Abstract Objectives Despite the convenience of once-daily dosing, the use of ceftriaxone for Staphylococcus aureus infections has significant limitations, including scarce clinical evidence and increasingly questionable pharmacodynamic activity. Our goal was to conduct an integrated pharmacokinetic–pharmacodynamic analysis of the appropriateness of ceftriaxone compared with cefazolin for treating serious MSSA infections. Methods Ceftriaxone and cefazolin activity against five clinical MSSA isolates was characterized in an in vitro pharmacodynamic model. Monte Carlo simulations were then used to evaluate various dosing regimens of ceftriaxone and cefazolin based on relevant patient pharmacokinetic data, significant pharmacodynamic targets derived from the in vitro studies (55%ƒT>MIC for bacteriostasis, 75%ƒT>MIC for 1 log10 bacterial kill, 100%ƒT>MIC for ≥3 log10 bacterial kill) and MIC distributions for MSSA from national surveillance data. Results Ceftriaxone at 1 g once daily had poor activity against MSSA with net bacterial growth predicted in 76% of simulated subjects. The standard 2 g of ceftriaxone once daily had predicted bacterial growth or bacteriostasis in 54% of cases with bactericidal effects in only 17%. Cefazolin at 2 g once daily was notably similar to ceftriaxone in expected target attainments. Cefazolin at 2 g twice daily demonstrated maximal pharmacodynamic activity with bactericidal effects in 97% of simulated subjects. Conclusions Given the limited activity of ceftriaxone against S. aureus, particularly for serious infections when bacterial kill is desired, the convenience of once-daily dosing should be weighed against the risks of using an overly broad, suboptimal therapy. Cefazolin warrants further consideration, particularly as optimal pharmacodynamics against MSSA may be achieved with twice-daily dosing in most patients. Introduction The convenience of once-daily ceftriaxone offers an attractive option for parenteral antibiotic therapy, particularly in outpatient settings.1–3 Ceftriaxone has broad-spectrum activity against Enterobacteriaceae and some Gram-positive bacteria, including Streptococcus spp. and MSSA. Although less active than earlier generations, ceftriaxone is classified as an anti-staphylococcal cephalosporin with labelled indications for lower respiratory tract, bloodstream, skin and soft tissue, and bone and joint infections.4 The benefits of once-daily ceftriaxone for treating Staphylococcus aureus infections must be weighed against the obvious risks of using an overly broad therapy with greater potential for collateral resistance and higher rates of Clostridium difficile infection.5 In addition, it is important to consider the scarce clinical evidence supporting the use of ceftriaxone for serious MSSA infections such as osteomyelitis, septic arthritis and bacteraemia. As reviewed by Sharff et al.,6 clinical data are limited to retrospective observational studies susceptible to the influence of small sample size, suboptimal comparators and/or ceftriaxone outpatient parenteral antimicrobial therapy (OPAT) preceded by effective first-line therapy (e.g. cefazolin, oxacillin/nafcillin/cloxacillin). Furthermore, ceftriaxone was marketed before the importance of antibiotic pharmacokinetics (PK)–pharmacodynamics (PD) was fully appreciated. For β-lactam therapy, the percentage of time that free concentrations exceed the antibiotic MIC (%fT>MIC) is integral to microbiological and clinical outcomes. Ceftriaxone exhibits a prolonged t½ of 6–8 h allowing for less frequent dosing than other cephalosporins. However, it also demonstrates concentration-dependent protein binding of >90%, resulting in relatively low free concentrations that are responsible for the pharmacological activity. Historically, MSSA susceptibility for the anti-staphylococcal cephalosporins, including ceftriaxone and cefazolin, was based on a breakpoint of 8 mg/L. In 2014, however, direct MIC testing was eliminated in favour of an inferred susceptibility for the anti-staphylococcal cephalosporins against all MSSA.7,8 Regardless, in vivo antibacterial activity and treatment response remain dependent on the