Cefazolin versus Antistaphylococcal Penicillins for the Treatment of Methicillin-SusceptibleStaphylococcus aureusBacteremia: A Systematic Review and Meta-Analysis

Cefazolin versus Antistaphylococcal Penicillins for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Systematic Review and Meta-Analysis | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Cefazolin versus Antistaphylococcal Penicillins for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Systematic Review and Meta-Analysis Connor Prosty , Dean Noutsios , Todd C. Lee , Nick Daneman , Joshua S. Davis , Nynke G. L. Jager , Nesrin Ghanem-Zoubi , Anna L. Goodman , Achim J. Kaasch , Ilse Kouijzer , Brendan J. McMullan , Emily G. McDonald , Steven Y. C. Tong , Sean W. X. Ong , the Staphylococcus aureus Network Adaptive Platform MSSA/PSSA domain specific working group doi: https://doi.org/10.1101/2025.02.17.25322429 Connor Prosty 1 Faculty of Medicine, McGill University , Montréal, QC, Canada 2 Division of Experimental Medicine, Department of Medicine, McGill University , Montréal, QC, Canada MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: connor.prosty{at}mail.mcgill.ca Dean Noutsios 1 Faculty of Medicine, McGill University , Montréal, QC, Canada MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Todd C. Lee 2 Division of Experimental Medicine, Department of Medicine, McGill University , Montréal, QC, Canada 3 Division of Infectious Diseases, Department of Medicine, McGill University Health Centre , QC, Montréal, Canada 4 Clinical Practice Assessment Unit, Department of Medicine, McGill University Health Centre , Montréal, QC, Canada MD MPH FIDSA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nick Daneman 5 Division of Infectious Diseases, Sunnybrook Health Sciences Centre , Toronto, ON, Canada 6 Institute of Health Policy, Management and Evaluation, University of Toronto , Toronto, ON, Canada MD MSc Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joshua S. Davis 7 School of Medicine and Public Health, University of Newcastle , Newcastle, Australia 8 Department of Immunology and Infectious Diseases, John Hunter Hospital , Newcastle, Australia 9 Global and Tropical Health Division, Menzies School of Health and Research , Darwin, Australia MBBS PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nynke G. L. Jager 10 Department of Pharmacy, Radboud Institute for Medical Innovation, Radboud University Medical Center , Nijmegen, The Netherlands PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nesrin Ghanem-Zoubi 11 Infectious Diseases Institute, Rambam Health Care Campus , Haifa, Israel MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anna L. Goodman 12 Medical Research Council Clinical Trials Unit, University College London , London, United Kingdom MD PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Achim J. Kaasch 13 Institute of Medical Microbiology and Hospital Hygiene, Faculty of Medicine, Heinrich Heine University Düsseldorf , Düsseldorf, Germany MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ilse Kouijzer 14 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen, The Netherlands MD PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Brendan J. McMullan 15 D epartment of Infectious Diseases, Sydney Children’s Hospital , Randwick, New South Wales, Australia MD PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Emily G. McDonald 2 Division of Experimental Medicine, Department of Medicine, McGill University , Montréal, QC, Canada 4 Clinical Practice Assessment Unit, Department of Medicine, McGill University Health Centre , Montréal, QC, Canada 16 Division of General Internal Medicine, Department of Medicine, McGill University Health Centre , Montréal, QC, Canada MD MSc Find this author on Google Scholar Find this author on PubMed Search for this author on this site Steven Y. C. Tong 17 Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity , Melbourne, Australia 18 Victorian Infectious Disease Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity , Melbourne, Australia MBBS PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sean W. X. Ong 5 Division of Infectious Diseases, Sunnybrook Health Sciences Centre , Toronto, ON, Canada 6 Institute of Health Policy, Management and Evaluation, University of Toronto , Toronto, ON, Canada 17 Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity , Melbourne, Australia 18 Victorian Infectious Disease Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity , Melbourne, Australia MBBS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF ABSTRACT Background There is debate on whether cefazolin or