A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations – results of a prematurely terminated study

A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of... Background: Studies have suggested the reduced effectiveness of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections with high vancomycin minimum inhibitory concentrations. Alternative agents such as daptomycin may be considered. We conducted a randomized controlled study comparing daptomycin against vancomycin in the treatment of MRSA bloodstream infections with high vancomycin minimum inhibitory concentrations. Methods: Patients were randomized to receive vancomycin or daptomycin for a minimum of 14 days. The primary end point was the rate of all-cause mortality at day 60. Results: A total of 14 patients were randomized in this study, with 7 patients in each treatment arm. The study was terminated early due to slow patient accrual. At day 60, there was one death in the vancomycin arm and none in the daptomycin arm. The median time to microbiological clearance was 4 days in both arms (IQR 3–5days inthe vancomycin arm and 3–7 days in daptomycin arm). Only one patient in the vancomycin arm had recurrence of bacteremia. Rates of adverse events were similar in botharms. Therewas onecaseofmusculoskeletal toxicity and one case of drug-related nephrotoxicity - both events occurred in the daptomycin arm. None of the patients in either treatment arm required cessation of study treatment or addition of a second anti-MRSA agent because of worsening infection. Conclusion: Based on the limited number of patients evaluated in this study, it remains unclear if alternative, more expensive agents such as daptomycin are superior to vancomycin in the treatment of high vancomycin minimum inhibitory concentration MRSA bloodstream infections. More studies are urgently needed but investigators may wish to consider employing novel, alternative trial methodologies to ensure a greater chance of success. (Continued on next page) * Correspondence: shirin.kalimuddin@singhealth.com.sg Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kalimuddin et al. Trials (2018) 19:305 Page 2 of 9 (Continued from previous page) Trial registration: ClinicalTrials.gov, NCT01975662. Registered on 5 November 2013. Keywords: Methicillin-resistant Staphylococcus aureus, Vancomycin, Daptomycin, Minimum inhibitory concentration, Bacteremia Background was published in Trials [11]. Subjects were first enrolled Staphylococcus aureus is one of the most common human on 13 February 2014 with the last subject visit on 25 pathogens that cause a wide range of clinical infections September 2015. worldwide. Infections caused by methicillin-resistant S. aur- eas (MRSA) are associated with increased mortality and Study population morbidity and increased length and cost of hospitalization Patients were eligible for the study if they were ≥ 21 years [1, 2]. Moreover, because MRSA is multidrug resistant, it of age, were inpatients at the time of enrolment and had leaves clinicians with few effective antimicrobial options [3]. a BSI due to MRSA with a vancomycin MIC ≥ 1.5 μg/ml Treating S. aureus infections has become increasing chal- but < 2 μg/ml as determined by the Epsilometer test lenging in recent, with the emergence of highly virulent (E-test) or the VITEK™-2 system (bioMerieux, Marcy MRSA strains. l’Etoile, France). Patients were excluded if they were al- Vancomycin, a tricyclic glycopeptide, is the standard lergic to vancomycin or daptomycin, pregnant or breast- first line treatment for patients with MRSA bloodstream feeding, unable to comply with study treatments and infections (BSI). Consensus guidelines, however, recom- procedures, unable to provide consent or had no legally mend clinicians to consider alternative agents for MRSA authorized representatives, currently enrolled in or had infections when the vancomycin minimum inhibitory con- participated in an interventional antibiotic or vaccine centration (MIC) is > 1 μg/ml, especially when clinical fail- trial within the past 3 months, expected to have less ure is suspected with vancomycin treatment [4]. One such than 24 h of life expectancy, polymicrobial bacteremia, alternative agent is daptomycin - a calcium-dependent pneumonia, receiving treatment with linezolid, tigecyline cyclic lipopeptide that is rapidly bactericidal against many or ceftaroline for more than 96 h prior to enrolment, re- gram-positive organisms including MRSA [5, 6]. A num- ceiving vancomycin or daptomycin treatment for more ber of recent studies have also suggested that vancomycin than 5 days prior to enrolment, or if they had baseline use, especially in infections caused by MRSA with high serum creatine kinase (CK) more than 1.5 times the vancomycin MICs, may be associated with poorer clinical upper limit of normal, presence of prosthetic heart outcomes when compared with an alternative anti-MRSA valves, or any other significant condition that would, in agent such as daptomycin; however, these were retrospect- the opinion of the investigator, compromise the patient’s ive and non- randomized studies [7–10]. safety or outcome of the trial. The study exclusion cri- To date, there has been no head-to-head randomized teria were amended from the published protocol [11]on trial comparing the safety and efficacy of daptomycin 7 August 2014 after consultation with the trial steering and vancomycin in the treatment of BSIs due to MRSA committee in an effort to improve recruitment, without with high vancomycin MICs. Clinicians are often faced compromising the rigor of the study design. When the with the dilemma of using the cheaper standard treat- trial was first commenced, patients were also excluded if ment, i.e. vancomycin, or switching to a newer and more they were on vancomycin or daptomycin for more than expensive alternative such as daptomycin in treating 96 h prior to enrolment, were on linezolid, tigecycline or such serious infections. This study was designed as a ceftaroline immediately prior to enrolment, had previous phase 2B randomized controlled trial to evaluate the effi- blood cultures positive for MRSA in the preceding cacy of daptomycin versus vancomycin in reducing month, or if there was more than 48 h between enrol- all-cause mortality in the treatment of MRSA BSIs due ment and reporting by the microbiology laboratory of to isolates with high vancomycin MICs. MRSA BSI with vancomycin MIC ≥ 1.5 μg/ml. Methods Antimicrobial therapy This study was an open-label randomized controlled Participants were randomized to receive either intraven- phase 2B trial conducted in a tertiary hospital in ous daptomycin or vancomycin. Patients in the vanco- Singapore. The trial was granted ethics approval by the mycin arm received a starting dose of 15 mg/kg body Singhealth Centralized Institute Review Board (CIRB) weight of vancomycin infused every 12 h over 2 h with (approval ID 2013/846/E). The trial was registered on appropriate dose adjustments in those with a creatinine ClinicalTrials.gov (NCT01975662). The study protocol clearance < 50 ml/min, so as to achieve a vancomycin Kalimuddin et al. Trials (2018) 19:305 Page 3 of 9 trough level of 15–20 μg/ml. Patients who were on growth of MRSA in blood cultures ≥ 7 days from index vancomycin prior to study inclusion had their doses ad- blood culture) and/or recurrence of MRSA BSI (defined justed accordingly to achieve a vancomycin trough of as a positive blood culture for MRSA at any point in 15–20 μg/ml. This dosing regimen was based on a con- time from the point of microbiological clearance up to sensus statement of the American Society of 60 days from the index blood culture), (ii) Cheng et al. Health-System Pharmacists, the IDSA, and The Society [8] i.e. a composite of microbiologic failure and/or recur- of Infectious Diseases Pharmacists on guidelines for rence of MRSA BSI, and (iii) Murray et al. [9] i.e. a com- vancomycin dosing [12, 13]. posite of all-cause mortality 60 days from index blood Patients randomized to the daptomycin arm with un- culture and/or microbiologic failure; and (2) to compare complicated bacteremia received 6 mg/kg body weight of time to microbiological clearance (defined as two con- daptomycin infused over 30 min every 24 h. This dosing secutive MRSA-negative blood cultures). However, due regimen was based on IDSA guidelines, which recommend to the small number of patients eventually recruited, the a minimum dose of 6 mg/kg of daptomycin every 24 h [4]. investigators felt it would be more relevant to report Some experts however do recommend a higher dose of all-cause mortality, microbiological failure, and recur- 8 mg/kg body weight in complicated infection or treatment rence of MRSA BSI as separate events rather than a failure due to the concentration-dependent effect of dapto- composite. mycin [14, 15]. Hence, daptomycin was dosed at 8 mg/kg Safety endpoints included (1) nephrotoxicity (defined body weight every 24 h in patients with complicated by an increase in serum creatinine level of 50 μmol/L bacteremia or endocarditis. In patients with creatinine from baseline or 50% above baseline), (2) musculoskel- clearance < 30 ml/min or in patients on hemodialysis, dap- etal toxicity (defined by a rise in serum CK of five times tomycin was administered every 48 h as per manufacturer’s the upper limit of normal), (3) the need to stop the study guidelines. There are currently no recommended peak or drug due to toxicity, (4) the need to discontinue study trough levels for daptomycin. drug due to worsening infection, and (5) the need for an Duration of treatment