complex relationship between antibiotic dosing, PK profile and pathogen MIC. As such, PK–PD analyses can be used to evaluate ceftriaxone for MSSA infections, including whether standard once-daily dosing is adequate and how it compares with first-line cephalosporins (i.e. cefazolin). Our goal was to conduct an integrated PK–PD analysis of the appropriateness of ceftriaxone compared with cefazolin for serious MSSA infections using in vitro PD modelling and Monte Carlo simulations. The former was presented at the Fifty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 2012 (Poster A-613) and the latter at IDWeek 2016, New Orleans, LA, USA, 2016 (Poster 283). Methods In vitro PD model (IPDM) IPDM studies were conducted to evaluate the antibacterial activity of ceftriaxone against MSSA. For comparison, cefazolin with a prolonged t½, as observed when used once daily in combination with probenecid, was tested. The findings were also used to characterize the overall PD of ceftriaxone and cefazolin against MSSA. A one-compartment model, described previously, was used to simulate infection in an immunocompromised host.9–11 The central compartment, containing 250 mL of Mueller–Hinton broth with 25 mg/L calcium and 12.5 mg/L magnesium (Mueller–Hinton II broth, Becton Dickinson & Company, Sparks, MD, USA), was continuously stirred and maintained at 37°C. A computerized pump (Masterflex, Cole-Parmer, Chicago, IL, USA) delivered fresh broth from a reservoir flask through the central compartment to produce the desired elimination t½. Five clinical MSSA isolates were tested in the IPDM studies. Ceftriaxone and cefazolin MICs were measured in triplicate using CLSI broth macrodilution methods and all were susceptible based on the last interpretive criteria for the anti-staphylococcal cephalosporins against S. aureus (i.e. MIC ≤ 8 mg/L).12 For ceftriaxone, one isolate had an MIC of 2 mg/L, two had MICs of 4 mg/L and two had MICs of 8 mg/L. For cefazolin, three isolates had MICs of 0.5 mg/L and two had MICs of 1 mg/L. Bacterial suspensions were prepared in Mueller–Hinton broth, adjusted to a turbidity equivalent to that of a 0.5 McFarland standard and injected into the central compartment to yield initial inocula of 1 × 106 cfu/mL. Clinical dosing equivalent to 2 g of ceftriaxone q24h with a 6 h t½ was studied,13 whereas cefazolin equivalent to 2 g q24h, but with an extended 4 h t½ simulating co-administration with probenecid, was tested.14,15 Dosing was designed to simulate free peak and trough concentrations in the IPDM of 22 mg/L and 1.4 mg/L, respectively, for ceftriaxone and 40 mg/L and 0.6 mg/L, respectively, for cefazolin. Samples were drawn from the central compartment immediately before and at 2, 4, 6 and 24 h after dosing. Samples were serially diluted in normal saline and plated in duplicate on Mueller–Hinton agar (Oxoid Inc., Nepean, Ontario, Canada). Plates were incubated at 35°C for 24 h and viable colonies were counted with a lower limit of detection of 1 × 102 cfu/mL. The antibiotic concentrations (within 15% of target) in the central compartment were confirmed with antibiotic bioassays using Bacillus subtilis ATCC 6633.9,16 The PK parameters were verified using linear regression analysis. Experiments were conducted in triplicate on separate occasions. Antibiotic activity at 24 h was characterized as bacterial kill or net bacterial growth relative to the initial inoculum. Antibiotic effect was examined using a two-way analysis of variance (ANOVA), whereas MIC effect was tested using a one-way ANOVA. The overall PD of ceftriaxone and cefazolin were modelled (e.g. linear, logarithmic, sigmoid Emax) to characterize the relationship between antibiotic %fT>MIC and bacterial colony count at 24 h. Statistical analyses were conducted using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA) and SYSTAT version 12 (Systat Software Inc., San Jose, CA, USA). Monte Carlo simulations Monte Carlo simulation methods in SYSTAT version 12 were used to evaluate the PK–PD of ceftriaxone and cefazolin in a cohort of 5000 subjects. Patient demographics were modelled using a Gaussian distribution of body weight (75 ± 10 kg) and