treatment of community-acquired pneumonia requiring hospitalization.Antimicrob Agents Chemother.1996;40:1175-1179.MAubierRVersterCRegameyPGeslinJBVerckenSparfloxacin European Study GroupOnce-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults.Clin Infect Dis.1998;26:1312-1320.GAPankuchMRJacobsPCAppelbaumSusceptibilities of 200 penicillin-susceptible and -resistant pneumococci to piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone.Antimicrob Agents Chemother.1994;38:2905-2907.DWHaasCWStrattonJPGriffinLWeeksSCAllsDiminished activity of ceftizoxime in comparison to cefotaxime and ceftriaxone against Streptococcus pneumoniae.Clin Infect Dis.1995;20:671-676.CThornsberryPHBurtonBHVanderhoofActivity of penicillin and three third-generation cephalosporins against US isolates of Streptococcus pneumoniae:a 1995 surveillance study.Diagn Microbiol Infect Dis1996;25:89-95.BEMurrayDiversity among multidrug-resistant enterococci.Emerg Infect Dis.1998;4:37-47.LCMcDonaldMJKuehnertFCTenoverWRJarvisVancomycin-resistant enterococci outside the health-care setting: prevalence, sources, and public health implications.Emerg Infect Dis.1997;3:311-317.PAFloresSMGordonVancomycin-resistant Staphylococcus aureus:an emerging public health threat.Cleve Clin J Med.1997;64:527-532.Centers for Disease Control and PreventionStaphylococcus aureuswith reduced susceptibility to vancomycin: United States, 1997.MMWR Morb Mortal Wkly Rep.1997;46:765-766.FCTenoverMVLancasterBCHillCharacterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides.J Clin Microbiol.1998;36:1020-1027.KHiramatsuHHanakiTInoKYabutaTOguriFCTenoverMethicillin-resistant Staphylococcus aureusclinical strain with reduced vancomycin susceptibility.J Antimicrob Chemother.1997;40:135-146.MCPloyCGrelaudCMarinLde LumleyFDenisFirst clinical isolate of vancomycin-intermediate Staphylococcus aureusin a French hospital [letter].Lancet.1998;351:1212.National Committee for Clinical Laboratory StandardsMethods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically.Vol 17. Wayne, Pa: National Committee for Clinical Laboratory Standards; 1997.Accepted for publication October 4, 1999.Dr Heffelfinger is a shareholder of Pfizer Inc, New York, NY; Merck, Whitehouse Station, NJ; and Abbott Laboratories, Abbot Park, Ill. Dr Klugman received research grants in the past year from Hoechst Marion Roussel, Swiftwater, Pa; Chiron Vaccines, Emeryville, Calif; South African Vaccine Producers, Johannesburg; SmithKline Beecham, Brentford, England; Roche Pharmaceuticals, Nutley, NJ; Bayer Corp, Pittsburgh, Pa; Swiss Serum Institute, Berne; Schering Plough, Madison, NJ; Wyeth-Lederle Vaccines, St Davids, Pa; Abbott Laboratories; Lilly, Indianapolis, Ind; Pasteur Meriéux, Lyon, France; and Pasteur MSD, Lyon. Dr Plouffe is in receipt of grants from Pfizer; Rhone Poulenc Rorer, Swiftwater; Bayer Corp; SmithKline Beecham; and Bristol Myers Squibb, New York; he has received honoraria from Pfizer, Ortho, Raritan, NJ; Bayer Corp; and Roche Pharmaceuticals; and he is a shareholder of Pfizer, SmithKline Beecham, and Merck. Dr Burch is an employee and shareholder of SmithKline Beecham. Dr Jacobs has received financial support, including research grants, honoraria, and speaker's fees, from Abbott Laboratories; Aventis, Swiftwater; Bayer Corp; Daiichi Pharmaceuticals, Tokyo, Japan; Eli Lilly & Co, Indianapolis; Glaxo Pharamceuticals, Greenford, England; Hoechst Marion Roussel; Meiji Pharmaceuticals, Tokyo; Pfizer Inc; Pharamcia-Upjohn, Peapack, NJ; R. W. Johnson, Raritan; Rhone Poulenc Rorer; Roche Pharmaceuticals; Roussel Uclaf Pharmaceuticals, Frankfurt, Germany; SmithKline Beecham; TAP Pharmaceuticals Inc, Deerfield, Ill; Warner Lambert Pharmaceuticals, Morris Plains, NJ; and Wyeth-Ayerst Laboratories, St Davids. Dr Kaplan is a member of the Pediatric Advisory Committee for ceftriaxone (Roche Pharmaceuticals) and the Pediatric Linezolid Advisory Committee (Pharmacia-Upjohn).Drug-Resistant Streptococcus pneumoniaeTherapeutic Working GroupJohn Bartlett, MD (Johns Hopkins University School of Medicine, Baltimore, Md); David Bell, MD (Antimicrobial Resistance Coordinator, Centers for Disease Control and Prevention [CDC], Atlanta, Ga); Robert Breiman, MD (National Vaccine Program Office, CDC); Daniel J. Burch, MD (Pharmaceutical Research and Manufacturers Association, Washington, DC); Jay C. Butler, MD (Respiratory Diseases Epidemiology Section, CDC); Martin Cetron, MD (Division of Quarantine, CDC); Joan Chesney, MD (American Academy of Pediatrics, Elk Grove Village, Ill); Mitchell Cohen, MD (Division of Bacterial and Mycotic Diseases, CDC); William Craig, MD (Infectious Diseases Society of America, Alexandria, Va); Ron Dagan, MD (Pediatric Infectious Disease Unit, Soroka Medical Center, Beer Sheva, Israel); Scott F. Dowell, MD (Respiratory Diseases Branch, CDC); Daniel Feikin, MD (Respiratory Diseases Branch, CDC); Thomas M. File, MD (Northeastern Ohio Universities College of Medicine, Summa Health System, Akron); Mary Gilchrist, PhD (Association of Public Health Laboratories, Washington, DC); James Heffelfinger, MD (Respiratory Diseases Branch, CDC); Michael Jacobs, MD, PhD (Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio); Dan Jernigan, MD (Washington State Department of Health, Seattle); Ronald N. Jones, MD (American Society for Microbiology, Washington, DC); James H. Jorgensen, PhD (National Committee for Clinical Laboratory Standards, Wayne, Pa); Sheldon Kaplan, MD (American Academy of Pediatrics); David Klein, PhD (National Institutes of Health/National Institute of Allergy and Infectious Disease, Bethesda, Md); Keith Klugman, MD (South African Institute for Medical Research, Johannesburg); Leah Raye Mabry, MD (American Academy of Family Physicians, Leahwood, Mo); Lionel A. Mandell, MD (American Thoracic Society, New York, NY, and Infectious Diseases Society of America, Alexandria, Va); Daniel R. Martin, MD (Society for Academic Emergency Medicine, Lansing, Mich); Bill Martone, MD (National Foundation for Infectious Diseases, Bethesda, Md); Joshua Metlay, MD, PhD (University of Pennsylvania School of Medicine, Philadelphia); John F. Moroney, MD (Epidemiology Program Office, CDC); Daniel M. Musher, MD (American College of Pathologists, Northfield, Ill); Michael Niederman, MD (State University of New York at Stony Brook); Thomas F. O'Brien, MD (World Health Organization Collaborating Center for Surveillance of Antimicrobial Resistance, Geneva, Switzerland); Michael A. Pfaller, MD (College of American Pathologists, Northfield, Ill); Joseph F. Plouffe, MD (Ohio State University Medical Center, Columbus); Alexander Rakowsky, MD (Food and Drug Administration, Rockville, Md); Frederick L. Ruben, MD (American Thoracic Society and American Lung Association, New York); Anne Schuchat, MD (Respiratory Diseases Branch, CDC); Benjamin Schwartz, MD (Division of Bacterial and Mycotic Diseases, CDC); Fred Tenover, PhD (Hospital Infections Program, CDC); Cynthia G. Whitney, MD (Respiratory Diseases Branch, CDC); Victor L. Yu, MD (University of Pittsburgh, Pittsburgh, Pa); George Zhanel, PhD (Society of Infectious Disease Pharmacists, Houston, Tex).Reprints: James D. Heffelfinger, MD, 2820 W Barrett St, Seattle, WA 98199 (e-mail: izh7@cdc.gov). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

Loading next page...