was determined based on the type additional anti-MRSA agent due to worsening infection. of bacteremia. Patients with uncomplicated bacteremia re- ceived a minimum of 14 days antibiotics and those with Assessments complicated bacteremia or infective endocarditis received a Baseline and serial clinical and laboratory data were col- minimum of 28–42 days of antibiotics from the date that lected at specified time points throughout the duration microbiological clearance was achieved. Uncomplicated of the study. Blood cultures were performed daily until bacteremia was defined as the isolation of MRSA from en- two consecutive MRSA-negative sets were achieved. rolment blood cultures in patients without endocarditis Blood tests for full blood count (FBC), creatinine and and without evidence of spread to other organs. Compli- serum CK were taken weekly. A vancomycin trough level cated bacteremia without endocarditis was defined as the was also measured pre the third or fourth dose of vanco- isolation of MRSA from blood cultures beyond 4 days from mycin and then weekly in patients in the vancomycin initial positive culture, the presence of spread of infection, arm. An echocardiogram was performed within the first or infection of prostheses not removed within 4 days. The 10 days of randomization to look for evidence of infect- definition of “definite” or “possibl” endocarditis (compli- ive endocarditis. All participants had a follow-up assess- cated bacteremia) was determined using the modified ment 60 days after the index culture, to determine Duke criteria [16]. mortality status. A repeat blood culture test was also performed at the last visit. Study outcomes The primary objective of this pilot study was to compare Sample size the efficacy of daptomycin versus vancomycin in the Simon’s randomized selection design was used to calcu- treatment of MRSA BSIs due to isolates with high late the sample size [17]. A total of 21 participants per vancomycin MICs (i.e. ≥ 1.5 μg/ml) in terms of all-cause arm were needed so as to guarantee a 90% probability of mortality 60 days from the time of index blood culture. correctly selecting the daptomycin arm as superior to Index blood culture was defined as the first blood cul- the vancomycin arm if it was truly superior by a margin ture which grew MRSA with a vancomycin MIC ≥ of 15%. This was calculated assuming a survival rate of 1.5 μg/ml. 75% at 60 days post index blood culture in the vanco- The planned secondary efficacy end points of the study mycin arm compared to a survival rate of 90% in the were as follows: (1) to compare the rates of “clinical fail- daptomycin arm, based on previously published retro- ure” as per the definitions in studies by (i) Moore et al. spective case–control and cohort studies [7–9]. This [7] i.e. a composite of all-cause mortality 60 days from type of design is to select one of two arms as being index blood culture, microbiologic failure (defined as worthy of further evaluation in a subsequent study but Kalimuddin et al. Trials (2018) 19:305 Page 4 of 9 not to confirm the superiority of the selected arm. As- (expressed as a fraction of the number of subjects), as suming an attrition rate of 20%, the target recruitment appropriate) by treatment group in the intention-to-treat was a minimum of 50 patients over the course of 2 (ITT) analysis population. The frequencies of deaths by years. 60 days post index culture, microbiologic failure, recur- rence of MRSA BSI, nephrotoxicity, musculoskeletal tox- Randomization icity, the need to discontinue study drug due to toxicity Once written informed consent was obtained from all and/or worsening infection, the need to add a second patients or their legally acceptable representatives, pa- anti-MRSA agent due to worsening infection, and the tients were randomized in a 1:1 ratio using permuted time to microbiological clearance were summarized by block randomization stratified by site, with the use of a treatment group and overall in the ITT analysis popula- computer-generated list of random numbers. The tion. The ITT analysis population was defined as all ran- randomization list was generated by the Singapore Clin- domized patients. The treatment group of patients in ical Research Institute (SCRI), with authorized personnel the ITT analysis population was the planned treatment randomizing patients via a direct web randomization group, i.e. according to the randomization list planned system. prior to the study commencement. The frequencies of total adverse and serious adverse events were calculated. Statistical analysis These were calculated for the treated population that A detailed statistical analysis plan was prepared. How- was defined as all randomized subjects who had taken at ever due to slow accrual of participants, the Trial Steer- least one dose of study treatment. The treatment group ing Committee took the decision to terminate the study of subjects in the treated population is according to the on 19 November 2015 before the target sample size treatment actually received after the randomization. could be reached. Given the small number of patients recruited into the study only descriptive analysis was ap- Results propriate. Demographic characteristics and other base- A total of 14 patients were randomized in this study. line characteristics (such as clinical measures taken at Figure 1 displays the allocation of patients into the study baseline) were summarized using descriptive statistics arms. Seven patients were randomized to receive vanco- (medians and interquartile ranges (IQR) or frequencies mycin and seven to receive daptomycin. All patients Fig. 1 Patient allocation into the study populations. “Significant conditions” included any condition in the investigator’s opinion that would compromise the patient’s safety in the trial. Reasons for exclusion listed under “others” included inability to comply with study treatments and procedures (n = 2), inability to provide consent (n = 1), prosthetic heart valve in situ (n = 1), creatine kinase (CK) ≥ 1.5 upper limit of normal (n = 1), on treatment with linezolid for more than 96 h prior to enrolment (n = 1), and patient demise prior to consent (n = 2). MRSA, methicillin-resistant Staphyloccus aureus; MIC, minimum inhibitory concentration Kalimuddin et al. Trials (2018) 19:305 Page 5 of 9 received at least one dose of study medication. A total of conducted. There were more patients in the vancomycin 9/14 patients were recruited after the study exclusion group with chronic kidney disease (3/7 compared to 2/7) criteria were amended (as described in “Study Popula- or both diabetes and chronic kidney disease (3/7 com- tion”): of these 9 patients, 4 would have been previously pared to 2/7). Most (12/14) of the patients were diagnosed excluded as they had been on treatment with vanco- with uncomplicated MRSA bacteremia at the start of the mycin for more than 96 h (but for less than 5 days), study treatment. The majority (12/14) of patients in both prior to randomization. groups received systemic antimicrobial therapy with Baseline characteristics of patients in each treatment vancomycin prior to initiation of the study drug. The arm are summarized in Table 1. Almost three quarters median duration of vancomycin treatment prior to (10/14) of the patients were male and had a median age enrollment was 3.5 days (IQR 3–5days). of 67.5 years (IQR 54.5–71 years): 10/14 patients were of All baseline isolates of MRSA were susceptible to Chinese ethnicity, which was consistent with the racial vancomycin with a MIC of 1.5 μg/ml except for one pa- demographic profile of the country where the study was tient in the vancomycin arm, with a MIC of 2 μg/ml. Median effective duration of treatment with the study drug was 15 days (IQR 14–41 days) in the vancomycin Table 1 Comparison of baseline characteristics between both arm and 15 days (IQR: 14–27 days) in the daptomycin treatment arms arm. There were no deaths in the daptomycin arm and Vancomycin Daptomycin All (n = 14) one death in the vancomycin arm. Overall median time (n =7) (n =7) to microbiological clearance was 4 days (IQR 3–5 days) Age in years (median, IQR) 70 (64, 71) 65 (50, 71) 67.5 (54.5, 71) in the vancomycin arm versus 4 days (IQR 3–7 days) in Age > 65 years 4 3 7 the daptomycin arm. Gender There were no cases of recurrence of MRSA BSI in the Male 5 5 10 daptomycin treatment arm and only one case in the vanco- mycin treatment arm. This was a 70-year-old woman with Female 2 2 4 end-stage renal failure who was on hemodialysis. She had a Ethnicity tunneled dialysis vascular catheter in-situ, which was re- Chinese 4 6 10 moved immediately upon diagnosis of MRSA BSI. She Malay 1 0 1 achieved microbiological clearance within 4 days and a Indian 1 1 2 new dialysis catheter was inserted. She completed a total Others 1 0 1 duration of 14 days of vancomycin for uncomplicated bacteremia. However, 18 days after completion of antibiotic Charlson comorbidity score 5 (4, 7) 5 (4, 8) 5 (4, 7) (median, IQR) therapy she developed another MRSA BSI The vanco- mycin MIC of 1.5 μg/ml remained unchanged. The patient Diabetes mellitus prior to 02 2 screening was treated with daptomycin but developed a maculopapu- CKD prior to screening 3 2 5 lar rash and subsequently completed the rest of her treat- ment with linezolid. Her day-60 blood culture test was Diabetes mellitus and CKD32 5 prior to screening negative. There were no cases of microbiological failure in ei- On vancomycin prior to 57 12 study enrolment ther treatment arm. One of the seven patients in the Duration of vancomycin 3 (3, 5) 4 (3, 