antistaphylococcal penicillins should be the first-line treatment for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. Ongoing trials are investigating whether cefazolin is non-inferior to (flu)cloxacillin, but it remains uncertain whether these findings would apply to other antistaphylococcal penicillins. Objective We conducted a systematic review and meta-analysis comparing cefazolin to each of the individual antistaphylococcal penicillins for MSSA bacteremia. Data Sources We updated a 2019 systematic review but specifically focused on evaluating outcomes by individual antistaphylococcal penicillins. Study Eligibility Criteria Comparative observational studies. Participants Patients with MSSA bacteremia. Interventions Cefazolin versus the antistaphylococcal penicillins. Assessment of Risk of Bias The risk of bias in non-randomized studies of interventions tool. Methods of Data Synthesis The primary outcome was 30-day all-cause mortality, and we assessed for non-inferiority of cefazolin using a prespecified non-inferiority margin of a pooled odds ratio (OR) <1.2. Secondary outcomes were 90-day mortality, treatment-related adverse events (TRAEs), discontinuation due to toxicity, and nephrotoxicity. Results No randomized data have been published. 30 observational studies at moderate or high risk of bias were included, which comprised 3869 patients who received cefazolin and 11644 patients who received antistaphylococcal penicillins (flucloxacillin=6721, unspecified=2440, nafcillin=1305, cloxacillin=1258, and oxacillin=120). Cefazolin was associated with a reduced odds of 30-day all-cause mortality (OR=0.73, 95%CI=0.62-0.85) compared to antistaphylococcal penicillins, meeting pre-specified non-inferiority as well as superiority. This effect was consistent versus flucloxacillin (OR=0.92, 95%CI=0.73-1.16), nafcillin (OR=0.58, 95%CI=0.28-1.17), cloxacillin (OR=0.42, 95%CI=0.11-1.58), and oxacillin (OR=0.31, 95%CI=0.03-2.75). Point estimates favored cefazolin for 90-day mortality, TRAEs, nephrotoxicity, and discontinuation due to toxicity overall and in each comparison with individual antistaphylococcal penicillins, except for TRAEs versus cloxacillin. Conclusions In moderate to low quality observational data, cefazolin was associated with superior effectiveness and safety as compared to antistaphylococcal penicillins overall and individually. INTRODUCTION Staphylococcus aureus bacteremia (SAB) is common, with an incidence ranging from 9-65 cases per 100,000 person-years,[ 1 ] and morbid with a 90-day all-cause mortality of ∼30%[ 2 ]. While there are multiple treatment options for methicillin-susceptible S. aureus (MSSA) bacteremia, there is no international consensus as to whether cefazolin or an antistaphylococcal penicillin is the optimal first-line treatment[ 3 ]. There are theoretical concerns that cefazolin may be suboptimal, particularly for infections with a high organism burden like endocarditis, because of the risk of an inoculum effect[ 4 ]. Because no international consensus guidelines on MSSA bacteremia have been published, recommendations are often extrapolated from native valve MSSA infective endocarditis (IE) guidelines. The European Society of Cardiology favors (flu)cloxacillin or cefazolin[ 5 ], the American Heart Association recommends nafcillin or oxacillin[ 6 ], the British Society for Antimicrobial Chemotherapy prefers flucloxacillin[ 7 ], whereas the WikiGuidelines have no preference between cefazolin, (flu)cloxacillin, nafcillin, or oxacillin[ 8 ] ( Supplemental Table 1 ). Drug availability also differs by setting ( e.g., flucloxacillin and cloxacillin are not commercially available in the United States). In contrast to the theoretical concerns over the inoculum effect, the observational evidence suggests that cefazolin is associated with less nephrotoxicity and similar effectiveness to antistaphylococcal penicillins[ 9 ]. Two ongoing randomized controlled trials (RCTs), the S. aureus Network Adaptive Platform (SNAP) trial ( NCT05137119 )[ 10 ] and the CloCeBa trial ( NCT03248063 )[ 11 ], will determine whether cefazolin is non-inferior to (flu)cloxacillin for the treatment of MSSA bacteremia. However, these trials will not compare cefazolin to other antistaphylococcal penicillins, specifically nafcillin and oxacillin, which are the preferred treatment for MSSA bacteremia in certain countries. The individual antistaphylococcal penicillins have distinct pharmacokinetic, pharmacodynamic, and in vitro properties, which could influence relative efficacy[ 12 , 13 ]. Further, there is observational data outside of MSSA bacteremia suggesting