uniform distribution of CLCR from 50 to 100 mL/min/72 kg. The incremental influence of renal function was tested separately. Various dosing regimens of ceftriaxone, ranging from 1 to 3 g every 12–24 h, and cefazolin, ranging from 1 to 3 g every 8–24 h, were simulated. A consistent infusion time of 0.5 h was applied to all doses. Using established one-compartment PK models for ceftriaxone13,17 and cefazolin,18–21 free plasma concentration profiles were simulated for each dosing regimen in each subject. Unlike the IPDM studies, Monte Carlo simulations were conducted for the more relevant cefazolin therapy alone (not co-administered with probenecid). Ceftriaxone and cefazolin MICs (broth microdilution) were incorporated into the model using surveillance data for 6490 clinical MSSA isolates from patients in 13 Canadian hospitals during 2007 to 2015, inclusive.22 Next, %fT>MIC was determined for each antibiotic regimen in each simulated subject at each potential MIC. Significant PD targets were derived from the IPDM study, including 55%ƒT>MIC for bacteriostasis, 75%ƒT>MIC for 1 log10 bacterial kill and 100%ƒT>MIC for 3 log10 bacterial kill (see the IPDM section in the Results section). The PTA for each antibiotic regimen at each MIC was then calculated as the proportion of simulated subjects achieving target. The overall or cumulative target attainment (CTA), also reported as the proportion of the population, was determined by multiplying the PTA at each MIC by the fraction of MSSA isolates with that MIC in the distribution and summing the values. An acceptable CTA was defined as achieving the desired PD target in at least 90% of simulated subjects, with the recognition that optimal therapy would cover all patients.23 Results IPDM Overall bacterial kill in the IPDM was significantly lower with ceftriaxone compared with cefazolin (0.20 ± 1.19 log10 versus 2.82 ± 1.11 log10 cfu/mL, P = 0.007). Ceftriaxone (2 g q24h) had variable activity, ranging from 0.85 ± 0.50 log10 cfu/mL of bacterial growth to 1.98 ± 0.71 log10 cfu/mL of bacterial kill at 24 h. As shown in Figure 1, the antibacterial activity of ceftriaxone was dependent on the MIC (P = 0.004), with notable bacterial kill for the most susceptible isolate only (MIC = 2 mg/L). Cefazolin (2 g q24h simulating co-administration with probenecid) produced bacterial kill at 24 h for all isolates (MIC = 0.5 or 1 mg/L), ranging from 1.84 to 3.51 log10 cfu/mL. The overall PD of ceftriaxone and cefazolin was best described by a logarithmic model of %ƒT>MIC and change in bacterial colony count (r2 = 0.92) with thresholds of 55%ƒT>MIC, 75%ƒT>MIC and 100%ƒT>MIC for bacteriostasis, 1 log10 bacterial kill and 3 log10 bacterial kill (bactericidal), respectively. Figure 1. View largeDownload slide Activity of once-daily cefazolin (2 g q24h simulating co-administration with probenecid) and once-daily ceftriaxone (2 g q24h) against MSSA in the IPDM. Squares are means and bars are standard deviations. Positive values indicate bacterial kill and negative values indicate net growth at 24 h relative to the initial inoculum. Figure 1. View largeDownload slide Activity of once-daily cefazolin (2 g q24h simulating co-administration with probenecid) and once-daily ceftriaxone (2 g q24h) against MSSA in the IPDM. Squares are means and bars are standard deviations. Positive values indicate bacterial kill and negative values indicate net growth at 24 h relative to the initial inoculum. Monte Carlo simulations Simulated ceftriaxone concentrations were consistent with a V of 12.8 ± 2.6 L, t½ of 9.2 ± 1.6 h and free fraction of 0.075 ± 0.003 (92.5% protein bound). Cefazolin profiles were described by a V of 11.3 ± 2.3 L, t½ of 3.2 ± 1.8 h and free fraction of 0.175 ± 0.006 (82.5% protein bound). For reference, the resultant free trough concentrations with once-daily ceftriaxone are shown in Figure 2. The simulated MIC distributions were characterized by ceftriaxone values ranging from 1 to 8 mg/L (MIC50 = 4 mg/L) and cefazolin values ranging from ≤0.5 to 1 mg/L (MIC50 ≤ 0.5 mg/L). Figure 2. View largeDownload slide Free steady-state trough concentrations with (a) 1 g of ceftriaxone q24h