Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review

Loubet, Paul; Burdet, Charles; Vindrios, William; Grall, Nathalie; Wolff, Michel; Yazdanpanah, Yazdan; Andremont, Antoine; Duval, Xavier; Lescure, François-Xavier

doi:10.1016/j.cmi.2017.07.003

Cited by 47 publications

(29 citation statements)

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“…In the UK and Australia, flucloxacillin is the recommended first-line anti-staphylococcal penicillin for MSSA infections, whereas other agents, such as nafcillin and cloxacillin, are recommended in the USA. There is no evidence supporting clinically relevant differential anti-staphylococcal activity between these antibiotics, 65,66 and, therefore, the authors believe that the results are generalisable across countries regardless of their chosen anti-staphylococcal penicillin. A total of 50.1% of patients received a glycopeptide at some point in their primary treatment, probably reflecting ongoing concerns about MRSA infections despite the overall low rates, particularly given the severity of disease in many of the trial participants.…”

Section: Chapter 6 Discussionmentioning

confidence: 87%

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT

Thwaites

Scarborough

Szubert

et al. 2018

Health Technol Assess

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Background Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Objectives To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. Design Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. Setting UK NHS trust hospitals. Participants Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. Interventions Adjunctive rifampicin (600–900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). Main outcome measures The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Results Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50–76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18–45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference –1.4%, 95% confidence interval (CI) –7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). Conclusions Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. Future work Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. Trial registrations Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.

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Section: Chapter 6 Discussionmentioning

confidence: 87%

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT

Thwaites

Scarborough

Szubert

et al. 2018

Health Technol Assess

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“…Others have even suggested a treatment benefit with cefazolin over antistaphylococcal penicillins [17, 24]. Several comprehensive reviews of these data have been published elsewhere [12, 25, 26]. Limitations of previous studies include small patient populations, retrospective study design, and lack of adverse effect analyses.…”

Section: Discussionmentioning

confidence: 88%

Does the Beta-Lactam Matter? Nafcillin versus Cefazolin for Methicillin-Susceptible <b><i>Staphylococcus aureus</i></b> Bloodstream Infections

et al. 2018

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Background: Antistaphylococcal penicillins have historically been regarded as the drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSI). However, recent outcomes data compared to cefazolin treatment are conflicting. Objective: This study compared treatment failure and adverse effects associated with nafcillin and cefazolin for MSSA BSI. Methods: Adult inpatients with MSSA BSI between January 1, 2009 and August 31, 2015 were included in this retrospective cohort study if they received ≥72 h of nafcillin or cefazolin as directed therapy after no more than 72 h of any empiric therapy. The primary composite endpoint was treatment failure defined by clinician documentation, 30-day recurrence of infection, all-cause 30-day in-hospital mortality, or loss to follow-up. Secondary outcomes included antibiotic-related acute kidney injury (AKI), acute interstitial nephritis (AIN), hepatotoxicity, and rash. Results: Among 157 patients, 116 (73.9%) received nafcillin and 41 (26.1%) received cefazolin. The baseline characteristics were similar except cefazolin-treated patients had higher APACHE II scores and more frequent renal dysfunction. No difference in the composite treatment failure outcome (28.4 vs. 31.7%; p = 0.69) was detected between the nafcillin and cefazolin groups, respectively. In a sensitivity analysis excluding patients without known follow-up, there was no significant difference of treatment failure. AKI, AIN, hepatotoxicity, and rash were all numerically more frequent among nafcillin-treated patients. Conclusions: Among nafcillin- or cefazolin-treated patients with MSSA BSI, there was no significant difference in treatment failure. Observing more frequent presumptive adverse effects associated with nafcillin receipt, future prospective studies evaluating cefazolin appear warranted.

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“…In addition, due to the frequency of adverse events occurring with ASP, cefazolin is increasingly used. However, the potential hydrolysis of cephalosporin by type A β-lactamase produced by some S. aureus strains exhibited in vitro inoculum effect, while animal studies produced conflicting results 7. This question will be investigated in this trial, as human data are lacking on this question.…”

Section: Discussionmentioning

confidence: 99%

“…Cefazolin, a semi-synthetic first-generation cephalosporin administered by parenteral route, could be a good candidate for several reasons: a similar efficacy, based on several large observational studies7–11; a favourable safety profile4 6 12–14 and a convenient administration schedule. These data led the American Heart Association, the Infectious Disease Society of America and the European Society of Cardiology to consider cefazolin as the first alternative line agent for treatment of MSSA-associated infective endocarditis 15 16.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of cloxacillin versus cefazolin for methicillin-susceptibleStaphylococcus aureusbacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial

et al. 2018

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IntroductionMethicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a common and severe disease responsible for approximately 65 000 deaths every year in Europe. Intravenous antistaphylococcal penicillins (ASP) such as cloxacillin are the current recommended antibiotics. However, increasing reports of toxicity and recurrent stock-outs of ASP prompted healthcare providers to seek for alternative antibiotic treatment. Based on retrospective studies, cefazolin, a first-generation cephalosporin, is recommended in patients at risk of severe ASP-associated toxicity.We hypothesised that cefazolin has a non-inferior efficacy in comparison to cloxacillin, with a better safety profile for the treatment of MSSA bacteraemia.Methods and analysisThe CloCeBa trial is an open-label, randomised, controlled, non-inferiority trial conducted in academic centres throughout France. Eligible patients are adults with MSSA bacteraemia without intravascular device or suspicion of central nervous system infection. Patients will be randomised (1:1) to receive either cloxacillin or cefazolin by the intravenous route, for the first 14 days of therapy. The evaluation criteria is a composite criteria of negative blood cultures at day 5, survival, absence of relapse and clinical success at day 90 after randomisation. Secondary evaluation criteria include both efficacy and safety assessments. Three ancillary studies are planned to describe the epidemiology of β-lactamase encoding genes, the ecological impact and pharmacokinetic/pharmacodynamic parameters of cefazolin and cloxacillin. Including 300 patients will provide 80% power to demonstrate the non-inferiority of cefazolin over cloxacillin, assuming 85% success rate with cloxacillin and taking into account loss-to-follow-up, with a 0.12 non-inferiority margin and a one-sided type I error of 0.025.Ethics and disseminationThis protocol received authorisation from the ethics committee Sud-Est I on 13 November 2017 (2017-87-PP)and French National Agency for Medicines and Health Products (170661A-43). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals.Trial registration numberNCT03248063 and 2017-003967-36.

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Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review

Abstract: Abstract.Background. Anti-staphylococcal penicillins (ASPs) are recommended as first-line agents in

Cited by 47 publications

References 49 publications

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT

Does the Beta-Lactam Matter? Nafcillin versus Cefazolin for Methicillin-Susceptible <b><i>Staphylococcus aureus</i></b> Bloodstream Infections

Efficacy of cloxacillin versus cefazolin for methicillin-susceptibleStaphylococcus aureusbacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial

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