that the antistaphylococcal penicillins may have distinct safety profiles[ 14 , 15 ]. There are limited data directly comparing the different antistaphylococcal penicillins; therefore, it remains unclear whether the relative efficacy of cefazolin versus (flu)cloxacillin will be extrapolatable to comparisons between cefazolin and other antistaphylococcal penicillins. Prior systematic reviews on the topic did not stratify comparisons by individual antistaphylococcal penicillins[ 9 , 16 – 20 ] and since the latest systematic review[ 9 ], new studies have been published. We therefore aimed to update the previous systematic review[ 9 ] while specifically seeking to compare cefazolin to each antistaphylococcal penicillin separately to determine if effects are consistent across the entire antistaphylococcal penicillin class, which will be unanswered by the ongoing trials. METHODS Protocol This study was conducted according to a pre-specified protocol registered on PROSPERO (CRD42024586270) and was conducted in accordance with guidance from PRISMA[ 21 ], MOOSE[ 22 ], and the Cochrane Handbook for Systematic Reviews of Interventions[ 23 ]. Search Strategy The search strategy of PubMed, the Web of Science, the Cochrane Library of Systematic Reviews, and clinicaltrials.gov from Weis et al.[ 9 ], initially conducted from database inception to June 26, 2018, was updated from June 26, 2018 to August 29, 2024 ( Supplemental Table 2 ). No language restrictions were used. Studies in languages other than French or English were translated to English using Google Translate. Study Selection The search results were imported into Covidence[ 24 ], de-duplicated, and screened by title and abstract by two independent reviewers (CP and DN). The full texts of relevant articles were retrieved and were screened in duplicate for fulfillment of the inclusion and exclusion criteria. The references lists of included articles and prior systematic reviews[ 9 , 16 – 20 ] were screened for additional studies relevant for inclusion. Disagreements throughout were resolved by consensus and if consensus could not be achieved a third reviewer (SWXO) adjudicated. Inclusion and Exclusion Criteria RCTs or observational studies comparing cefazolin to any antistaphylococcal penicillins for MSSA bacteremia (regardless of its susceptibility to penicillin) were included. Case reports or series and conference abstracts were excluded. Studies comparing adjunctive therapies ( e.g., ertapenem) or not reporting on the primary or secondary outcomes were excluded. Antistaphylococcal penicillins were defined as any of the following: cloxacillin, flucloxacillin, dicloxacillin, oxacillin, or nafcillin. Quality Assessment Study quality was evaluated in duplicate using the Cochrane Risk of Bias in Non-Randomized Studies I (ROBINS-I) tool[ 25 ]. Overall ratings corresponded to the lowest quality ranking in any one domain[ 25 ]. Disagreements were resolved by consensus. The robvis package[ 26 ] was used for visualization of quality assessments. Outcomes The primary outcome was 30-day all-cause mortality for cefazolin versus the individual antistaphylococcal penicillins. For the primary outcome, we prespecified a non-inferiority margin of less than 1.2 for the upper bound of the 95% confidence interval (95%CI) of the odds ratio (OR) for cefazolin versus the antistaphylococcal penicillins, corresponding to the non-inferiority margin used for the SNAP trial[ 10 ]. The secondary outcomes were 90-day all-cause mortality, treatment-related adverse events (TRAE, as defined by the study), treatment discontinuation due to toxicity, and nephrotoxicity (as defined by the study). Analyses were conducted for cefazolin versus the antistaphylococcal penicillins, stratified by the individual antistaphylococcal penicillins. Subgroup effects by antistaphylococcal penicillins were tested by the Q-test[ 23 ]. A post hoc subgroup analysis was conducted for patients with IE. Data Extraction In addition to the primary and secondary outcomes, the following variables were extracted in duplicate by independent reviewers: author, year, study design, number of centers, country, sex, study arms, and mean/median age, as well as the proportion admitted to the intensive care unit (ICU) and with IE at study entry. Adjusted data from propensity matched cohorts were extracted over unadjusted data, when presented. Otherwise, raw data were extracted. When data pertaining to the primary or secondary outcomes were unreported or if only pooled data across antistaphylococcal penicillins were reported instead of stratified by individual antistaphylococcal penicillins, study authors were contacted by email up to 3 times to request these data. Statistical Analyses Analyses were performed with R (Version 4.3.2, R Foundation for Statistical Computing, Vienna, Austria) using the metafor [ 27 ] and meta [ 28 ] packages. Data were pooled by a frequentist random-effects inverse variance meta-analysis using a DerSimonian and Laird estimator for inter-study variance[ 29 ]. A 0.5 continuity correction was added for 0 event cells. I 2 was used to evaluate inter-study heterogeneity; values >50% were considered as significant heterogeneity[ 23 ]. 