 
/lp/american-medical-association/management-of-community-acquired-pneumonia-in-the-era-of-pneumococcal-9NiDX85HMh

References (74)

Publisher
American Medical Association
Copyright
Copyright 2000 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6106
eISSN
2168-6114
DOI
10.1001/archinte.160.10.1399
Publisher site
See Article on Publisher Site

Abstract

ObjectiveTo provide recommendations for the management of community-acquired pneumonia and the surveillance of drug-resistant Streptococcus pneumoniae(DRSP).MethodsWe addressed the following questions: (1) Should pneumococcal resistance to β-lactam antimicrobial agents influence pneumonia treatment? (2) What are suitable empirical antimicrobial regimens for outpatient treatment of community-acquired pneumonia in the DRSP era? (3) What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era? and (4) How should clinical laboratories report antibiotic susceptibility patterns for, S pneumoniaeand what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest? Experts in the management of pneumonia and the DRSP Therapeutic Working Group, which includes clinicians, academicians, and public health practitioners, met at the Centers for Disease Control and Prevention in March 1998 to discuss the management of pneumonia in the era of DRSP. Published and unpublished data were summarized from the scientific literature and experience of participants. After group presentations and review of background materials, subgroup chairs prepared draft responses, which were discussed as a group.ConclusionsWhen implicated in cases of pneumonia, S pneumoniaeshould be considered susceptible if penicillin minimum inhibitory concentration (MIC) is no greater than 1 µg/mL, of intermediate susceptibility if MIC is 2 µg/mL, and resistant if MIC is no less than 4 µg/mL. For outpatient treatment of community-acquired pneumonia, suitable empirical oral antimicrobial agents include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral β-lactam with good activity against pneumococci (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). Suitable empirical antimicrobial regimens for inpatient pneumonia include an intravenous β-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S pneumoniaecan also be used to treat adults with community-acquired pneumonia. To limit the emergence of fluoroquinolone-resistant strains, the new fluoroquinolones should be limited to adults (1) for whom one of the above regimens has already failed, (2) who are allergic to alternative agents, or (3) who have a documented infection with highly drug-resistant pneumococci (eg, penicillin MIC ≥4 µg/mL). Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by DRSP.SINCE THE first description of a Streptococcus pneumoniaeisolate with diminished susceptibility to penicillin in 1967,resistance to penicillin and other antimicrobial agents among S pneumoniaeisolates has been increasing.Population-based active surveillance data from 7 geographic areas in the United States in 1997 showed that 21% of invasive pneumococcal isolates were not fully susceptible to penicillin (minimum inhibitory concentration [MIC] ≥0.1 µg/mL), 12% had penicillin MIC of no less than 2 µg/mL, and 7% had penicillin MIC of no less than 4 µg/mL.Surveillance data collected from 27 institutions in the United States from February through June 1997 revealed that 28% of respiratory tract isolates of S pneumoniaehad penicillin MIC of no less than 0.1 µg/mL and 16% had penicillin MIC of no less than 2 µg/mL.Streptococcus pneumoniaeis the most commonly identified cause of community-acquired pneumonia, accounting for 9% to 55% of cases of community-acquired pneumonia among patients requiring hospitalization.Nevertheless, the clinical impact of pneumonia caused by drug-resistant S pneumoniae(DRSP) is in debate. Much of the confusion and controversy concerning this issue is related to problems with the designation of pneumococcal resistance to penicillin. The National Committee for Clinical Laboratory Standards currently categorizes pneumococcal isolates as penicillin susceptible if MIC is no greater than 0.06 µg/mL, of intermediate susceptibility if MIC is 0.1 to 1.0 µg/mL, and resistant if MIC is no less than 2.0 µg/mL.Although these categories may have clinical relevance for some agents used to treat otitis media and meningitis, they are not appropriate for guiding treatment of pneumonia. An increased rate of treatment failure has been documented among children with acute otitis media caused by nonsusceptible S pneumoniae(penicillin MIC ≥0.1 µg/mL) treated with selected oral cephalosporins; treatment failures also have been reported among children and adults with meningitis caused by nonsusceptible strains treated with penicillin or third-generation cephalosporins.In contrast, some comparative studies of pneumococcal pneumonia among children and adults indicate that pneumococcal resistance does not have a deleterious impact on treatment outcome.However, recently published studiesand case reportssuggest that pneumococcal resistance may have an impact on mortality and other outcome measures in pneumonia.Although the association between penicillin resistance and clinical outcome has been uncertain until recently, resistance has been shown to influence which antimicrobial agents clinicians choose for treatment of pneumococcal pneumonia. In fact, the choice of antibiotic by clinicians may be influenced more by the MIC interpretation (ie, susceptible, intermediate, or resistant) than by the status of the patient or by evaluation of outcome data available in the literature.Thus, modifying the MIC break points so that more pneumococcal pneumonia isolates are reported appropriately as susceptible may improve care and also lead to a decrease in the use of broad-spectrum antimicrobial therapy in favor of more narrow-spectrum therapy.The Drug-Resistant Streptococcus pneumoniaeTherapeutic Working Group (DRSPTWG), consisting of clinicians, academicians, and public health practitioners, was convened by the Centers for Disease Control and Prevention, Atlanta, Ga, in March 1998 to attempt to resolve these and other issues regarding the clinical impact of DRSP on pneumococcal pneumonia and to develop recommendations for the treatment of pneumonia when DRSP is a possibility. The focus of these recommendations is on community-acquired pneumonia among immunocompetent patients. Subgroups of the DRSPTWG drafted responses to 4 specific questions, which were then discussed by the entire group. The conclusions of these subgroups are presented below.DISCUSSION GROUP CONCLUSIONSQuestion 1Should pneumococcal resistance to β-lactams influence community-acquired pneumonia treatment?Evidence now indicates that patients hospitalized for pneumococcal pneumonia caused by strains currently defined as having intermediate susceptibility to penicillin (MIC=0.1-1.0 µg/mL) respond well to treatment with adequate intravenous doses of β-lactams (eg, 4 million to 15 million units per day of penicillin G for adults and 100,000 to 300,000 U/kg per day for children older than 1 month in 4 to 6 divided doses; or 2-12 g of ampicillin sodium daily for adults or 100-300 mg/kg per day for children older than 1 month in 4 to 6 divided doses). Comparative studies of adults and children have reported that infection with penicillin-nonsusceptible pneumococci (MIC ≥0.1 µg/mL) does not influence the outcome of pneumonia treatment.Most of these patients were infected by pneumococci that had penicillin MICs in the intermediate range. There are conflicting data on the outcome after treatment of pneumonia caused by pneumococcal strains with penicillin MICs in the resistant range (≥2 µg/mL).Despite some reports of poor outcome among patients infected with intermediate-susceptibility strains,most available evidence indicates that standard treatment with a β-lactam antimicrobial agent is effective against pneumococcal pneumonia caused by strains with penicillin MIC of no greater than 1 µg/mL. Two of the reports of treatment failures did not include comparison groups,and a third did not adjust for possible confounders, such as severity of illness at the time of admission.Therefore, it was unclear if drug resistance caused poor response. Subsequent studies comparing patients infected by penicillin-susceptible strains with patients infected by intermediate-susceptibility