5) 3.5 (3, 5) vancomycin arm did not complete the study treatment treatment prior to due to development of a vancomycin allergy, which enrolment, days (median, manifested as maculopapular rash. One of the seven pa- IQR) tients in the daptomycin arm did not complete the study On daptomycin prior to 00 0 treatment due to musculoskeletal toxicity with markedly study enrolment elevated CK. None of the patients in either treatment arm Diagnosis at enrolment required cessation of study treatment or addition of a sec- Uncomplicated bacteremia 7 5 12 ond anti-MRSA agent because of worsening infection. Complicated bacteremia 02 2 One of the seven patients in the daptomycin arm experi- without endocarditis enced musculoskeletal toxicity, compared to none in the Endocarditis 0 0 0 vancomycin arm. None of the patients in the vancomycin Vancomycin MIC (median, 1.5 (1.5, 1.5) 1.5 (1.5, 1.5) 1.5 (1.5, 1.5) arm experienced drug-related nephrotoxicity compared to IQR) one patient in the daptomycin arm. The primary and sec- Data are number of cases, unless otherwise stated ondary efficacy outcomes of the study are summarized in Abbreviations: CKD chronic kidney disease, MIC minimum inhibitory concentration, IQR interquartile range Table 2. Kalimuddin et al. Trials (2018) 19:305 Page 6 of 9 Table 2 Primary and secondary efficacy and safety outcomes Table 3 Adverse events in the treated population Study variables Vancomycin Daptomycin All (n = 14) Vancomycin Daptomycin All (n =7) (n =7) (n =7) (n =7) (n = 14) Day-60 mortality 1 0 1 Serious adverse events 43 7 Microbiological failure 0 0 0 Adverse events Recurrence 1 0 1 Cardiac arrhythmia 2 1 3 Time to microbiological 4 (3, 5) 4 (3, 7) 4 (3, 5) General cardiac 21 3 clearance, days (median, IQR) Constitutional symptoms 02 2 Musculoskeletal toxicity 0 1 1 Dermatologic 30 3 Nephrotoxicity 0 1 1 Adrenal insufficiency 0 1 1 Study drug discontinued due11 2 Eosinophilia 0 1 1 to toxicity Fall 1 1 2 Study drug discontinued due00 0 to worsening infection Nausea and vomiting 0 1 1 Addition of a second MRSA00 0 Anemia 1 1 2 agent due to worsening Infection 34 7 infection Neurological 21 3 Data are number of cases, unless otherwise stated Abbreviations: IQR interquartile range, MRSA methicillin-resistant Pain 2 1 3 staphylococcus bacteremia Hematuria 0 1 1 Data are number of cases In the vancomycin arm this included intracranial hemorrhage, catheter- related infection, acute coronary syndrome and vascular access complication. Overall, adverse events (AEs) were similar in the two In the daptomycin arm this included catheter-related infection and hypotension study arms (Table 3). Of note, 3/7 patients in the vanco- Including adverse events termed “acute coronary event”, “hypotension”, and “pulmonary edema” mycin arm had dermatologic manifestations, compared to Including events termed “somnolence” and “fever” none in the daptomycin arm. These dermatologic mani- Including events termed “rash-maculopapular” and “pruritus” festations included pruritus and maculopapular rash. Including events termed “catheter-related infection” and “urinary tract infection” Including events termed “seizure”, “intracranial hemorrhage”, and “dizziness” There was one death in the vancomycin arm and none in the daptomycin arm. The patient who died was a 71-year-old man with an MRSA BSI due to a urinary tract infection and upper limb cellulitis. His other co- success of treatment with daptomycin versus standard morbidities included ischemic heart disease, sick sinus treatment with vancomycin plus gentamicin in patients syndrome and severe chronic obstructive pulmonary dis- with S. aureus bacteremia and endocarditis [26]. In sub- ease requiring long-term oxygen therapy. On day 2 of set analysis daptomycin had a greater success rate (al- study treatment, the patient suffered a cardiac arrest. though not statistically different) among patients with Prior to his demise, the patient had achieved microbio- MRSA BSI when compared to standard treatment (44% logical clearance. The coroner determined the cause of with daptomycin vs. 31.8% with standard treatment; p = death as ischemic heart disease. 0.28). However, almost all of the MRSA isolates in this study had an MIC ≤ 1 μg/ml, hence it is difficult to con- Discussion clude from these results whether daptomycin is truly su- A rise in MIC to vancomycin within the susceptible perior to vancomycin in the treatment of MRSA range (≤ 2 mg/L) has been observed over recent years infections with high vancomycin MICs. Four retrospect- [18–20]. This phenomenon has been termed “MIC ive studies comparing daptomycin and vancomycin for creep”. Patients with MRSA BSI with a vancomycin MIC BSIs due to MRSA with a high vancomycin MIC demon- ≥ 1.5 μg/ml tend to have higher treatment failure rates strated that daptomycin was associated with a more fa- (ranging from 50 to 90%) compared to those with lower vorable outcome in terms of both clinical success and MIC values [21–25]. A number of studies have also sug- mortality, compared to vancomycin [7–10]. However, gested that vancomycin use, especially in infections these were retrospective studies so the results need to be caused by MRSA with high vancomycin MICs, may be interpreted with caution. associated with poorer clinical outcomes when com- In our randomized study, there was only one death pared with an alternative anti-MRSA agent such as dap- and one case of recurrence of MRSA BSI in the vanco- tomycin [7–10]. mycin arm and none in the daptomycin arm. There were Fowler and colleagues conducted a prospective no cases of microbiological failure in either treatment open-label randomized controlled trial to compare the arm. Overall outcomes in both arms were better than Kalimuddin et al. Trials (2018) 19:305 Page 7 of 9 previously reported in MRSA BSI with a high vanco- This study was initially designed as a multicenter mycin MIC. Earlier studies, which have used varying def- studyinvolving threesites.Although224patients were initions, have reported a success rate of 61to 73% in prescreened in the three institutions, all 14 patients patients with MRSA BSI with high vancomycin MICs were eventually recruited from a single institution. treated with either vancomycin or daptomycin [7, 8]. None of the 54 patients with MRSA BSI prescreened There are a number of possible factors that may have from the other two institutions were eligible for the led to this improved observed outcome. In our study, study - 52 patients had MRSA BSI with vancomycin vancomycin trough levels were measured at strict inter- MIC < 1.5 μg/ml, one patient had polymicrobial vals to ensure levels were maintained within the thera- bacteremia and one patient died before he could be re- peutic window of 15–20 mg/ml. In patients whose cruited. Of the 170 patients prescreened from the even- trough levels were below target, dose adjustments were tual recruiting institution, close to 50% (n = 82) had made in consultation with an infectious disease pharma- MRSA BSI with vancomycin MIC ≥ 1.5 μg/ml but even- cist. As such, vancomcyin under-dosing, which has been tually only 14 patients were randomized. The most associated with poorer outcomes [13], was avoided. Pa- common reasons for exclusion were concomitant pneu- tients with concomitant pneumonia, prosthetic valve monia in 18% (n = 15), exceeding the time allowed on endocarditis and those with less than 24 h of life expect- vancomycin prior to enrolment in 13% (n = 11) and ancy were excluded from our study. These are all condi- polymicrobial bacteremia in 10% (n = 8). There were 18 tions that have been associated with poorer overall patients who were eligible for the study but declined to outcome [27, 28]. In addition, all patients were managed participate. by an infectious disease physician - at least two studies The overall recruitment rate of the study was lower have shown that this is associated with improved out- than expected with fewer patients than initially pro- comes in patients with MRSA BSI [29, 30]. However, jected being eligible for the study. An attempt was due to the small sample size we acknowledge that the made mid-way through the study to improve recruit- improved overall outcome observed may have merely ment by modifying the exclusion criteria (as described been due to chance. earlier) but this did not have a significant impact on One patient in the daptomycin arm developed elevated improving recruitment rates and the investigators felt CK compared to none in the vancomycin arm (Table 3). that allowing further modifications to the exclusion cri- This is consistent with previous studies where CK eleva- teria would adversely affect the safety and integrity of tions were more common in the daptomycin group [7, the study. Nine patients were recruited after modifica- 9, 26]. In our study, three patients in the vancomycin tion of the exclusion criteria and of these, four patients treatment arm had dermatologic manifestations. This is would have been previously excluded. Of note, 11 pa- not unexpected, as cutaneous adverse effects have been tients were excluded because they exceeded the dur- reported to be the commonest adverse events related to ation allowed on vancomycin prior to enrolment (this vancomycin use [31–33]. Nephrotoxicity is often a con- was initially capped at 96 h and subsequently increased cern with vancomycin, especially in patients with under- to 5 days mid-way through the study to try and im- lying renal insufficiency. However, none of the patients prove enrolment). As part of our institutional practice, in the vancomycin arm developed significant increases a large