95% confidence intervals (95%CI) were computed using a Wald-type normal distribution. Sensitivity Analyses We pre-specified the following sensitivity analyses for the primary outcome: (i) restricting the analysis to studies at low or moderate risk of bias, (ii) including only studies conducted in high income countries, based on the World Bank classification (as drug availability and outcomes may differ significantly across high vs. low-income settings), and (iii) patients with IE. Publication bias of the primary outcome was assessed by visual inspection of a funnel plot and by Egger’s test[ 23 ]. The influence of individual studies on the overall estimate of the primary outcome was evaluated by a leave-one-out meta-analysis[ 23 ]. Certainty of Evidence The certainty of evidence for the primary and secondary outcomes was evaluated in duplicate by independent reviewers using the GRADE criteria[ 30 ] and presented using GRADEpro GDT[ 31 ]. RESULTS Search Results and Population Characteristics A total of 263 records were screened, 45 were evaluated by full text, of which, 15 were excluded with justification ( Figure 1 ). The remaining 30 studies[ 32 – 61 ] were published from 2011-2024 and spanned 10 high-income countries. Four of the included studies were restricted to patients with IE[ 38 , 40 , 44 , 62 ], three focused on only penicillin-susceptible S. aureus [ 49 , 55 , 57 ], and one was limited to patients on hemodialysis[ 54 ]. A total of 3869 patients received cefazolin and 11644 received antistaphylococcal penicillins. Flucloxacillin was the most commonly administered antistaphylococcal penicillin (N=6721, 4 studies[ 37 , 42 , 55 , 56 ]), followed by nafcillin (N=1305, 13 studies[ 33 , 36 , 39 , 41 , 43 , 45 , 48 , 50 , 52 , 57 , 58 , 60 , 61 ]), cloxacillin (N=1258, 7 studies[ 34 , 38 , 40 , 49 , 51 , 54 , 59 ]), and oxacillin (N=120, 4 studies[ 41 , 46 , 53 , 60 ]). Data stratified by individual antistaphylococcal penicillin was not available for four studies[ 35 , 44 , 47 , 62 ] (N=2240) and 2 studies reported data on two antistaphylococcal penicillins[ 41 , 60 ]. The population was predominantly male (67.1%) and the mean/median ages ranged from 50-71 years. Further study details are presented in Supplemental Tables 3 and 4 . Download figure Open in new tab Figure 1. PRISMA diagram. Study Quality The majority of studies (N=27, 90.0%) were at high risk of bias[ 32 – 34 , 36 – 42 , 44 , 46 – 61 ] due to concerns spanning multiple domains, and the remaining 3 studies (10.0%) were at moderate risk of bias[ 35 , 43 , 45 ] ( Figure 2 ). First, adjustments for confounding by indication were inadequate or absent. Second, there was potential for immortal time bias, especially when patients were classified according to their definitive therapy. Third, important co-interventions such as surgical interventions or adjunctive agents were often imbalanced or unreported. Fourth, loss to follow-up was frequently unreported and no study had a pre-specified statistical analysis plan. Fifth, there was potential for ascertainment bias in the measurement of TRAEs and nephrotoxicity given that outcome assessment was not blinded. Download figure Open in new tab Figure 2. Risk of bias assessment. 30-Day All-Cause Mortality In the 16 studies that reported on 30-day all-cause mortality, cefazolin was associated with a reduced odds of 30-day mortality compared to antistaphylococcal penicillins (8.6% [227/2631] vs. 11.9% [1113/9338], OR=0.73, 95%CI=0.62-0.85, I 2 =0.0%, 16 studies, Figure 3 ). There was no significant difference in treatment effect within a subgroup analysis of the individual antistaphylococcal penicillins (P=0.3). Point estimates continued to favor cefazolin when results were stratified by individual antistaphylococcal penicillins, but none were statistically significant, including: flucloxacillin (10.6% [92/865] vs. 11.3% [752/6665], OR=0.92, 95%CI=0.73-1.16, I 2 =0%, 3 studies), nafcillin (3.5% [16/462] vs. 6.8% [33/486], OR=0.58, 95%CI=0.28-1.17, I 2 =0.0%, 7 studies), cloxacillin (7.9% [3/38] vs. 18.6% [18/97], OR=0.42, 95%CI=0.11-1.58, I 2 =0.0%, 3 studies), and oxacillin (1.8% [4/227] vs. 2.3% [1/42], OR=0.31, 95%CI=0.03-2.75, I 2 =0.0%, 2 studies). Cefazolin met the pre-specified margin for non-inferiority when compared to antistaphylococcal penicillins as an entire group, as well as flucloxacillin and nafcillin individually, which had the largest number of patients available for comparisons. Download figure Open in new tab Figure 3. Forest plot of 30-day all-cause mortality for cefazolin vs. individual antistaphylococcal penicillins (ASP), the red line represents the non-inferiority margin. 