and (b) 2 g of ceftriaxone q24h in a representative sample of 1000 simulated subjects with a Gaussian distribution of body weight (75 ± 10 kg) and uniform distribution of CLCR from 50 to 100 mL/min/72 kg. Broken lines represent the MIC50 of 4 mg/L for MSSA. Figure 2. View largeDownload slide Free steady-state trough concentrations with (a) 1 g of ceftriaxone q24h and (b) 2 g of ceftriaxone q24h in a representative sample of 1000 simulated subjects with a Gaussian distribution of body weight (75 ± 10 kg) and uniform distribution of CLCR from 50 to 100 mL/min/72 kg. Broken lines represent the MIC50 of 4 mg/L for MSSA. The CTA for all once-daily and twice-daily regimens of ceftriaxone and cefazolin are depicted in descending order in Figure 3. Thrice-daily cefazolin (1 g and 2 g q8h) achieved the bactericidal target (i.e. 100%ƒT>MIC) in all simulated subjects (data not shown). For an acceptable CTA of achieving target in at least 90% of cases, once-daily regimens attained at least bacteriostasis (i.e. ≥55%ƒT>MIC) with 3 g of cefazolin q24h (CTA 99%), 3 g of ceftriaxone q24h (CTA 97%) and 2 g of cefazolin q24h (CTA 96%). See Figure 3(a). None of the once-daily regimens of ceftriaxone or cefazolin reached an acceptable CTA for bacterial kill (i.e. ≥75%ƒT>MIC) in the simulated subjects. See Figure 3(b). Overall, the standard 2 g of ceftriaxone once daily had predicted bacterial growth or bacteriostasis in a majority of simulated subjects (14% and 40%, respectively), with at least 1 log10 bacterial kill in 46% of cases, including bactericidal effects in only 17%. Cefazolin at 2 g once daily was similar to ceftriaxone with predicted bacterial growth in 4%, bacteriostasis in 46% and at least 1 log10 bacterial kill in 50% of simulated subjects, including bactericidal effects in 15%. Figure 3. View largeDownload slide CTA against MSSA for various ceftriaxone and cefazolin dosing regimens in simulated subjects with a Gaussian distribution of body weight of 75 ± 10 kg and uniform distribution of CLCR from 50 to 100 mL/min/72 kg. Hatched bars correspond to ceftriaxone, grey bars correspond to cefazolin and continuous horizontal lines represent an acceptable CTA defined as achieving the desired PD target in at least 90% of cases. CRO, ceftriaxone; CFZ, cefazolin. Figure 3. View largeDownload slide CTA against MSSA for various ceftriaxone and cefazolin dosing regimens in simulated subjects with a Gaussian distribution of body weight of 75 ± 10 kg and uniform distribution of CLCR from 50 to 100 mL/min/72 kg. Hatched bars correspond to ceftriaxone, grey bars correspond to cefazolin and continuous horizontal lines represent an acceptable CTA defined as achieving the desired PD target in at least 90% of cases. CRO, ceftriaxone; CFZ, cefazolin. For an acceptable CTA of achieving target in at least 90% of cases, twice-daily regimens attained at least bacteriostasis (i.e. ≥55%ƒT>MIC) with 2 g of cefazolin q12h (CTA 100%), 1 g of cefazolin q12h (CTA 100%), 2 g of ceftriaxone q12h (CTA 99%) and 1 g of ceftriaxone q12h (CTA 92%). At least 1 log10 bacterial kill (i.e. ≥75%ƒT>MIC) was reached in 99% of simulated subjects with 2 g of ceftriaxone q12h versus only 78% with 1 g q12h. However, this target for bacterial kill was achieved with 2 g of cefazolin q12h (CTA 100%) and even 1 g q12h (CTA 99%). Finally, the bactericidal PD target (i.e. 100%ƒT>MIC) was attained with 2 g of cefazolin q12h (CTA 97%) and 2 g of ceftriaxone q12h (CTA 95%). See Figure 3(c). The influences of renal function on the CTA of 2 g of ceftriaxone once daily and 2 g of cefazolin once daily, for comparison, are depicted in Figure S1 (available as Supplementary data at JAC Online). Consistent with the degree of renal excretion, target attainment increased modestly with decreasing renal function. As expected, the effects were more pronounced from cefazolin which undergoes more renal elimination. Discussion Few studies have characterized the PK–PD of ceftriaxone against S. aureus. Our study evaluated various dosing regimens of ceftriaxone and cefazolin using Monte Carlo simulations that incorporated PD targets derived from IPDM studies. Our key findings were that: (i) 1 g of ceftriaxone once daily had poor activity against MSSA with bacterial growth predicted in 76% of cases; (ii) the standard 2 g of ceftriaxone once daily had modest activity, where bacterial kill was expected in only 50%, including bactericidal effects in 17% of cases; and (iii) 2 g of cefazolin twice daily demonstrated maximal PD activity against MSSA with bactericidal effects in 97% of simulated subjects. The use of ceftriaxone for S. aureus infections is based on its original anti-staphylococcal classification, labelled indications and more recent inferred susceptibility against MSSA. Although once-daily ceftriaxone can be particularly advantageous for OPAT,1–3 its use can extend to the treatment of MSSA infections in these and even hospitalized patients.24,25 Notably, there is limited clinical evidence, even for labelled indications, with PK–PD that predicts poor activity against MSSA. It is important to consider that convenience may drive the inadvertent use of suboptimal therapy, particularly for serious MSSA infections. Clinical experience with ceftriaxone may also be prone to crediting treatment success to ceftriaxone OPAT even though it was preceded by effective first-line therapy. On the other hand, treatment failure may be attributed to a serious infection or other patient-related risk factors. The role of ceftriaxone in treating MSSA bacteraemia is controversial. A retrospective cohort study by Paul et al.24 analysed patients with MSSA bacteraemia treated with β-lactam antibiotics. The authors found that empirical therapy with ceftriaxone or cefotaxime (n = 194) was associated with more than twice the 30-day mortality with cloxacillin or cefazolin (n = 131) (adjusted OR = 2.24, 95% CI = 1.2–4.1, P = 0.008). Although definitive therapy based on culture results was also evaluated, the comparisons were made among cloxacillin, cefazolin and other β-lactams combining second- and third-generation cephalosporins, β-lactam-β-lactamase inhibitors and carbapenems. Patel et al.26 conducted another retrospective study of patients with MSSA bloodstream infections treated with ceftriaxone compared with standard of care therapy (SOCT). Notably, SOCT included treatment with cefazolin, nafcillin or vancomycin, the latter of which is known to have inferior activity against S. aureus. Although clinical cure at 6 months was not significantly different between ceftriaxone (83%, 35/42) and SOCT (76%, 39/51) (P = 0.30), the response rate was particularly low for vancomycin that was included in the latter (58%, 7/12). Furthermore, ceftriaxone was more likely administered as OPAT (64% versus 24%) that may have been preceded by other therapy. Current practice guidelines for osteoarticular infections include ceftriaxone as a first-line/preferred treatment option for MSSA native vertebral osteomyelitis (2 g q24h) and prosthetic joint infections (1–2 g q24h).27,28 The latter was made without consensus and with subsequent debate regarding the need for twice-daily ceftriaxone as guided by the oxacillin MIC.29 Again the clinical evidence for treating osteoarticular infections is based on retrospective studies published over several decades.6 A notable study by Wieland et al.30 conducted a cohort propensity score-weighted analysis of ceftriaxone (n = 72, 2 g q24h) compared with oxacillin (n = 50, 4 g q6h) for MSSA osteomyelitis or septic arthritis. Treatment success was similar at 3–6 months (83% for ceftriaxone versus 86% for oxacillin, P = 0.6) and beyond 6 months (77% for ceftriaxone versus 81% for oxacillin, P = 0.4). Notably, 22% and 29% of patients were lost at early and late follow-up, respectively. Although not statistically significant, treatment success for prosthetic infections beyond 6 months was 69% for ceftriaxone compared with 92% for oxacillin. It is also important to consider that oxacillin dosing every 6 h may not have been optimal, given its time-dependent activity and rapid t½ of 30 min. Housman et al.31 demonstrated this issue in a Monte Carlo simulation study of common parenteral therapies against MSSA. The nafcillin dosing interval had substantial impact on its PD activity where 1 g q6h achieved