strains provide strong evidence that no increased mortality or treatment failure is associated with strains currently defined as having intermediate susceptibility to penicillin.Few of these studies, however, were able to adjust for important confounders. These studies, if analyzed together, include more than 240 patients with pneumococcal pneumonia caused by intermediate-susceptibility strains, and therefore would be able to detect a 5% to 10% increase in clinical treatment failures.In addition, pharmacokinetic and pharmacodynamic considerations suggest that β-lactam therapy would be effective against pneumococcal strains with intermediate susceptibility to penicillin. The duration of time that serum or tissue levels exceed the MIC is the crucial pharmacodynamic factor correlated with the therapeutic efficacy of β-lactams against pneumococci, and the presence of free-drug concentrations above the MIC for at least 40% to 50% of the dosing interval is the critical determinant.If the goal of therapy is to achieve serum concentrations higher than the MIC for more than 40% of the dosing interval, 8 million to 15 million units of penicillin G daily in 4 to 6 divided doses may effectively treat adults with pneumonia caused by S pneumoniaestrains with MIC of no greater than 4 µg/mL.In children, somewhat higher dosages, ranging from 100,000 to 300,000 U/kg per day in 4 to 6 divided doses, have been commonly used and similarly produce effective serum concentrations.This predicted efficacy reflects the higher likelihood that the drug will accumulate in well-perfused alveoli in concentrations approximating those in the bloodstream than it will in middle ear fluid in otitis media, which acts as a closed-space infection, or in cerebrospinal fluid in meningitis, in which the blood-brain barrier intervenes. Also based on these considerations, intravenous penicillin might not be expected to have an effect on pneumococcal strains with penicillin MIC of no less than 8 µg/mL.Some evidence suggests that there is increased risk of mortalityor complicationsat penicillin MIC of 2 to 4 µg/mL, whereas other evidence indicates that there is no increased clinical failure at this level of resistance.In these reports, approximately 100 of the pneumonia cases were caused by strains currently categorized as resistant to penicillin, and nearly all resistant isolates had penicillin MIC of 2 to 4 µg/mL. The increase in mortality seen in one studywas confined to patients with pneumococcal isolates with penicillin MIC of no less than 4 µg/mL. Importantly, the increased mortality in this large study was confined to deaths occurring after the fourth day of hospitalization, consistent with the previous observation that early hospital mortality is not influenced by antibiotic treatment.None of the other studies comparing outcomes of pneumococcal pneumonia caused by penicillin-susceptible and penicillin-resistant strains included analyses confined to this subgroup.These data (Figure 1) suggest that most pneumonia caused by isolates defined as not fully susceptible to penicillin should respond well to treatment with a β-lactam antibiotic using optimal dosing, although treatment failures may occur at higher levels of resistance. Therefore, we believe that the susceptibility categories for S pneumoniae, when implicated as the cause of pneumonia, should be redefined. Pneumococcal strains currently defined as having intermediate susceptiblity to penicillin should be considered susceptible in the case of pneumonia. Some data indicate that strains with penicillin MIC of 2 µg/mL could also be considered susceptible if treated daily with penicillin G, 100,000 to 300,000 U/kg (or with ampicillin sodium or cefotaxime sodium, 100 mg/kg).Data are insufficient to support the use of β-lactams against strains with penicillin MIC of no less than 4 µg/mL. We recommend that the susceptibility categories for cases of pneumonia be changed so that S pneumoniaeisolates with penicillin MIC of no greater than 1 µg/mL be classified as susceptible; isolates with MIC of 2 µg/mL, intermediate; and isolates with MICs of no less than 4 µg/mL, resistant. Patients with pneumococcal pneumonia caused by strains with penicillin MIC of no greater than 1 µg/mL would therefore be treated appropriately with optimal dosage of intravenous penicillin G and selected other oral and parenteral β-lactams.The relationship between pneumococcal resistance and treatment outcomes for patients with pneumonia. Horizontal lines indicate the current National Committee for Clinical Laboratory Standards (NCCLS) break points.Good evidence exists that for Streptococcus pneumoniaestrains with penicillin minimum inhibitory concentration (MIC) of up to 1 µg/mL, resistance does not increase the likelihood of treatment failures.For strains with penicillin MICs of 2 and 4 µg/mL, some evidence indicates no increase in pneumonia treatment failures,whereas other evidence indicates increased mortalityor complications.Too few patients with pneumonia and pneumococcal isolates with penicillin MICs of no less than 8 µg/mL have been studied to draw appropriate conclusions, but pharmacodynamic considerations indicate theoretical reasons for concern.Asterisk indicates no significant difference in outcome between patients infected with strains of intermediate penicillin susceptibility vs penicillin-sensitive strains; S, susceptible; I, intermediate; and R, resistant.Question 2What are suitable empirical antimicrobial regimens for treatment of outpatient community-acquired pneumonia in the DRSP era?Empirical antibiotic treatment for outpatients with pneumonia should always be active against S pneumoniaebecause this organism is one of the most commonly identified causes of bacterial pneumonia, and because it causes more severe disease than other commonly identified pathogens. When possible, chest radiography should be performed to substantiate the diagnosis of pneumonia, and an etiologic diagnosis should be attempted (ie, sputum Gram stain should be performed and routine culture should be considered, recognizing that the sensitivity and specificity of these tests vary widely for different pathogens and that they will not detect atypical agents) for all persons with suspected pneumonia. As discussed above, pneumococci with penicillin MIC of no greater than 2 µg/mL should respond to β-lactam therapy. Population-based active surveillance data from 7 geographic areas in the United States in 1997 showed that 7% of invasive S pneumoniaeisolates in the United States had penicillin MIC of greater than 2 µg/mL.The relative importance of S pneumoniaeas a cause of outpatient community-acquired pneumonia is difficult to define because diagnostic tests are not performed on many outpatients, and when tests are performed, they often do not include the collection of sputum specimens. However, a review of the literature indicates that S pneumoniaeaccounts for 2% to 27% of cases of community-acquired pneumonia among persons treated on an ambulatory basis.We therefore estimate that 0.14% (7% of 2%) to 1.9% (7% of 27%) of outpatients with bacterial pneumonia have pneumococcal infections with levels of resistance high enough to warrant consideration of alternative treatment.Table 1shows the relative efficacy of commonly used antimicrobial agents for treating pneumococcal pneumonia, categorized by penicillin MIC. Recommendations for the empirical treatment of outpatient pneumonia are summarized in Table 2. Because pneumonia that is treated on an outpatient basis is generally not immediately life-threatening, and because S pneumoniaeisolates with penicillin MICs of no less than 4 µg/mL are uncommon, activity against highly penicillin-resistant pneumococci is not necessary for an initial regimen. Suitable empirical regimens for first-line therapy include a macrolide (eg, erythromycin, clarithromycin, or azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral β-lactam with good antipneumococcal activity (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). We favor the use of a macrolide or doxycycline because their broad coverage of atypical pathogens (particularly Mycoplasma pneumoniae) offsets their decreased efficacy against pneumococci. In addition, macrolides are the current recommendation of the American Thoracic Society for uncomplicated pneumonia in adults without comorbid