90-Day All-Cause Mortality The point estimate for 90-day all-cause mortality favored cefazolin and met the prespecified non-inferiority margin (17.1% [359/2097] vs. 24.1% [801/3318], OR=0.80, 95%CI=0.61-1.05, I 2 =29.0%, 14 studies, Figure 4 ). Effects were consistent across individual antistaphylococcal penicillins (P=0.8) and all favored cefazolin without achieving statistical significance. Download figure Open in new tab Figure 4. Forest plot of 90-day all-cause mortality for cefazolin vs. individual antistaphylococcal penicillins (ASP), the red line represents the non-inferiority margin. Safety Outcomes Cefazolin was associated with a reduced odds of TRAEs compared to antistaphylococcal penicillins (11.0% [116/1052] vs. 23.5% [412/1755], OR=0.33, 95%CI=0.18-0.63, I 2 =75.8%, 14 studies, Figure 5 ). There were significant imbalances in subgroup analyses by individual antistaphylococcal penicillins (P<0.1). The point estimate favored cloxacillin (7.4% [6/81] vs. 2.4%, OR=1.65, 95%CI=0.47-5.87, I 2 =0.0%, 3 studies). However the remaining estimates favored cefazolin over nafcillin (8.7% [67/771] vs. 35.3% [364/1031], OR=0.53, 95%CI=0.17-1.65, I 2 =53.2%, 8 studies) and oxacillin (2.8% [11/397] vs. 10.7% [12/112], OR=0.39, 95%CI=0.04-4.22, I 2 =76.6%, 3 studies). No studies on flucloxacillin reported TRAEs. Download figure Open in new tab Figure 5. Forest plot of treatment-related mortality for cefazolin vs. individual antistaphylococcal penicillins (ASP). Discontinuation due to toxicity was reduced with cefazolin compared to antistaphylococcal penicillins (2.1% [14/669] vs. 16.8% [142/843], OR=0.13, 95%CI=0.06-0.27, I 2 =20.4%, 10 studies, Figure 6 ) and effects were consistent across individual antistaphylococcal penicillins (P=0.8), with each estimate favoring cefazolin. Cefazolin was associated with significantly less toxicity than nafcillin (2.2% [12/542] vs. 20.0% [115/576], OR=0.09, 95%CI=0.03-0.30, I 2 =51.4%, 7 studies) and oxacillin (1.0% [3/294] vs. 13.0% [7/54], OR=0.15, 95%CI=0.04-0.67, I 2 =0.0%, 2 studies). There were insufficient studies to perform a meta-analysis of discontinuation due to toxicity for cloxacillin and flucloxacillin. Download figure Open in new tab Figure 6. Forest plot of discontinuation due to toxicity for cefazolin vs. individual antistaphylococcal penicillins (ASP). Nephrotoxicity was also lower with cefazolin versus antistaphylococcal penicillins (4.4% [48/1103] vs. 13.7% [205/1498], OR=0.30, 95%CI=0.20-0.46, I 2 =13.6%, 13 studies, Figure 7 ) and this effect was consistent across individual antistaphylococcal penicillins (P=0.5) with each estimate favoring cefazolin. Cefazolin was associated with significantly reduced nephrotoxicity compared to nafcillin (3.5% [30/850] vs. 15.2% [181/1194], OR=0.24, 95%CI=0.16-0.37, I 2 =0.0%, 9 studies), but not compared to oxacillin (0.3% [1/397] vs. 0.9% [1/112], OR=0.57, 95%CI=0.06-5.56, I 2 =0.0%, 3 studies). None of the flucloxacillin or cloxacillin studies reported of nephrotoxicity. Download figure Open in new tab Figure 7. Forest plot of nephrotoxicity for cefazolin vs. individual antistaphylococcal penicillins (ASP). GRADE Recommendations The certainty of evidence that, compared to antistaphylococcal penicillins, cefazolin was non-inferior for 30-day and 90-day all-cause mortality was low and very low, respectively. Certainty that cefazolin reduced: TRAEs was low; discontinuation due to toxicity was high; and nephrotoxicity was moderate ( Supplemental Table 5 ). Subgroup Analyses All studies were conducted in high income countries, which precluded this subgroup analysis. Excluding the studies at serious risk of bias favored cefazolin for 30-day all-cause mortality but was not statistically significant and did not meet the prespecified non-inferiority margin due to sample size (5.5% [9/164] vs. 7.7% [19/248], OR=0.72, 95%CI=0.28-1.85, I 2 =6.3%, 3 studies, Supplemental Figure 1 ). Subgroup analysis of patients with IE did not meet non-inferiority for 30-day