a target of >30%ƒT>MIC in only 9% of simulated subjects, whereas 1 g q4h reached the target in 89% of cases.31 Importantly, even the much higher dose of 4 g q6h reported in the Wieland et al.30 study would only cover the MIC for an additional two t½s or 17% of the dosing interval. An early simulation study by Sader et al.32 evaluated broad-spectrum cephalosporins against staphylococci. Ceftriaxone at 1 g q24h was limited in achieving >40%ƒT>MIC against isolates with an MIC of 4 mg/L, equivalent to the MIC50 and MIC90 of their global surveillance data. The authors concluded that a susceptibility breakpoint of 2 mg/L would be needed to achieve their PD target in at least 90% of simulated subjects. Using this PK–PD breakpoint, only 34% of their MSSA isolates would have been susceptible to ceftriaxone. Although reported in a different format, their findings were consistent with ours, where 1 g of ceftriaxone q24h achieved ≥55%ƒT>MIC in only 24% of cases. In the more recent simulation study by Housman et al.,31 1 g of ceftriaxone q24h and 2 g of ceftriaxone q24h achieved >30%ƒT>MIC in only 11% and 55% of cases, respectively. Their results were lower than ours, where 1 g q24h and 2 g q24h reached a higher target of ≥55%ƒT>MIC in 24% and 86% of cases, respectively. Although Housman et al.31 did not report simulated PK and concentration data, the difference may be explained by their use of a ceftriaxone PK model for critically ill patients. Whereas their study confirmed that thrice-daily cefazolin achieved >30%ƒT>MIC in 100% of cases, our study extended this finding to a target of 100%ƒT>MIC. Our study also demonstrated that this bactericidal target was even achieved with the more convenient, twice-daily cefazolin (2 g q12h) in 97% of simulated subjects. Our study shares the limitations of simulation-based research that depends on the quality and strength of individual variables incorporated into the model. We used well-established PK data for ceftriaxone and cefazolin in non-critically ill adult patients. We also used ceftriaxone and cefazolin MICs from national surveillance data that were consistent with other reports.31,32 Finally, we reported findings for a range of targets, including ≥55%, ≥75% and 100%ƒT>MIC. PD targets for cephalosporins in the literature are variable, typically 30%–40%ƒT>MIC for bacteriostasis and 60%–70%ƒT>MIC for maximum bacterial kill.33 Although our targets were modestly higher at 55%ƒT>MIC for bacteriostasis and 75%–100%ƒT>MIC for different magnitudes of bacterial kill, they are consistent with clinical PD studies of ceftazidime and cefepime where thresholds of 60%–100%ƒT>MIC were associated with better treatment responses.34,35 Given the limited activity of ceftriaxone against S. aureus, particularly for serious infections when bacterial kill is desired, the convenience of once-daily dosing should be weighed against the risk of using an overly broad, suboptimal therapy. Cefazolin warrants further consideration, particularly since optimal PD against MSSA may be achieved with twice-daily dosing in most patients. Acknowledgements The IPDM data were presented at the Fifty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 2012 (Poster A-613) and the Monte Carlo simulation data were presented at IDWeek 2016, New Orleans, LA, USA, 2016 (Poster 283). Funding Internal funding. Transparency declarations None to declare. Supplementary data Figure S1 is available as Supplementary data at JAC Online. References 1 Yan M , Elligsen M , Simor A et al. Patient characteristics and outcomes of outpatient parenteral antimicrobial therapy: a retrospective study . Can J Infect Dis Med Microbiol 2016 ; 2016 : 8435257 . Google Scholar PubMed 2 Williams D , Baker C , Kind A et al. The history and evolution of outpatient parenteral antibiotic therapy (OPAT) . Int J Antimicrob Agents 2015 ; 46 : 307 – 12 . Google Scholar CrossRef Search ADS PubMed 3 Seaton R , Barr D. Outpatient parenteral antibiotic therapy: principles and practice . 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Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Apr 4, 2018
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