features,and macrolides and doxycycline are among the agents recommended by the Infectious Diseases Society of America.However, macrolides are not usually recommended for empirical therapy in children younger than 5 years, because the broad spectrum of coverage of atypical agents generally is not believed to be important for this age group. An alternative regimen for selected adult patients is a fluoroquinolone with antipneumococcal activity (eg, grepafloxacin, levofloxacin, or sparfloxacin). The use of sparfloxacin may be limited because of concerns of phototoxicity. Because of new data showing an association with serious liver damage, the Food and Drug Administration issued a public health advisory recommending that trovafloxacin be used only for patients with serious and life- or limb-threatening infections who receive initial treatment in an inpatient health care facility and for whom physicians believe that the benefit of the agent outweighs its potential risk. For children younger than 5 years, in whom atypical agents are uncommon and in whom doxycycline and fluoroquinolones should be avoided, β-lactams may be the best choice. Detailed descriptions of the diagnostic evaluation and duration of therapy for community-acquired pneumonia can be found in the guidelines published by the Infectious Diseases Society of Americaand in those published by the American Thoracic Society.Table 1. Commonly Used Antimicrobial Agents for Treating Pneumonia*AgentPenicillin MIC, ug/mL†≤0.06 (Susceptible)0.12-1 (Intermediate)Resistant24≥8PenicillinsPenicillin V++++−−−Penicillin G++++++++±−Ampicillin sodium (oral)+++++±−−Ampicillin (parenteral)++++++++±−Amoxicillin++++++−−Piperacillin sodium++++++−−Ticarcillin+++−−−CephalosporinsCefotaxime sodium++++++++±−Ceftriaxone sodium++++++++±−Cefepime hydrochloride++++++±−Cefuroxime axetil (parenteral)++++++−−Cefuroxime (oral)+++++±−−Ceftizoxime+++++−−−Cefprozil+++++−−−Cefpodoxime proxetil+++++−−−Ceftazidime++++−−−Cefaclor+++−−−−Cefixime+++−−−−Fluoroquinolones‡New (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)+++++++++++++Ofloxacin (or ciprofloxacin hydrochloride)++++++±−MacrolidesAzithromycin++++±−−Clarithromycin++++±−−Erythromycin++++±−−OthersVancomycin hydrochloride++++++++++++++Clindamycin++++++++−Imipenem (or meropenem)++++++±−−Doxycycline (or tetracycline)++++++−−Chloramphenicol++++++±−−Trimethoprim-sulfamethoxazole++±−−−*MIC indicates minimum inhibitory concentration; +++, estimated percentage of pneumococci in MIC category covered by agent is at least 90%, good evidence of clinical efficacy; ++, estimated percentage of pneumococci in MIC category covered by agent is at least 75%, probable clinical efficacy; +, estimated percentage of pneumococci in MIC category covered by agent is at least 50%, possible clinical efficacy; ±, estimated percentage of pneumococci in MIC category covered by agent is at least 40% and/or little evidence of clinical efficacy; and −, estimated percentage of pneumococci in MIC category covered by agent is less than 40% and/or no evidence of clinical efficacy. Ratings estimate clinical efficacy and in vitro susceptibility in pneumococcal pneumonia.†Susceptibility (susceptible, intermediate, or resistant) is defined by National Committee for Clinical Laboratory Standards.‡These agents should be reserved as second-line agents because of concerns about emerging resistance and they are not approved by the Food and Drug Administration (FDA) for use in children younger than 18 years. Their relative antipneumococcal activity differs slightly, with that of trovafloxacin equal or superior to that of grepafloxacin, which equals that of sparfloxacin, which is superior to that of levofloxacin.The use of sparfloxacin may need to be limited because of concerns of phototoxicity. Because of new data showing an association with serious liver damage, the FDA issued a public health advisory recommending that trovafloxacin be used only for patients with serious and life- or limb-threatening infections who receive initial treatment in an inpatient health care facility and for whom physicians believe that the benefit of the agent outweighs potential risk.Table 2. Recommended Empiric Regimens for Treating Community-Acquired Pneumonia*Empiric TreatmentPenicillin MIC, ug/mLComments≤0.060.12-124≥8OutpatientsMacrolide (erythromycin, clarithromycin, or azithromycin)++++±−−Covers atypical pathogens (Mycoplasmaspecies, Chlamydiaspecies, and Legionellaspecies)Doxycycline (or tetracycline)++++++−−Covers atypical pathogens; not FDA-approved for children younger than 8 yOral ß-lactam (cefuroxime axetil, amoxicillin, or amoxicillin-clavulanate potassium)++++++−−Does not cover atypical pathogens; alternatively, cefpodoxime or cefprozil may be usedFluoroquinolone (grepafloxacin, levofloxacin, or sparfloxacin)†+++++++++++++Not first-line treatment because of concerns about emerging resistance; not FDA approved for use in children; covers atypical pathogensHospitalized (Nonintensive Care Unit) PatientsParenteral ß-lactam (cefuroxime, cefotaxime sodium, ceftriaxone sodium, or ampicillin sodium–sulbactam sodium) plus macrolide (erythromycin, clarithromycin, or azithromycin)++++++++±−Cefotaxime and ceftriaxone have superior activity against resistant pneumococci in comparison with ampicillin-sulbactam and with cefuroximeFluoroquinolone (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)†+++++++++++++See previous comments about fluoroquinolonesIntubated or Intensive Care Unit Patients‡Intravenous ß-lactam (ceftriaxone or cefotaxime sodium) plus intravenous macrolide (erythromycin or azithromycin)++++++++±−Ceftriaxone or cefotaxime are preferred over other ß-lactams because of their superior activity against resistant pneumococci; clarithromycin has no intravenous formulationIntravenous ß-lactam (ceftriaxone or cefotaxime) plus fluoroquinolone (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)†++++++++++++Ceftriaxone or cefotaxime are preferred over other ß-lactams; see previous comments about fluoroquinolonesFluoroquinolone (eg, grepafloxacin, levofloxacin, sparfloxacin, or trovafloxacin)†++++++++++See previous comments about fluoroquinolones; efficacy of monotherapy for critically ill persons with pneumococcal pneumonia has not been established*FDA indicates Food and Drug Administration. Other abbreviations are given in the first footnote to Table 1. Ratings estimate clinical efficacy and in vitro susceptibility among persons with pneumococcal pneumonia. In-depth information on empiric treatment of pneumonia is given by the Infectious Diseases Society of Americaand the American Thoracic Society guidelines.†The relative antipneumococcal activity of these agents differs slightly, with that of trovafloxacin equal or superior to that of grepafloxacin, which equals that of sparfloxacin, which is superior to that of levofloxacin.The use of sparfloxacin may need to be limited because of concerns of phototoxicity. Because of new data showing an association with serious liver damage, the FDA issued a public health advisory recommending that trovafloxacin be used only for patients with serious and life- or limb-threatening infections who receive initial treatment in an inpatient health care facility and for whom physicians believe that the benefit of the agent outweighs its potential risk.