proportion of patients are prescribed empirical in serum creatinine despite the majority having chronic vancomycin therapy on admission if they have signs of kidney disease. In our study, vancomycin trough levels infection and have had recent healthcare contact. Many were monitored regularly and maintained within a tight of these patients would have received more than 4–5 therapeutic window of 15–20 μg/ml. In addition, none days of vancomycin therapy by the time the vanco- of the patients received concomitant treatment with an mycin MIC result was known, making them ineligible aminoglycoside, which has been shown to increase rates for the study. The investigators felt that extending the of nephrotoxicity [34]. In contrast, one patient in the period allowed on vancomycin therapy beyond 5 days daptomycin arm experienced nephrotoxicity, which was would make it impossible for daptomycin efficacy to be deemed by the study investigators to be “possibly re- assessed with sufficient rigor. Attempts were also made lated” to daptomycin. To our knowledge, daptomycin in- to increase the number of enrolment sites but these duced nephrotoxicity has not been previously reported. proved unsuccessful, mainly due to the small baseline This patient was concomitantly receiving high-dose numbers of patients with MRSA bacteremia at these diuretics, which may have led to dehydration and smaller sites. After consultation with the trial steering pre-renal impairment. In addition, the patient’s serum committee, a decision was made to terminate the study creatinine returned to baseline without cessation of early as it was felt that it would not be realistically pos- study drug. Hence, it remains unclear if the patient’s sible to achieve the target sample size within the allo- renal impairment was truly caused by daptomycin. cated funding period. Kalimuddin et al. Trials (2018) 19:305 Page 8 of 9 Conclusions data analysis and interpretation. All authors were involved in preparation of the manuscript (via critical review) and approved the final version. In summary, based on current available evidence, it re- mains unclear if alternative, newer and more expensive Ethics approval and consent to participate agents such as daptomycin are truly superior to vanco- The trial was granted ethics approval by the Singhealth Centralized Institute Review Board (CIRB) (approval ID 2013/846/E). Written informed consent was mycin in the treatment of BSI due to MRSA with high obtained from all patients before enrolment into the study. vancomycin MIC. The question of what should be the optimal recommended treatment for such infections re- Competing interests mains important to answer, and more studies are ur- The authors declare that they have no competing interests. gently needed. However, randomized controlled trials evaluating this are complicated and difficult to execute - Publisher’sNote primarily due to the heterogeneous and complex patient Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. profile associated with MRSA BSI. Enrolment rates are likely to be low and multicenter trials providing a large Author details patient pool will be needed to achieve sufficient patient Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore. School of Population Health and recruitment for an adequately powered study. An alter- Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College native to such conventional randomized controlled trials 3 London, Guy’s Campus, London SE1 1UL, UK. NIHR Biomedical Research may be pragmatic adaptive platform trials - such novel Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London, Guy’s Hospital, London SE1 9RT, UK. Geriatric Education and methodologies are already being employed successfully Research Institute, 2 Yishun Central 2, Singapore 768024, Singapore. Division in oncology trials [35–37]. Platform studies make use of of Infectious Diseases, National University Health System, 5 Lower Kent Ridge a universal trial master protocol to study the optimal Rd, Singapore 119074, Singapore. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 21 Lower Kent Ridge treatment for a disease and its subgroups, while the Rd, Singapore 119077, Singapore. Department of Infectious Diseases, pragmatic design embeds the trial in routine provision Communicable Disease Centre, Tan Tock Seng Hospital, 11 Jalan Tan Tock of care and allows for minimal exclusion criteria, in turn Seng, Singapore 308433, Singapore. improving recruitment rates. In addition, the use of Received: 30 November 2017 Accepted: 21 May 2018 response-adaptive randomization results in greater prob- ability of patients in a particular sub-group being ran- domized to interventions that are performing better References 1. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, within that sub-group [37, 38]. Thus, better therapies Carmeli Y. Comparison of mortality associated with methicillin-resistant and move through the evaluation process faster, resulting in methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. greater trial efficiency. Investigators interested in evalu- Clin Infect Dis. 2003;36(1):53–9. 2. Ben-David D, Novikov I, Mermel LA. Are there differences in hospital cost ating the optimal treatment for MRSA bacteremia may between patients with nosocomial methicillin-resistant Staphylococcus wish to consider employing such novel trial methodolo- aureus bloodstream infection and those with methicillin-susceptible S. gies, so as to ensure a greater chance of success. aureus bloodstream infection? Infect Control Hosp Epidemiol. 2009;30(5): 453–60. Abbreviations 3. Rodvold KA, McConeghy KW. Methicillin-resistant Staphylococcus aureus AEs: Adverse events; BSI: Bloodstream infection; CIRB: Centralized Institute therapy: past, present and future. Clin Infect Dis. 2014;58(Suppl 1):S20–7. Review Board; CK: Creatine kinase; FBC: Full blood count; IQR: Interquartile 4. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical range; ITT: Intention to treat; MIC: Minimum inhibitory concentration; practice guidelines by the Infectious Diseases Society of America for the MRSA: Methicillin-resistant Staphylococcus aureus; SCRI: Singapore Clinical treatment of methicillin-resistant Staphylococcus aureus infections in adults Research Institute and children. Clin Infect Dis. 2011;52(3):e18–55. 5. Barry AL, Fuchs PC, Brown SD. In vitro activities of daptomycin against 2,789 Acknowledgements clinical isolates from 11 north American medical centers. Antimicrob Agents The authors thank the Singapore Clinical Research Network (SCRN) for their Chemother. 2001;45(6):1919–22. support throughout the study, in particular Ms Ding Ying and Ms Siew Hwa 6. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating Soh. We thank the study participants for volunteering their time and research infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. coordinators Ms Christina Titin and Ms Abigail Soh for their dedication and hard 2004;38(7):994–1000. work throughout the study. 7. Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos MJ. Daptomycin versus vancomycin for bloodstream infections due to Funding methicillin-resistant Staphylococcus aureus with a high vancomycin This work was funded by the Ministry of Health, Singapore, awarded through minimum inhibitory concentration: a case-control study. Clin Infect Dis. the Singapore Infectious Disease Initiative grant (SIDI/2013/007). The funders 2012;54(1):51–8. had no role in study design, data collection, or the decision to submit the 8. Cheng CW, Hsu PC, Yang CC, Chang HJ, Siu LK, Wu TL, et al. Influence of work for publication. early daptomycin therapy on treatment outcome of methicillin-resistant Staphylococcus aureus bacteraemia with high vancomycin minimum Availability of data and materials inhibitory concentrations. Int J Antimicrob Agents. 2013;41(3):293–4. The datasets used and/or analyzed during the current study are available 9. Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P, et al. Early use of from the corresponding author on reasonable request. daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 Authors’ contributions mg/L: a matched cohort study. Clin Infect Dis. 2013;56(11):1562–9. SK, SA, TTT, and JGHL were study investigators. SK, TTT, and RP were involved in 10. Claeys KC, Zasowski EJ, Casapao AM, Lagnf AM, Nagel JL, Nguyen CT, et al. the study concept and design. SK, SPO, YFZC, RP, and JGHL were involved in Daptomycin improves outcomes regardless of vancomycin MIC in a Kalimuddin et al. Trials (2018) 19:305 Page 9 of 9 propensity-matched analysis of methicillin-resistant Staphylococcus aureus 30. Lahey T, Shah R, Gittzus J, Schwartzman J, Kirkland K. Infectious diseases bloodstream infections. Antimicrob Agents Chemother. 2016;60(10):5841–8. consultation lowers mortality from Staphylococcus aureus bacteremia. 11. Kalimuddin S, Phillips R, Gandhi M, de Souza NN, Low JG, Archuleta S, et al. Medicine. 2009;88(5):263–7. Vancomycin versus daptomycin for the treatment of methicillin-resistant 31. O'Sullivan TL, Ruffing MJ, Lamp KC, Warbasse LH, Rybak MJ. Prospective Staphylococcus aureus bacteremia due to isolates with high vancomycin evaluation of red man syndrome in patients receiving vancomycin. J Infect minimum inhibitory concentrations: study protocol for a phase IIB Dis. 1993;168(3):773–6. randomized controlled trial. Trials. 2014;15:233. 32. Polk RE, Healy DP, Schwartz LB, Rock DT, Garson ML, Roller K. Vancomycin and the red-man syndrome: pharmacodynamics of histamine release. J 12. Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC Jr, Craig WA, Billeter Infect Dis. 1988;157(3):502–7. M, et al. Therapeutic monitoring of vancomycin in adults summary of 33. Wallace MR, Mascola JR, Oldfield EC 3rd. Red man syndrome: incidence, consensus recommendations from the American Society of Health-System etiology, and prophylaxis. J Infect Dis. 1991;164(6):1180–5. Pharmacists, the Infectious Diseases Society of America, and the Society of 34. Hazlewood KA, Brouse SD, Pitcher WD, Hall RG. Vancomycin-associated Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29(11):1275–9. nephrotoxicity: grave concern or death by character assassination? Am J 13. Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC, Craig WA, Billeter M, Med. 2010;123(2):182.e1–7. et al. Vancomycin therapeutic guidelines: a summary of consensus 35. Ford I, Norrie J. Pragmatic Trials. N Engl J Med. 2016;375(5):454–63. recommendations from the Infectious Diseases Society of America, the 36. Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for American Society of Health-System Pharmacists, and the Society of evaluating multiple treatments. JAMA. 2015;313(16):1619–20. Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325–7. 37. Saville BR, Berry SM. Efficiencies of platform clinical trials: a vision of the 14. Figueroa DA, Mangini E, Amodio-Groton M, Vardianos B, Melchert A, Fana C, future. Clin Trials. 2016;13(3):358–66. et al. Safety of high-dose intravenous daptomycin treatment: three-year 38. Berry DA. Adaptive clinical trials in oncology. Nat Rev Clin Oncol. 2011;9(4): cumulative experience in a clinical program. Clin Infect Dis. 2009;49(2):177–80. 199–207. 15. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother. 2006;50(10):3245–9. 16. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30(4):633–8. 17. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep. 1985;69(12):1375–81. 18. Chang W, Ma X, Gao P, Lv X, Lu H, Chen F. Vancomycin MIC creep in methicillin-resistant Staphylococcus aureus (MRSA) isolates from 2006 to 2010 in a hospital in China. Indian J Med Microbiol. 2015;33(2):262–6. 19. Miller CE, Batra R, Cooper BS, Patel AK, Klein J, Otter JA, et al. An association between bacterial genotype combined with a high-vancomycin minimum inhibitory concentration and risk of endocarditis in methicillin-resistant Staphylococcus aureus bloodstream infection. Clin Infect Dis. 2012;54(5): 591–600. 20. Sader HS, Fey PD, Limaye AP, Madinger N, Pankey G, Rahal J, et al. Evaluation of vancomycin and daptomycin potency trends (MIC creep) against methicillin-resistant Staphylococcus aureus isolates collected in nine U.S. medical centers from 2002 to 2006. Antimicrob Agents Chemother. 2009;53(10):4127–32. 21. Moise PA, Sakoulas G, Forrest A, Schentag JJ. Vancomycin in vitro bactericidal activity and its relationship to efficacy in clearance of methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2007;51(7):2582–6. 22. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol. 2004;42(6):2398–402. 23. Takesue Y, Nakajima K, Takahashi Y, Ichiki K, Ishihara M, Wada Y, et al. Clinical characteristics of vancomycin minimum inhibitory concentration of 2 mug/ml methicillin-resistant Staphylococcus aureus strains isolated from patients with bacteremia. J Infect Chemother. 2011;17(1):52–7. 24. van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis. 2012;54(6):755–71. 25. Yoon YK, Kim JY, Park DW, Sohn JW, Kim MJ. Predictors of persistent methicillin-resistant Staphylococcus aureus bacteraemia in patients treated with vancomycin. J Antimicrob Chemother. 2010;65(5):1015–8. 26. Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355(7):653–65. 27. Hill EE, Herijgers P, Claus P, Vanderschueren S, Herregods MC, Peetermans WE. Infective endocarditis: changing epidemiology and predictors of 6-month mortality: a prospective cohort study. Eur Heart J. 2007;28(2):196–203. 28. Rubinstein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin- resistant Staphylococcus aureus. Clin Infect Dis. 2008;46(Suppl 5):S378–85. 29. Fries BL, Licitra C, Crespo A, Akhter K, Busowski MT, Salazar D, et al. Infectious diseases consultation and the management of Staphylococcus aureus bacteremia. Clin Infect Dis. 2014;58(4):598–9. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Trials Springer Journals

A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations – results of a prematurely terminated study

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Medicine & Public Health; Medicine/Public Health, general; Biomedicine, general; Statistics for Life Sciences, Medicine, Health Sciences
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Abstract

Background: Studies have suggested the reduced effectiveness of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections with high vancomycin minimum inhibitory concentrations. Alternative agents such as daptomycin may be considered. We conducted a randomized controlled study comparing daptomycin against vancomycin in the treatment of MRSA bloodstream infections with high vancomycin minimum inhibitory concentrations. Methods: Patients were randomized to receive vancomycin or daptomycin for a minimum of 14 days. The primary end point was the rate of all-cause mortality at day 60. Results: A total of 14 patients were randomized in this study, with 7 patients in each treatment arm. The study was terminated early due to slow patient accrual. At day 60, there was one death in the vancomycin arm and none in the daptomycin arm. The median time to microbiological clearance was 4 days in both arms (IQR 3–5days inthe vancomycin arm and 3–7 days in daptomycin arm). Only one patient in the vancomycin arm had recurrence of bacteremia. Rates of adverse events were similar in botharms. Therewas onecaseofmusculoskeletal toxicity and one case of drug-related nephrotoxicity - both events occurred in the daptomycin arm. None of the patients in either treatment arm required cessation of study treatment or addition of a second anti-MRSA agent because of worsening infection. Conclusion: Based on the limited number of patients evaluated in this study, it remains unclear if alternative, more expensive agents such as daptomycin are superior to vancomycin in the treatment of high vancomycin minimum inhibitory concentration MRSA bloodstream infections. More studies are urgently needed but investigators may wish to consider employing novel, alternative trial methodologies to ensure a greater chance of success. (Continued on next page) * Correspondence: shirin.kalimuddin@singhealth.com.sg Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kalimuddin et al. Trials (2018) 19:305 Page 2 of 9 (Continued from previous page) Trial registration: ClinicalTrials.gov, NCT01975662. Registered on 5 November 2013. Keywords: Methicillin-resistant Staphylococcus aureus, Vancomycin, Daptomycin, Minimum inhibitory concentration, Bacteremia Background was published in Trials [11]. Subjects were first enrolled Staphylococcus aureus is one of the most common human on 13 February 2014 with the last subject visit on 25 pathogens that cause a wide range of clinical infections September 2015. worldwide. Infections caused by methicillin-resistant S. aur- eas (MRSA) are associated with increased mortality and Study population morbidity and increased length and cost of hospitalization Patients were eligible for the study if they were ≥ 21 years [1, 2]. Moreover, because MRSA is multidrug resistant, it of age, were inpatients at the time of enrolment and had leaves clinicians with few effective antimicrobial options [3]. a BSI due to MRSA with a vancomycin MIC ≥ 1.5 μg/ml Treating S. aureus infections has become increasing chal- but < 2 μg/ml as determined by the Epsilometer test lenging in recent, with the emergence of highly virulent (E-test) or the VITEK™-2 system (bioMerieux, Marcy MRSA strains. l’Etoile, France). Patients were excluded if they were al- Vancomycin, a tricyclic glycopeptide, is the standard lergic to vancomycin or daptomycin, pregnant or breast- first line treatment for patients with MRSA bloodstream feeding, unable to comply with study treatments and infections (BSI). Consensus guidelines, however, recom- procedures, unable to provide consent or had no legally mend clinicians to consider alternative agents for MRSA authorized representatives, currently enrolled in or had infections when the vancomycin minimum inhibitory con- participated in an interventional antibiotic or vaccine centration (MIC) is > 1 μg/ml, especially when clinical fail- trial within the past 3 months, expected to have less ure is suspected with vancomycin treatment [4]. One such than 24 h of life expectancy, polymicrobial bacteremia, alternative agent is daptomycin - a calcium-dependent pneumonia, receiving treatment with linezolid, tigecyline cyclic lipopeptide that is rapidly bactericidal against many or ceftaroline for more than 96 h prior to enrolment, re- gram-positive organisms including MRSA [5, 6]. A num- ceiving vancomycin or daptomycin treatment for more ber of recent studies have also suggested that vancomycin than 5 days prior to enrolment, or if they had baseline use, especially in infections caused by MRSA with high serum creatine kinase (CK) more than 1.5 times the vancomycin MICs, may be associated with poorer clinical upper limit of normal, presence of prosthetic heart outcomes when compared with an alternative anti-MRSA valves, or any other significant condition that would, in agent such as daptomycin; however, these were retrospect- the opinion of the investigator, compromise the patient’s ive and non- randomized studies [7–10]. safety or outcome of the trial. The study exclusion cri- To