‡Vancomycin hydrochloride may be indicated for the treatment of selected critically ill children with community-acquired pneumonia for whom coverage of drug-resistant Streptococcus pneumoniaemust be ensured.Macrolides do not provide optimal coverage of penicillin-resistant pneumococci, because macrolide resistance is common among such strains (approximately 60%)and because macrolide resistance is often high when present.Although evidence of the clinical impact of macrolide resistance is limited, a study showed that treatment with erythromycin failed for 2 of 3 patients hospitalized with community-acquired pneumonia caused by macrolide-resistant S pneumoniaestrains; evidence from patients with other pneumococcal syndromes indicates that macrolide resistance is likely to have a clinical impact when present.Existing data are insufficient to determine whether macrolides can be used effectively against macrolide-resistant pneumococcal strains in which lower-level resistance results from increased drug efflux (mefE-encoded resistance), with resulting MIC of 1 to 32 µg/mL.Adequate concentrations of macrolides may be able to overcome this resistance. However, when macrolide resistance is caused by a ribosomal methylase encoded by ermAM, with resulting MIC generally of no less than 64 µg/mL,resistance presumably cannot be overcome by increasing the dosage.Several studies and surveillance data suggest that some newly available fluoroquinolones are efficacious for the treatment of pneumonia caused by S pneumoniae, including penicillin-resistant strains.We will consider these agents as a group, although some evidence indicates that their antipneumococcal activity differs slightly (ie, antipneumoccocal activity of trovafloxacin equals or is superior to that of grepafloxacin; grepafloxacin and sparfloxacin have equal activity; and antipneumoccocal activity of sparfloxacin is superior to that of levofloxacin),trovafloxacin should not be used for outpatient community-acquired pneumonia because of data showing an association between the use of this agent and hepatotoxic effects. Also, concerns about phototoxic effects resulting from the use of sparfloxacin may limit the use of this agent. In one study, microbiologic eradication from sputum was reported among all 30 patients with pneumococcal pneumonia treated with oral levofloxacin.In a study of in vitro susceptibility of S pneumoniaeclinical isolates to levofloxacin, none of 180 isolates (including 60 isolates with intermediate susceptibility to penicillin and 60 penicillin-resistant isolates) was resistant to this agent.A surveillance study of antimicrobial resistance in respiratory tract pathogens found levofloxacin was active against 97% of 9190 pneumococcal isolates and found no cross-resistance with penicillin, amoxicillin-clavulanate, ceftriaxone sodium, cefuroxime, or clarithromycin.However, a recent report found an increased incidence of ciprofloxacin hydrochloride resistance among penicillin-resistant pneumococcal isolates.We do not advocate the use of newer fluoroquinolones for first-line treatment because of their very broad spectrum of activity, because of concerns that resistance among pneumococci will rapidly emerge after widespread use of this class of antimicrobial agents, and because their activity against pneumococci with high penicillin resistance (MIC ≥4 µg/mL) makes it important that they be reserved for selected patients with community-acquired pneumonia. Such patients include adults for whom one of the first-line regimens has already failed, who are allergic to alternative agents, or who have a documented infection with highly drug-resistant pneumococci (ie, penicillin MIC ≥4 µg/mL). Use of fluoroquinolones has been shown to result in increased resistance in S pneumoniaein vitro,and population-based surveillance in the United States has shown a statistically significant increase in ofloxacin resistance among pneumococcal isolates between January 1, 1995, and December 31, 1997 (unpublished data, Active Bacterial Core Surveillance, Centers for Disease Control and Prevention). Furthermore, fluoroquinolone use may result in resistance among gram-negative organisms as well.The following β-lactams are not recommended because of poor in vitro activity against strains of S pneumoniaewith penicillin MIC of greater than 1 µg/mL: penicillin V potassium, all of the first-generation cephalosporins, cefaclor, cefixime, ceftibuten, and loracarbef.Trovafloxacin is not recommended for the treatment of outpatients with community-acquired pneumonia because of new data showing an association between the use of this agent and serious liver injury. Rifampin should not be used as single-agent therapy because resistance rapidly emerges when this drug is used alone.A combination of trimethoprim and sulfamethoxazole is not recommended because of high rates of resistance (18% to 26%) among invasive isolatesand evidence that it is less effective than amoxicillin for the management of pneumonia in children, independent of susceptibility results.Question 3What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era?The inpatient management of community-acquired pneumonia should be based largely on the severity of illness at the time of admission. An etiologic diagnosis should be attempted for all patients by means of Gram stains, cultures, and other tests as appropriate.No simple empirical regimen can cover all potential pathogens. Therefore, for moderately ill patients, defined as those who are hospitalized but who do not require admission to an intensive care unit, initial antimicrobial treatment should target the suspected etiologic agents and may omit coverage of rare pathogens (including highly resistant pneumococci, ie, with penicillin MIC ≥4 µg/mL). However, for critically ill patients, defined as those who are intubated or in an intensive care unit, treatment should provide more comprehensive coverage.For moderately ill persons, initial treatment should include a parenteral β-lactam, such as cefuroxime, ceftriaxone, cefotaxime, or a combination of ampicillin sodium and sulbactam sodium, and a macrolide, such as erythromycin, azithromycin, or clarithromycin, as outlined in Table 2. An attractive alternative for adults is a fluoroquinolone with improved activity against S pneumoniae. Although such fluoroquinolones may be active against isolates of S pneumoniaethat are highly resistant to β-lactams,they should be reserved for selected patients, as previously discussed.For critically ill persons, empirical treatment should cover the agents most likely to cause severe disease, as outlined in Table 2. First-line therapy in this situation should include an intravenous β-lactam, such as ceftriaxone or cefotaxime, and an intravenous macrolide, such as erythromycin or azithromycin. Alternatively, intravenous ceftriaxone or cefotaxime and a fluoroquinolone with antipneumococcal activity may be used for critically ill adults. A fluoroquinolone with improved activity against S pneumoniaemay be used alone for adults, but caution should be exercised, because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients with pneumococcal pneumonia has not been determined. Critically ill patients, as defined above, have been excluded from most trials of fluoroquinolones for community-acquired pneumonia.Drugs that are not appropriate for treating hospitalized patients with pneumococcal pneumonia in the era of DRSP include first-generation cephalosporins and ceftazidime, ceftizoxime, and ticarcillin because of the high rate of resistance to these agents among penicillin-resistant pneumococci.Vancomycin hydrochloride has remained uniformly active against pneumococci, but ample evidence shows that overuse of vancomycin has led to resistance among other pathogens.To date, a few isolates of Staphylococcus aureuswith reduced susceptibility to vancomycin (MIC=8 µg/mL) have been discovered.Although isolates highly resistant to penicillin (MIC ≥4 µg/mL) are increasingly common, the availability of new agents means that an antimicrobial agent other than vancomycin with demonstrated in vitro activity against most isolates is generally available for patients with pneumonia. In addition, the clinical efficacy of vancomycin for the treatment of critically ill patients with pneumococcal pneumonia has not been well documented. Therefore, vancomycin should not be used routinely for the treatment of adults with pneumococcal pneumonia. However, vancomycin should be included in the initial antimicrobial regimen for any person with suspected bacterial meningitis. In addition, because fluoroquinolones are not currently approved for treatment of children, treatment with vancomycin may be appropriate for selected critically ill children with community-acquired pneumonia, in whom coverage of DRSP must be ensured (using the criteria for fluoroquinolone use in adults). Vancomycin therapy, if included in an empirical treatment regimen, should be promptly discontinued if a subsequently isolated etiologic agent does not require treatment with the drug.Question 4How should clinical laboratories report antibiotic susceptibility patterns for S pneumoniae, and what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest?The current categories for defining susceptibility concentrations (ie, susceptible, intermediate, and resistant) are not clinically useful for the treatment of patients with pneumococcal