date, there has been no head-to-head randomized teria were amended from the published protocol [11]on trial comparing the safety and efficacy of daptomycin 7 August 2014 after consultation with the trial steering and vancomycin in the treatment of BSIs due to MRSA committee in an effort to improve recruitment, without with high vancomycin MICs. Clinicians are often faced compromising the rigor of the study design. When the with the dilemma of using the cheaper standard treat- trial was first commenced, patients were also excluded if ment, i.e. vancomycin, or switching to a newer and more they were on vancomycin or daptomycin for more than expensive alternative such as daptomycin in treating 96 h prior to enrolment, were on linezolid, tigecycline or such serious infections. This study was designed as a ceftaroline immediately prior to enrolment, had previous phase 2B randomized controlled trial to evaluate the effi- blood cultures positive for MRSA in the preceding cacy of daptomycin versus vancomycin in reducing month, or if there was more than 48 h between enrol- all-cause mortality in the treatment of MRSA BSIs due ment and reporting by the microbiology laboratory of to isolates with high vancomycin MICs. MRSA BSI with vancomycin MIC ≥ 1.5 μg/ml. Methods Antimicrobial therapy This study was an open-label randomized controlled Participants were randomized to receive either intraven- phase 2B trial conducted in a tertiary hospital in ous daptomycin or vancomycin. Patients in the vanco- Singapore. The trial was granted ethics approval by the mycin arm received a starting dose of 15 mg/kg body Singhealth Centralized Institute Review Board (CIRB) weight of vancomycin infused every 12 h over 2 h with (approval ID 2013/846/E). The trial was registered on appropriate dose adjustments in those with a creatinine ClinicalTrials.gov (NCT01975662). The study protocol clearance < 50 ml/min, so as to achieve a vancomycin Kalimuddin et al. Trials (2018) 19:305 Page 3 of 9 trough level of 15–20 μg/ml. Patients who were on growth of MRSA in blood cultures ≥ 7 days from index vancomycin prior to study inclusion had their doses ad- blood culture) and/or recurrence of MRSA BSI (defined justed accordingly to achieve a vancomycin trough of as a positive blood culture for MRSA at any point in 15–20 μg/ml. This dosing regimen was based on a con- time from the point of microbiological clearance up to sensus statement of the American Society of 60 days from the index blood culture), (ii) Cheng et al. Health-System Pharmacists, the IDSA, and The Society [8] i.e. a composite of microbiologic failure and/or recur- of Infectious Diseases Pharmacists on guidelines for rence of MRSA BSI, and (iii) Murray et al. [9] i.e. a com- vancomycin dosing [12, 13]. posite of all-cause mortality 60 days from index blood Patients randomized to the daptomycin arm with un- culture and/or microbiologic failure; and (2) to compare complicated bacteremia received 6 mg/kg body weight of time to microbiological clearance (defined as two con- daptomycin infused over 30 min every 24 h. This dosing secutive MRSA-negative blood cultures). However, due regimen was based on IDSA guidelines, which recommend to the small number of patients eventually recruited, the a minimum dose of 6 mg/kg of daptomycin every 24 h [4]. investigators felt it would be more relevant to report Some experts however do recommend a higher dose of all-cause mortality, microbiological failure, and recur- 8 mg/kg body weight in complicated infection or treatment rence of MRSA BSI as separate events rather than a failure due to the concentration-dependent effect of dapto- composite. mycin [14, 15]. Hence, daptomycin was dosed at 8 mg/kg Safety endpoints included (1) nephrotoxicity (defined body weight every 24 h in patients with complicated by an increase in serum creatinine level of 50 μmol/L bacteremia or endocarditis. In patients with creatinine from baseline or 50% above baseline), (2) musculoskel- clearance < 30 ml/min or in patients on hemodialysis, dap- etal toxicity (defined by a rise in serum CK of five times tomycin was administered every 48 h as per manufacturer’s the upper limit of normal), (3) the need to stop the study guidelines. There are currently no recommended peak or drug due to toxicity, (4) the need to discontinue study trough levels for daptomycin. drug due to worsening infection, and (5) the need for an Duration of treatment was determined based on the type additional anti-MRSA agent due to worsening infection. of bacteremia. Patients with uncomplicated bacteremia re- ceived a minimum of 14 days antibiotics and those with Assessments complicated bacteremia or infective endocarditis received a Baseline and serial clinical and laboratory data were col- minimum of 28–42 days of antibiotics from the date that lected at specified time points throughout the duration microbiological clearance was achieved. Uncomplicated of the study. Blood cultures were performed daily until bacteremia was defined as the isolation of MRSA from en- two consecutive MRSA-negative sets were achieved. rolment blood cultures in patients without endocarditis Blood tests for full blood count (FBC), creatinine and and without evidence of spread to other organs. Compli- serum CK were taken weekly. A vancomycin trough level cated bacteremia without endocarditis was defined as the was also measured pre the third or fourth dose of vanco- isolation of MRSA from blood cultures beyond 4 days from mycin and then weekly in patients in the vancomycin initial positive culture, the presence of spread of infection, arm. An echocardiogram was performed within the first or infection of prostheses not removed within 4 days. The 10 days of randomization to look for evidence of infect- definition of “definite” or “possibl” endocarditis (compli- ive endocarditis. All participants had a follow-up assess- cated bacteremia) was determined using the modified ment 60 days after the index culture, to determine Duke criteria [16]. mortality status. A repeat blood culture test was also performed at the last visit. Study outcomes The primary objective of this pilot study was to compare Sample size the efficacy of daptomycin versus vancomycin in the Simon’s randomized selection design was used to calcu- treatment of MRSA BSIs due to isolates with high late the sample size [17]. A total of 21 participants per vancomycin MICs (i.e. ≥ 1.5 μg/ml) in terms of all-cause arm were needed so as to guarantee a 90% probability of mortality 60 days from the time of index blood culture. correctly selecting the daptomycin arm as superior to Index blood culture was defined as the first blood cul- the vancomycin arm if it was truly superior by a margin ture which grew MRSA with a vancomycin MIC ≥ of 15%. This was calculated assuming a survival rate of 1.5 μg/ml. 75% at 60 days post index blood culture in the vanco- The planned secondary efficacy end points of the study mycin arm compared to a survival rate of 90% in the were as follows: (1) to compare the rates of “clinical fail- daptomycin arm, based on previously published retro- ure” as per the definitions in studies by (i) Moore et al. spective case–control and cohort studies [7–9]. This [7] i.e. a composite of all-cause mortality 60 days from type of design is to select one of two arms as being index blood culture, microbiologic failure (defined as worthy of further evaluation in a subsequent study but Kalimuddin et al. Trials (2018) 19:305 Page 4 of 9 not to confirm the superiority of the selected arm. As- (expressed as a fraction of the number of subjects), as suming an attrition rate of 20%, the target recruitment appropriate) by treatment group in the intention-to-treat was a minimum of 50 patients over the course of 2 (ITT) analysis population. The frequencies of deaths by years. 60 days post index culture, microbiologic failure, recur- rence of MRSA BSI, nephrotoxicity, musculoskeletal tox- Randomization icity, the need to discontinue study drug due to toxicity Once written informed consent was obtained from all and/or worsening infection, the need to add a second patients or their legally acceptable representatives, pa- anti-MRSA agent due to worsening infection, and the tients were randomized in a 1:1 ratio using permuted time to microbiological clearance were summarized by block randomization stratified by site, with the use of a treatment group and overall in the ITT analysis popula- computer-generated list of random numbers. The tion. The ITT analysis population was defined as all ran- randomization list was generated by the Singapore Clin- domized patients. The treatment group of patients in ical Research Institute (SCRI), with authorized personnel the ITT analysis population was the planned treatment randomizing patients via a direct web randomization group, i.e. according to the randomization list planned system. prior to the study commencement. The frequencies of total adverse and serious adverse events were calculated. Statistical analysis These were calculated for the treated population that A detailed statistical analysis plan was prepared. How- was defined as all randomized subjects who had taken at ever due to slow accrual of participants, the Trial Steer- least one dose of study treatment. The treatment group ing Committee took the decision to terminate the study of subjects in the treated population is according to the on 19 November 2015 before the target sample size treatment actually received after the randomization. could be reached. Given the small number of patients recruited into the study only descriptive analysis was