pneumonia and should be modified, as discussed above. The DRSPTWG recommends that penicillin break points be shifted upward for isolates that cause pneumonia (but not meningitis and otitis media) to make the break points more clinically meaningful and to assist clinicians in treatment decisions. For categorization of these isolates, we recommend defining penicillin susceptibility as an MIC of no greater than 1 µg/mL, intermediate susceptibility as an MIC of 2 µg/mL, and resistance as an MIC of no less than 4 µg/mL. This recommendation will require changes in the way laboratories report and clinicians interpret susceptibility results, because susceptibility break points will differ according to the clinical syndrome being treated.Laboratories should report MICs and susceptibility categories for penicillin and for extended-spectrum cephalosporins for all pneumococcal isolates from appropriately collected sputum, from other lower respiratory tract specimens, from blood, and from all other sterile sites. Non–β-lactam susceptibility results may be reported to physicians by category (ie, susceptible, intermediate, or resistant), based on disk diffusion testing, or by category and MIC, based on MIC testing of appropriately collected respiratory and other relevant pneumococcal isolates.The drugs that should be included in surveillance studies depend on whether the surveillance system under consideration is a local, hospital laboratory–based system or a large reference laboratory. The DRSPTWG identified 6 antimicrobial agents that should be included in surveillance by all local laboratories: penicillin, cefotaxime (or ceftriaxone), erythromycin, doxycycline (or tetracycline), clindamycin, and fluoroquinolones with antipneumococcal activity. The DRSPTWG identified 2 other agents that could also be included, depending on available resources and on the interests of the clinicians in the area: trimethoprim-sulfamethoxazole and vancomycin.The list for large reference laboratories was designed to be comprehensive. The agents identified as important to include on this list are penicillin, amoxicillin, ceftriaxone (or cefotaxime), cefuroxime, cefpodoxime proxetil (or cefprozil), erythromycin, clindamycin, fluoroquinolones with antipneumococcal activity, vancomycin, trimethoprim-sulfamethoxazole, doxycycline (or tetracycline), and meropenem. Surveillance on the local, regional, national, and even international level should be encouraged. When possible, active surveillance and population studies should be performed. To derive the maximum benefit from a surveillance system, clinicians need to be fully aware of the population studied by that system. The population should be clearly defined not only before the initiation of surveillance but also when the results are reported, because S pneumoniaesusceptibility can vary widely by demographic factors such as age, race, and geographic area. Final surveillance reports should list MICs or zone diameter values in addition to susceptibility categories. Laboratories conducting surveillance should use approved methodsand should state these methods in their annual reports.SUMMARY AND RECOMMENDATIONSIn response to increasing rates of resistance among pneumococcal isolates, particularly among highly resistant strains, the DRSPTWG makes the following recommendations:For pneumococcal isolates causing pneumonia, penicillin susceptibility categories should be shifted upward so that the susceptible category includes all isolates with MIC of no greater than 1 µg/mL, the intermediate category includes isolates with MIC of 2 µg/mL, and the resistant category includes isolates with MIC of no less than 4 µg/mL.Suitable empirical antimicrobial regimens for outpatients with community-acquired pneumonia include a macrolide (eg, erythromycin, clarithromycin, or azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral β-lactam with good antipneumococcal activity (eg, cefuroxime, amoxicillin, or amoxicillin-clavulanate). An oral fluoroquinolone with improved activity against S pneumoniaealso may be used for the treatment of adults for whom one of these regimens has already failed, who are allergic to alternative agents, or who have a documented infection with highly drug-resistant pneumococci (ie, penicillin MIC ≥4 µg/mL). For children younger than 5 years in whom atypical agents are uncommon and for whom doxycycline and fluoroquinolones should be avoided, β-lactams may be the best choice.A suitable empirical antimicrobial regimen for moderately ill patients hospitalized for pneumonia includes a parenteral β-lactam such as cefuroxime, cefotaxime, ceftriaxone, or ampicillin-sulbactam, and a macrolide, such as erythromycin, azithromycin, or clarithromycin. An alternative for adults is a fluoroquinolone with antipneumococcal activity. However, these drugs should be reserved for selected patients.A suitable empirical antimicrobial regimen for critically ill persons hospitalized for pneumonia includes an intravenous β-lactam, such as cefotaxime or ceftriaxone, and an intravenous macrolide, such as erythromycin or azithromycin. Alternatively, intravenous ceftriaxone or cefotaxime and a fluoroquinolone with improved activity against S pneumoniaemay be used for critically ill adults. A fluoroquinolone with improved antipneumococcal activity may be used alone, but caution should be exercised because the efficacy of the new fluoroquinolones as monotherapy for critically ill patients with pneumococcal pneumonia has not been determined.Vancomycin is not routinely indicated for treatment of community-acquired pneumonia or of pneumonia caused by DRSP. However, vancomycin should be included in the initial antimicrobial regimen for any person with suspected bacterial meningitis. In addition, treatment with vancomycin may be appropriate for selected critically ill children with community-acquired pneumonia. Vancomycin therapy, if included in an empirical treatment regimen, should be promptly discontinued if a subsequently isolated etiologic agent does not require treatment with the drug.Laboratories should report MICs for penicillin and for extended-spectrum cephalosporins for all pneumococcal isolates from appropriately collected specimens. Antimicrobial agents that should be included in surveillance by all local laboratories are penicillin, cefotaxime (or ceftriaxone), erythromycin, doxycycline (or tetracycline), clindamycin, and fluoroquinolones with antipneumococcal activity. In addition to these, reference laboratories should survey amoxicillin, cefuroxime, cefpodoxime (or cefprozil), clindamycin, vancomycin, trimethoprim-sulfamethoxazole, and meropenem.DHansmanMMBullenA resistant pneumococcus [letter].Lancet.1967;2:264-265.JSSpikaRRFacklamBDPlikaytisMJOxtobyAntimicrobial resistance of Streptococcus pneumoniaein the United States, 1979-1987.J Infect Dis.1991;163:1273-1278.RFBreimanJCButlerFCTenoverJAElliottRRFacklamEmergence of drug-resistant pneumococcal infections in the United States.JAMA.1994;271:1831-1835.CThornsberrySDBrownYCYeeSKBouchillonJKMarlerTRichIncreasing penicillin resistance in Streptococcus pneumoniaein the US: effect on susceptibility to oral cephalosporins.Infect Med.1993;10(suppl D):S15-S24.CGWhitneyNBarrettMFarleyIncreasing prevalence of drug-resistant Streptococcus pneumoniae(DRSP): implications for therapy for pneumonia.In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 51.GVDoernMAPfallerKKuglerJFreemanRNJonesPrevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniaein North America: 1997 results from the SENTRY Antimicrobial Surveillance Program.Clin Infect Dis.1998;27:764-770.TJMarrieHDurantLYatesCommunity-acquired pneumonia requiring hospitalization: 5-year prospective study.Rev Infect Dis.1989;11:586-599.GDFangMFineJOrloffNew and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases.Medicine (Baltimore).1990;69:307-316.MTKauppinenEHervaPKujalaMLeinonenPSaikkuHSyrjalaThe etiology of community-acquired pneumonia among hospitalized patients during a Chlamydia pneumoniaeepidemic in Finland.J Infect Dis.1996;172:1330-1335.BJMarstonJFPlouffeTMFileIncidence of community-acquired pneumonia requiring hospitalization.Arch Intern Med.1997;157:1709-1718.TJMarrieCommunity-acquired pneumonia: epidemiology, etiology, treatment.Infect Dis Clin North Am.1998;12:723-740.National Committee for Clinical Laboratory StandardsPerformance Standards