ap- Results propriate. Demographic characteristics and other base- A total of 14 patients were randomized in this study. line characteristics (such as clinical measures taken at Figure 1 displays the allocation of patients into the study baseline) were summarized using descriptive statistics arms. Seven patients were randomized to receive vanco- (medians and interquartile ranges (IQR) or frequencies mycin and seven to receive daptomycin. All patients Fig. 1 Patient allocation into the study populations. “Significant conditions” included any condition in the investigator’s opinion that would compromise the patient’s safety in the trial. Reasons for exclusion listed under “others” included inability to comply with study treatments and procedures (n = 2), inability to provide consent (n = 1), prosthetic heart valve in situ (n = 1), creatine kinase (CK) ≥ 1.5 upper limit of normal (n = 1), on treatment with linezolid for more than 96 h prior to enrolment (n = 1), and patient demise prior to consent (n = 2). MRSA, methicillin-resistant Staphyloccus aureus; MIC, minimum inhibitory concentration Kalimuddin et al. Trials (2018) 19:305 Page 5 of 9 received at least one dose of study medication. A total of conducted. There were more patients in the vancomycin 9/14 patients were recruited after the study exclusion group with chronic kidney disease (3/7 compared to 2/7) criteria were amended (as described in “Study Popula- or both diabetes and chronic kidney disease (3/7 com- tion”): of these 9 patients, 4 would have been previously pared to 2/7). Most (12/14) of the patients were diagnosed excluded as they had been on treatment with vanco- with uncomplicated MRSA bacteremia at the start of the mycin for more than 96 h (but for less than 5 days), study treatment. The majority (12/14) of patients in both prior to randomization. groups received systemic antimicrobial therapy with Baseline characteristics of patients in each treatment vancomycin prior to initiation of the study drug. The arm are summarized in Table 1. Almost three quarters median duration of vancomycin treatment prior to (10/14) of the patients were male and had a median age enrollment was 3.5 days (IQR 3–5days). of 67.5 years (IQR 54.5–71 years): 10/14 patients were of All baseline isolates of MRSA were susceptible to Chinese ethnicity, which was consistent with the racial vancomycin with a MIC of 1.5 μg/ml except for one pa- demographic profile of the country where the study was tient in the vancomycin arm, with a MIC of 2 μg/ml. Median effective duration of treatment with the study drug was 15 days (IQR 14–41 days) in the vancomycin Table 1 Comparison of baseline characteristics between both arm and 15 days (IQR: 14–27 days) in the daptomycin treatment arms arm. There were no deaths in the daptomycin arm and Vancomycin Daptomycin All (n = 14) one death in the vancomycin arm. Overall median time (n =7) (n =7) to microbiological clearance was 4 days (IQR 3–5 days) Age in years (median, IQR) 70 (64, 71) 65 (50, 71) 67.5 (54.5, 71) in the vancomycin arm versus 4 days (IQR 3–7 days) in Age > 65 years 4 3 7 the daptomycin arm. Gender There were no cases of recurrence of MRSA BSI in the Male 5 5 10 daptomycin treatment arm and only one case in the vanco- mycin treatment arm. This was a 70-year-old woman with Female 2 2 4 end-stage renal failure who was on hemodialysis. She had a Ethnicity tunneled dialysis vascular catheter in-situ, which was re- Chinese 4 6 10 moved immediately upon diagnosis of MRSA BSI. She Malay 1 0 1 achieved microbiological clearance within 4 days and a Indian 1 1 2 new dialysis catheter was inserted. She completed a total Others 1 0 1 duration of 14 days of vancomycin for uncomplicated bacteremia. However, 18 days after completion of antibiotic Charlson comorbidity score 5 (4, 7) 5 (4, 8) 5 (4, 7) (median, IQR) therapy she developed another MRSA BSI The vanco- mycin MIC of 1.5 μg/ml remained unchanged. The patient Diabetes mellitus prior to 02 2 screening was treated with daptomycin but developed a maculopapu- CKD prior to screening 3 2 5 lar rash and subsequently completed the rest of her treat- ment with linezolid. Her day-60 blood culture test was Diabetes mellitus and CKD32 5 prior to screening negative. There were no cases of microbiological failure in ei- On vancomycin prior to 57 12 study enrolment ther treatment arm. One of the seven patients in the Duration of vancomycin 3 (3, 5) 4 (3, 5) 3.5 (3, 5) vancomycin arm did not complete the study treatment treatment prior to due to development of a vancomycin allergy, which enrolment, days (median, manifested as maculopapular rash. One of the seven pa- IQR) tients in the daptomycin arm did not complete the study On daptomycin prior to 00 0 treatment due to musculoskeletal toxicity with markedly study enrolment elevated CK. None of the patients in either treatment arm Diagnosis at enrolment required cessation of study treatment or addition of a sec- Uncomplicated bacteremia 7 5 12 ond anti-MRSA agent because of worsening infection. Complicated bacteremia 02 2 One of the seven patients in the daptomycin arm experi- without endocarditis enced musculoskeletal toxicity, compared to none in the Endocarditis 0 0 0 vancomycin arm. None of the patients in the vancomycin Vancomycin MIC (median, 1.5 (1.5, 1.5) 1.5 (1.5, 1.5) 1.5 (1.5, 1.5) arm experienced drug-related nephrotoxicity compared to IQR) one patient in the daptomycin arm. The primary and sec- Data are number of cases, unless otherwise stated ondary efficacy outcomes of the study are summarized in Abbreviations: CKD chronic kidney disease, MIC minimum inhibitory concentration, IQR interquartile range Table 2. Kalimuddin et al. Trials (2018) 19:305 Page 6 of 9 Table 2 Primary and secondary efficacy and safety outcomes Table 3 Adverse events in the treated population Study variables Vancomycin Daptomycin All (n = 14) Vancomycin Daptomycin All (n =7) (n =7) (n =7) (n =7) (n = 14) Day-60 mortality 1 0 1 Serious adverse events 43 7 Microbiological failure 0 0 0 Adverse events Recurrence 1 0 1 Cardiac arrhythmia 2 1 3 Time to microbiological 4 (3, 5) 4 (3, 7) 4 (3, 5) General cardiac 21 3 clearance, days (median, IQR) Constitutional symptoms 02 2 Musculoskeletal toxicity 0 1 1 Dermatologic 30 3 Nephrotoxicity 0 1 1 Adrenal insufficiency 0 1 1 Study drug discontinued due11 2 Eosinophilia 0 1 1 to toxicity Fall 1 1 2 Study drug discontinued due00 0 to worsening infection Nausea and vomiting 0 1 1 Addition of a second MRSA00 0 Anemia 1 1 2 agent due to worsening Infection 34 7 infection Neurological 21 3 Data are number of cases, unless otherwise stated Abbreviations: IQR interquartile range, MRSA methicillin-resistant Pain 2 1 3 staphylococcus bacteremia Hematuria 0 1 1 Data are number of cases In the vancomycin arm this included intracranial hemorrhage, catheter- related infection, acute coronary syndrome and vascular access complication. Overall, adverse events (AEs) were similar in the two In the daptomycin arm this included catheter-related infection and hypotension study arms (Table 3). Of note, 3/7 patients in the vanco- Including adverse events termed “acute coronary event”, “hypotension”, and “pulmonary edema” mycin arm had dermatologic manifestations, compared to Including events termed “somnolence” and “fever” none in the daptomycin arm. These dermatologic mani- Including events termed “rash-maculopapular” and “pruritus” festations included pruritus and maculopapular rash. Including events termed “catheter-related infection” and “urinary tract infection” Including events termed “seizure”, “intracranial hemorrhage”, and “dizziness” There was one death in the vancomycin arm and none in the daptomycin arm. The patient who died was a 71-year-old man with an MRSA BSI due to a urinary tract infection and upper limb cellulitis. His other co- success of treatment with daptomycin versus standard morbidities included ischemic heart disease, sick sinus treatment with vancomycin plus gentamicin in patients syndrome and severe chronic obstructive pulmonary dis- with S. aureus bacteremia and endocarditis [26]. In sub- ease requiring long-term oxygen therapy. On day 2 of set analysis daptomycin had a greater success rate (al- study treatment, the patient suffered a cardiac arrest. though not statistically different) among patients with Prior to his demise, the patient had achieved microbio- MRSA BSI when compared to standard treatment (44% logical clearance. The coroner determined the cause of with daptomycin vs. 31.8% with standard treatment; p = death as ischemic heart disease. 