for Antimicrobial Susceptibility Tests (M 100-S8).Villanova, Pa: National Committee for Clinical Laboratory Standards; 1998. Vol 18.RDaganOAbramsonELeibovitzImpaired bacteriologic response to oral cephalosporins in acute otitis media caused by intermediate resistance to penicillin.Pediatr Infect Dis J.1996;15:980-985.RDaganOAbramsonELeibovitzBacteriologic response to oral cephalosporins: are established susceptibility breakpoints appropriate in the case of acute otitis media?J Infect Dis.1997;176:1253-1259.IRFriedlandKPKlugmanFailure of chloramphenicol in penicillin-resistant pneumococcal meningitis.Lancet.1992;339:405-408.CCJohnTreatment failure with use of a third-generation cephalosporin for penicillin-resistant pneumococcal meningitis: case report and review.Clin Infect Dis.1994;18:188-193.MJCatalanJMFernandezAVazquezEVde SeijasASuarezJCde QuirosFailure of cefotaxime in the treatment of meningitis due to relatively resistant Streptococcus pneumoniae.Clin Infect Dis.1994;18:766-769.KPKlugmanIRFriedlandJSBradleyBactericidal activity against cephalosporin-resistant Streptococcus pneumoniaein cerebrospinal fluid of children with acute bacterial meningitis.Antimicrob Agents Chemother.1995;39:1988-1992.KOClevelandMGThrelkeldFCTenoverRJLeggiadroDrug-resistant pneumococcal meningitis in an American adult [letter].Clin Infect Dis.1995;20:1572-1573.RPallaresJLinaresMVadilloResistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.N Engl J Med.1995;333:474-480.IRFriedlandComparison of the response to antimicrobial therapy of penicillin-resistant and penicillin-susceptible pneumococcal disease.Pediatr Infect Dis.1995;14:885-890.DFeikinASchuchatMKolczakMortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997.Am J Public Health.2000;90:223-229.GSTurretSBlumBAFazalJEJustmanEETelzakPenicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high HIV seroprevalence.Clin Infect Dis.1999;29:321-327.SCBuckinghamSPBrownVHJoaquinBreakthrough bacteremia and meningitis during treatment parenterally with cephalosporins for pneumococcal pneumonia.J Pediatr.1998;132:174-176.SFDowellTSmithKLeversedgeJSnitzerPneumonia treatment failure associated with highly resistant pneumococci.Clin Infect Dis.1999;29:462-463.DBJerniganSFDowellLALiedtkeLJStrausbaughInfectious Diseases Society of America Emerging Infections Network (EIN)Factors influencing antibiotic selection for community-acquired pneumonia (CAP).In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 683.IRFriedlandKPKlugmanAntibiotic-resistant pneumococcal disease in South African children.AJDC.1992;146:920-923.EChoiHLeeClinical outcome of invasive infections by penicillin-resistant Streptococcus pneumoniaein Korean children.Clin Infect Dis.1998;26:1346-1354.SLDeeksRPalacioRRuinskyRisk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae.Pediatrics.1999;103:409-413.CFeldmanJMKallenbachSDMillerJRThorburnHJKoornhofCommunity-acquired pneumonia due to penicillin-resistant pneumococci.N Engl J Med.1985;313:615-617.HSachoKPKlugmanHJKoornhofCommunity-acquired pneumonia in an adult due to a multiply-resistant pneumococcus [letter].J Infect.1987;14:188-189.RPallaresFGudiolJLinaresRisk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.N Engl J Med.1987;317:18-22.WACraigPharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.Clin Infect Dis.1998;26:1-12.CSBryanRTalwaniMSStinsonPenicillin dosing for pneumococcal pneumonia.Chest.1997;112:1657-1664.JPHieberJDNelsonA pharmacologic evaluation of penicillin in children with purulent meningitis.N Engl J Med.1977;297:410-413.American Academy of Pediatrics Committee on Infectious DiseasesTherapy for children with invasive pneumococcal infections.Pediatrics.1997;99:289-299.KPKlugmanThe clinical relevance of antibiotic resistance in the management of pneumococcal pneumonia.Infect Dis Clin Pract.1998;7:180-184.RAustrianJGoldPneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia.Ann Intern Med.1964;60:759-776.EBerntssonTLagergardOStrannegardBTrollforsEtiology of community-acquired pneumonia in outpatients.Eur J Clin Microbiol.1986;5:446-447.DBLangilleLYatesTJMarrieSerological investigation of pneumonia as it presents to the physician's office.Can J Infect Dis.1993;4:328.BO'DohertyDADutchmanRPettitAMaroliRandomized, double-blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia.J Antimicrob Chemother.1997;40(suppl A):73-81.LWubbelLMunizAAhmedEtiology and treatment of community-acquired pneumonia in ambulatory children.Pediatr Infect Dis J.1999;18:98-104.GVDoernMAPfallerMEErwinABBrueggemannRNJonesThe prevalence of fluoroquinolone resistance among clinically significant respiratory tract isolates of Streptococcus pneumoniaein the United States and Canada: 1997 results from the SENTRY Antimicrobial Surveillance Program.Diagn Microbiol Infect Dis.1998;32:313-316.JHJorgensenLMWeigelMJFerraroJMSwensonFCTenoverActivities of newer fluoroquinolones against Streptococcus pneumoniaeclinical isolates including those with mutations in the gyrA, parC, and parE loci.Antimicrob Agents Chemother.1999;43:329-334.JGBartlettRFBreimanLAMandellTMFileCommunity-acquired pneumonia in adults: guidelines for management.Clin Infect Dis.1998;26:811-838.MSNiedermanJBBassGDCampbellGuidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy.Am Rev Respir Dis.1993;148:1418-1426.PPGleasonWNKapoorRAStoneMedical outcomes and antimicrobial costs with the use of the American Thoracic Society guidelines for outpatients with community-acquired pneumonia.JAMA.1997;278:32-39.LMEdnieMAVisalliMRJacobsPCAppelbaumComparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci.Antimicrob Agents Chemother.1996;40:1950-1952.JHoffmanMSCetronMMFarleyThe prevalence of drug-resistant Streptococcus pneumoniaein Atlanta.N Engl J Med.1995;333:481-486.GVDoernABrueggemannHPHolley JrAMRauchAntimicrobial resistance of Streptococcus pneumoniaerecovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.Antimicrob Agents Chemother.1996;40:1208-1213.JSutcliffeATait-KamradtLWondrackStreptococcus pneumoniaeand Streptococcus pyogenesresistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system.Antimicrob Agents Chemother.1996;40:1817-1824.JCCraftGNotarioRHomDShortridgeRKFlammCan erythromycin-resistant Streptococcus pneumoniaebe treated with a macrolide?In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 264.MAubierHLodeGGialdroni-GrassiSparfloxacin for the treatment of community-acquired pneumonia: a pooled data analysis of two studies.J Antimicrob Chemother.1996;77(suppl A):73-82.MAJacksonVFBurryLCOlsonSEDuthieGLKearnsBreakthrough sepsis in macrolide-resistant pneumococcal infection.Pediatr Infect Dis.1996;15:1049-1051.RDaganLPiglanskyPYagupskyDMFlissALeibermanELeibovitzBacteriologic response in acute otitis media: comparison between azithromycin, cefaclor and amoxicillin.In: Programs and Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sep 28-Oct 1, 1997; Toronto, Ontario, Canada.Washington, DC: American Society for Microbiology; 1997. Abstract K-103.BWeisblumErythromycin resistance by ribosome modification.Antimicrob Agents Chemother.1995;39:577-585.LKMcDougalFCTenoverLNLeeDetection of TN917-like sequences within a TN916-like conjugative transposon (TN3872) in erythromycin-resistant isolates of Streptococcus pneumoniae.Antimicrob Agents Chemother.1998;42:2312-2318.TMFileJSegretiLDunbarA multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia.Antimicrob Agents Chemother.1997;41:1965-1972.KPKlugmanTCapperABryskierIn vitro susceptibility of penicillin-resistant Streptococcus pneumoniaeto levofloxacin, selection of resistant mutants, and time-kill synergy studies of levofloxacin combined with vancomycin, teicoplanin, fusidic acid, and rifampin.Antimicrob Agents Chemother.1996;40:2802-2804.CThornsberryPOgilvieJKahnYMaurizSurveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae,and Moraxella catarrhalisin the United States in 1996-1997 respiratory season: The Laboratory Investigator Group.Diagn Microbiol Infect Dis.1997;29:249-257.CEGoldsmithJEMoorePGMurphyJEAmblerIncreased incidence of ciprofloxacin resistance in penicillin-resistant pneumococci in Northern Ireland.J Antimicrob Chemother.1998;41:420-421.TDaviesGPankuchBDewasseMJacobsPAppelbaumIn vitro development of resistance to five quinolones and amoxicillin/clavulanate in Streptococcus pneumoniae.In: Programs and Abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, CO.Washington, DC: Infectious Diseases Society of America; 1998. Abstract 227.DMCappellettyMJRybakBactericidal activities of cefprozil, penicillin, cefaclor, cefixime, and loracarbef against penicillin-susceptible and -resistant Streptococcus pneumoniaein an in vitro pharmacodynamic infection model.Antimicrob Agents Chemother.1996;40:1148-1152.JVerhaegenLVerbistIn-vitro activity of 21 β-lactam antibiotics against penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae.J Antimicrob Chemother.1998;41:381-385.KMCitronJRMayRifamycin antibiotics in chronic purulent bronchitis.Lancet.1969;2:982-983.KPKlugmanPneumococcal resistance to antibiotics.Clin Microbiol Rev.1990;3:171-196.WlStrausASQaziZKundiNKNomaniBSchwartzPakistan Co-trimoxazole Study GroupAntimicrobial resistance and clinical effectiveness of co-trimoxazole versus amoxycillin for pneumonia among children in Pakistan: randomised controlled trial.Lancet.1998;352:270-274.JFPlouffeMTHerbertTMFileOfloxacin versus standard therapy in treatment of community-acquired pneumonia requiring hospitalization.Antimicrob Agents Chemother.1996;40:1175-1179.MAubierRVersterCRegameyPGeslinJBVerckenSparfloxacin European Study GroupOnce-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults.Clin Infect Dis.1998;26:1312-1320.GAPankuchMRJacobsPCAppelbaumSusceptibilities of 200 penicillin-susceptible and -resistant pneumococci to piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone.Antimicrob Agents Chemother.1994;38:2905-2907.DWHaasCWStrattonJPGriffinLWeeksSCAllsDiminished activity of ceftizoxime in comparison to cefotaxime and ceftriaxone against Streptococcus pneumoniae.Clin Infect Dis.1995;20:671-676.CThornsberryPHBurtonBHVanderhoofActivity of penicillin and three third-generation cephalosporins against US isolates of Streptococcus pneumoniae:a 1995 surveillance study.Diagn Microbiol Infect Dis1996;25:89-95.BEMurrayDiversity among multidrug-resistant enterococci.Emerg Infect Dis.1998;4:37-47.LCMcDonaldMJKuehnertFCTenoverWRJarvisVancomycin-resistant enterococci outside the health-care setting: prevalence, sources, and public health implications.Emerg Infect Dis.1997;3:311-317.PAFloresSMGordonVancomycin-resistant Staphylococcus aureus:an emerging public health threat.Cleve Clin J Med.1997;64:527-532.Centers for Disease Control and PreventionStaphylococcus aureuswith reduced susceptibility to vancomycin: United States, 1997.MMWR Morb Mortal Wkly Rep.1997;46:765-766.FCTenoverMVLancasterBCHillCharacterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides.J Clin Microbiol.1998;36:1020-1027.KHiramatsuHHanakiTInoKYabutaTOguriFCTenoverMethicillin-resistant Staphylococcus aureusclinical strain with reduced vancomycin susceptibility.J Antimicrob Chemother.1997;40:135-146.MCPloyCGrelaudCMarinLde LumleyFDenisFirst clinical isolate of vancomycin-intermediate Staphylococcus aureusin a French hospital [letter].Lancet.1998;351:1212.National Committee for Clinical Laboratory StandardsMethods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically.Vol 17. Wayne, Pa: National Committee for Clinical Laboratory Standards; 1997.Accepted for publication October 4, 1999.Dr Heffelfinger is a shareholder of Pfizer Inc, New York, NY; Merck, Whitehouse Station, NJ; and Abbott Laboratories, Abbot Park, Ill. Dr Klugman received research grants in the past year from Hoechst Marion Roussel, Swiftwater, Pa; Chiron Vaccines, Emeryville, Calif; South African Vaccine Producers, Johannesburg; SmithKline Beecham, Brentford, England; Roche Pharmaceuticals, Nutley, NJ; Bayer Corp, Pittsburgh, Pa; Swiss Serum Institute, Berne; Schering Plough, Madison, NJ; Wyeth-Lederle Vaccines, St Davids, Pa; Abbott Laboratories; Lilly, Indianapolis, Ind; Pasteur Meriéux, Lyon, France; and Pasteur MSD, Lyon. Dr Plouffe is in receipt of grants from Pfizer; Rhone Poulenc Rorer, Swiftwater; Bayer Corp; SmithKline Beecham; and Bristol Myers Squibb, New York; he has received honoraria from Pfizer, Ortho, Raritan, NJ; Bayer Corp; and Roche Pharmaceuticals; and he is a shareholder of Pfizer, SmithKline Beecham, and Merck. Dr Burch is an employee and shareholder of SmithKline Beecham. Dr Jacobs has received financial support, including research grants, honoraria, and speaker's fees, from Abbott Laboratories; Aventis, Swiftwater; Bayer Corp; Daiichi Pharmaceuticals, Tokyo, Japan; Eli Lilly & Co, Indianapolis; Glaxo Pharamceuticals, Greenford, England; Hoechst Marion Roussel; Meiji Pharmaceuticals, Tokyo; Pfizer Inc; Pharamcia-Upjohn, Peapack, NJ; R. W. Johnson, Raritan; Rhone Poulenc Rorer; Roche Pharmaceuticals; Roussel Uclaf Pharmaceuticals, Frankfurt, Germany; SmithKline Beecham; TAP Pharmaceuticals Inc, Deerfield, Ill; Warner Lambert Pharmaceuticals, Morris Plains, NJ; and Wyeth-Ayerst Laboratories, St Davids. Dr Kaplan is a member of the Pediatric Advisory Committee for ceftriaxone (Roche Pharmaceuticals) and the Pediatric Linezolid Advisory Committee (Pharmacia-Upjohn).Drug-Resistant Streptococcus pneumoniaeTherapeutic Working GroupJohn Bartlett, MD (Johns Hopkins University School of Medicine, Baltimore, Md); David Bell, MD (Antimicrobial Resistance Coordinator, Centers for Disease Control and Prevention [CDC], Atlanta, Ga); Robert Breiman, MD (National Vaccine Program Office, CDC); Daniel J. Burch, MD (Pharmaceutical Research and Manufacturers Association, Washington, DC); Jay C. Butler, MD (Respiratory Diseases Epidemiology Section, CDC); Martin Cetron, MD (Division of Quarantine, CDC); Joan Chesney, MD (American Academy of Pediatrics, Elk Grove Village, Ill); Mitchell Cohen, MD (Division of Bacterial and Mycotic Diseases, CDC); William Craig, MD (Infectious Diseases Society of America, Alexandria, Va); Ron Dagan, MD (Pediatric Infectious Disease Unit, Soroka Medical Center, Beer Sheva, Israel); Scott F. Dowell, MD (Respiratory Diseases Branch, CDC); Daniel Feikin, MD (Respiratory Diseases Branch, CDC); Thomas M. File, MD (Northeastern Ohio Universities College of Medicine, Summa Health System, Akron); Mary Gilchrist, PhD (Association of Public Health Laboratories, Washington, DC); James Heffelfinger, MD (Respiratory Diseases Branch, CDC); Michael Jacobs, MD, PhD (Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio); Dan Jernigan, MD (Washington State Department of Health, Seattle); Ronald N. Jones, MD (American Society for Microbiology, Washington, DC); James H. Jorgensen, PhD (National Committee for Clinical Laboratory Standards, Wayne, Pa); Sheldon Kaplan, MD (American Academy of Pediatrics); David Klein, PhD (National Institutes of Health/National Institute of Allergy and Infectious Disease, Bethesda, Md); Keith Klugman, MD (South African Institute for Medical Research, Johannesburg); Leah Raye Mabry, MD (American Academy of Family Physicians, Leahwood, Mo); Lionel A. Mandell, MD (American Thoracic Society, New York, NY, and Infectious Diseases Society of America, Alexandria, Va); Daniel R. Martin, MD (Society for Academic Emergency Medicine, Lansing, Mich); Bill Martone, MD (National Foundation for Infectious Diseases, Bethesda, Md); Joshua Metlay, MD, PhD (University of Pennsylvania School of Medicine, Philadelphia); John F. Moroney, MD (Epidemiology Program Office, CDC); Daniel M. Musher, MD (American College of Pathologists, Northfield, Ill); Michael Niederman, MD (State University of New York at Stony Brook); Thomas F. O'Brien, MD (World Health Organization Collaborating Center for Surveillance of Antimicrobial Resistance, Geneva, Switzerland); Michael A. Pfaller, MD (College of American Pathologists, Northfield, Ill); Joseph F. Plouffe, MD (Ohio State University Medical Center, Columbus); Alexander Rakowsky, MD (Food and Drug Administration, Rockville, Md); Frederick L. Ruben, MD (American Thoracic Society and American Lung Association, New York); Anne Schuchat, MD (Respiratory Diseases Branch, CDC); Benjamin Schwartz, MD (Division of Bacterial and Mycotic Diseases, CDC); Fred Tenover, PhD (Hospital Infections Program, CDC); Cynthia G. Whitney, MD (Respiratory Diseases Branch, CDC); Victor L. Yu, MD (University of Pittsburgh, Pittsburgh, Pa); George Zhanel, PhD (Society of Infectious Disease Pharmacists, Houston, Tex).Reprints: James D. Heffelfinger, MD, 2820 W Barrett St, Seattle, WA 98199 (e-mail: izh7@cdc.gov).

Journal

JAMA Internal MedicineAmerican Medical Association

Published: May 22, 2000

There are no references for this article.