0.28). However, almost all of the MRSA isolates in this study had an MIC ≤ 1 μg/ml, hence it is difficult to con- Discussion clude from these results whether daptomycin is truly su- A rise in MIC to vancomycin within the susceptible perior to vancomycin in the treatment of MRSA range (≤ 2 mg/L) has been observed over recent years infections with high vancomycin MICs. Four retrospect- [18–20]. This phenomenon has been termed “MIC ive studies comparing daptomycin and vancomycin for creep”. Patients with MRSA BSI with a vancomycin MIC BSIs due to MRSA with a high vancomycin MIC demon- ≥ 1.5 μg/ml tend to have higher treatment failure rates strated that daptomycin was associated with a more fa- (ranging from 50 to 90%) compared to those with lower vorable outcome in terms of both clinical success and MIC values [21–25]. A number of studies have also sug- mortality, compared to vancomycin [7–10]. However, gested that vancomycin use, especially in infections these were retrospective studies so the results need to be caused by MRSA with high vancomycin MICs, may be interpreted with caution. associated with poorer clinical outcomes when com- In our randomized study, there was only one death pared with an alternative anti-MRSA agent such as dap- and one case of recurrence of MRSA BSI in the vanco- tomycin [7–10]. mycin arm and none in the daptomycin arm. There were Fowler and colleagues conducted a prospective no cases of microbiological failure in either treatment open-label randomized controlled trial to compare the arm. Overall outcomes in both arms were better than Kalimuddin et al. Trials (2018) 19:305 Page 7 of 9 previously reported in MRSA BSI with a high vanco- This study was initially designed as a multicenter mycin MIC. Earlier studies, which have used varying def- studyinvolving threesites.Although224patients were initions, have reported a success rate of 61to 73% in prescreened in the three institutions, all 14 patients patients with MRSA BSI with high vancomycin MICs were eventually recruited from a single institution. treated with either vancomycin or daptomycin [7, 8]. None of the 54 patients with MRSA BSI prescreened There are a number of possible factors that may have from the other two institutions were eligible for the led to this improved observed outcome. In our study, study - 52 patients had MRSA BSI with vancomycin vancomycin trough levels were measured at strict inter- MIC < 1.5 μg/ml, one patient had polymicrobial vals to ensure levels were maintained within the thera- bacteremia and one patient died before he could be re- peutic window of 15–20 mg/ml. In patients whose cruited. Of the 170 patients prescreened from the even- trough levels were below target, dose adjustments were tual recruiting institution, close to 50% (n = 82) had made in consultation with an infectious disease pharma- MRSA BSI with vancomycin MIC ≥ 1.5 μg/ml but even- cist. As such, vancomcyin under-dosing, which has been tually only 14 patients were randomized. The most associated with poorer outcomes [13], was avoided. Pa- common reasons for exclusion were concomitant pneu- tients with concomitant pneumonia, prosthetic valve monia in 18% (n = 15), exceeding the time allowed on endocarditis and those with less than 24 h of life expect- vancomycin prior to enrolment in 13% (n = 11) and ancy were excluded from our study. These are all condi- polymicrobial bacteremia in 10% (n = 8). There were 18 tions that have been associated with poorer overall patients who were eligible for the study but declined to outcome [27, 28]. In addition, all patients were managed participate. by an infectious disease physician - at least two studies The overall recruitment rate of the study was lower have shown that this is associated with improved out- than expected with fewer patients than initially pro- comes in patients with MRSA BSI [29, 30]. However, jected being eligible for the study. An attempt was due to the small sample size we acknowledge that the made mid-way through the study to improve recruit- improved overall outcome observed may have merely ment by modifying the exclusion criteria (as described been due to chance. earlier) but this did not have a significant impact on One patient in the daptomycin arm developed elevated improving recruitment rates and the investigators felt CK compared to none in the vancomycin arm (Table 3). that allowing further modifications to the exclusion cri- This is consistent with previous studies where CK eleva- teria would adversely affect the safety and integrity of tions were more common in the daptomycin group [7, the study. Nine patients were recruited after modifica- 9, 26]. In our study, three patients in the vancomycin tion of the exclusion criteria and of these, four patients treatment arm had dermatologic manifestations. This is would have been previously excluded. Of note, 11 pa- not unexpected, as cutaneous adverse effects have been tients were excluded because they exceeded the dur- reported to be the commonest adverse events related to ation allowed on vancomycin prior to enrolment (this vancomycin use [31–33]. Nephrotoxicity is often a con- was initially capped at 96 h and subsequently increased cern with vancomycin, especially in patients with under- to 5 days mid-way through the study to try and im- lying renal insufficiency. However, none of the patients prove enrolment). As part of our institutional practice, in the vancomycin arm developed significant increases a large proportion of patients are prescribed empirical in serum creatinine despite the majority having chronic vancomycin therapy on admission if they have signs of kidney disease. In our study, vancomycin trough levels infection and have had recent healthcare contact. Many were monitored regularly and maintained within a tight of these patients would have received more than 4–5 therapeutic window of 15–20 μg/ml. In addition, none days of vancomycin therapy by the time the vanco- of the patients received concomitant treatment with an mycin MIC result was known, making them ineligible aminoglycoside, which has been shown to increase rates for the study. The investigators felt that extending the of nephrotoxicity [34]. In contrast, one patient in the period allowed on vancomycin therapy beyond 5 days daptomycin arm experienced nephrotoxicity, which was would make it impossible for daptomycin efficacy to be deemed by the study investigators to be “possibly re- assessed with sufficient rigor. Attempts were also made lated” to daptomycin. To our knowledge, daptomycin in- to increase the number of enrolment sites but these duced nephrotoxicity has not been previously reported. proved unsuccessful, mainly due to the small baseline This patient was concomitantly receiving high-dose numbers of patients with MRSA bacteremia at these diuretics, which may have led to dehydration and smaller sites. After consultation with the trial steering pre-renal impairment. In addition, the patient’s serum committee, a decision was made to terminate the study creatinine returned to baseline without cessation of early as it was felt that it would not be realistically pos- study drug. Hence, it remains unclear if the patient’s sible to achieve the target sample size within the allo- renal impairment was truly caused by daptomycin. cated funding period. Kalimuddin et al. Trials (2018) 19:305 Page 8 of 9 Conclusions data analysis and interpretation. All authors were involved in preparation of the manuscript (via critical review) and approved the final version. In summary, based on current available evidence, it re- mains unclear if alternative, newer and more expensive Ethics approval and consent to participate agents such as daptomycin are truly superior to vanco- The trial was granted ethics approval by the Singhealth Centralized Institute Review Board (CIRB) (approval ID 2013/846/E). Written informed consent was mycin in the treatment of BSI due to MRSA with high obtained from all patients before enrolment into the study. vancomycin MIC. The question of what should be the optimal recommended treatment for such infections re- Competing interests mains important to answer, and more studies are ur- The authors declare that they have no competing interests. gently needed. However, randomized controlled trials evaluating this are complicated and difficult to execute - Publisher’sNote primarily due to the heterogeneous and complex patient Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. profile associated with MRSA BSI. Enrolment rates are likely to be low and multicenter trials providing a large Author details patient pool will be needed to achieve sufficient patient Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore. School of Population Health and recruitment for an adequately powered study. An alter- Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College native to such conventional randomized controlled trials 3 London, Guy’s Campus, London SE1 1UL, UK. NIHR Biomedical Research may be pragmatic adaptive platform trials - such novel Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London, Guy’s Hospital, London SE1 9RT, UK. Geriatric Education and methodologies are already being employed successfully Research Institute, 2 Yishun Central 2, Singapore 768024, Singapore. Division in oncology trials [35–37]. Platform studies make use of of Infectious Diseases, National University Health System, 5 Lower Kent Ridge a universal trial master protocol to study the optimal Rd, Singapore 119074, Singapore. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 21 Lower Kent Ridge treatment for a disease and its subgroups, while the Rd, Singapore 119077, Singapore. Department of Infectious Diseases, pragmatic design embeds the trial in routine provision Communicable Disease Centre, Tan Tock Seng Hospital, 11 Jalan Tan Tock of care and allows for minimal exclusion criteria, in turn Seng, Singapore 308433, Singapore. improving recruitment rates. In addition, the use of Received: 30 November 2017 Accepted: 21 May 2018 response-adaptive randomization results in greater prob- ability of patients in a particular sub-group being ran- domized to interventions that are performing better References 1. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, within that sub-group [37, 38]. Thus, better therapies Carmeli Y. Comparison of mortality associated with methicillin-resistant and move through the evaluation process faster, resulting in methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. greater trial efficiency. Investigators interested in evalu- Clin Infect Dis. 2003;36(1):53–9. 2. 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