all-cause mortality but cefazolin was favored (8.2% [5/61] vs. 15.7% [83/527], OR=0.35, 95%CI=0.05-2.72, I2=42.0%, 2 studies, Supplemental Figure 2 ). There was no evidence of publication bias by funnel plot asymmetry or Egger’s test for the primary and secondary outcomes ( Supplemental Figures 3 - 7 ). When the McDanel et al. study[ 47 ] was omitted from the meta-analysis of 30-day all-cause mortality, the pooled estimate was no longer statistically significant for superiority (OR=0.87, 95%CI=0.70-1.07, Supplemental Figure 8 ), but continued to meet non-inferiority. Otherwise, no studies with disproportionate impact on the overall estimates were identified ( Supplemental Figures 8 - 12 ). Meta-regression was not performed because there were less than 10 studies[ 23 ] reporting each of the predictors of interest for the primary outcome. DISCUSSION In this systematic review and meta-analysis of moderate to low quality observational studies, cefazolin was non-inferior to antistaphylococcal penicillins for 30-day mortality, non-inferior for 90-day mortality, and was associated with less toxicity across all safety outcomes. These results are consistent with previous reviews on the topic 8,11–15 ; however, our study adds an additional 16 studies comprising 2654 patients compared to the most recent review[ 9 ]. Cefazolin was favorable compared to antistaphylococcal penicillins overall and individually (except cloxacillin for TRAEs) across all safety outcomes tested, including a 7-fold reduction in discontinuation due to toxicity and 3-fold reduction in occurrence of nephrotoxicity. This is an especially important consideration in the predominantly elderly and comorbid population with MSSA bacteremia, who frequently have chronic kidney disease[ 47 ] and for deep-seated MSSA infections like IE or osteomyelitis where therapy can be 6 weeks in duration. Cefazolin is also advantageous over antistaphylococcal penicillins because of less frequent dosing, which both reduces nursing resources needed for inpatients and facilitates outpatient parenteral antibiotic therapy. Cefazolin can be given thrice weekly on hemodialysis which eliminates the need for additional catheters in this population[ 63 ]. There are considerable geographic differences in the choice of antistaphylococcal penicillins or cefazolin as first-line therapy for MSSA bacteremia[ 3 ]. There is also regional variability in the selection and availability of antistaphylococcal penicillins that is reflected by differing international guideline recommendations[ 5 – 8 ] ( Supplemental Table 1 ). The SNAP[ 10 ] and CloCeBa[ 11 ] trials are comparing cefazolin to (flu)cloxacillin. If these trials demonstrate that cefazolin is non-inferior to (flu)cloxacillin for mortality, particularly if associated with a superior safety profile, the results of this meta-analysis suggest that it would be reasonable to extrapolate the findings of SNAP and CloCeBa to the other antistaphylococcal penicillins ( i.e., nafcillin and oxacillin). Strengths of this systematic review include a thorough exploration of multiple effectiveness and safety outcomes and stratification by individual antistaphylococcal penicillins. Further, the minimal statistical heterogeneity and consistent results across subgroups and sensitivity analyses bolster our findings. However, this review is subject to certain limitations, many of which are inherent to the studies included. First, most of the studies were at high risk of bias due to confounding by indication and the potential for immortal time bias. Second, between study differences in the definition and measurement of TRAEs and nephrotoxicity may produce heterogeneity. Third, we were unable to complete several pre-specified subgroup and sensitivity analyses due to a lack of granularity in the reported data. Fourth, there were no eligible studies of dicloxacillin, few studies of oxacillin, and pediatric data were lacking. Nevertheless, we believe that these results represent the most current and comprehensive comparison of cefazolin vs. antistaphylococcal penicillins. CONCLUSION The current body of observational evidence suggests that cefazolin may be associated with reduced mortality and toxicity compared to antistaphylococcal penicillins. These results were consistent across comparisons with individual antistaphylococcal penicillins, suggesting that any differences compared to cefazolin are likely similar across the antistaphylococcal penicillins class. Data Availability All data produced in the present study are available upon reasonable request to the authors AUTHOR CONTRIBUTIONS Conceptualization - SWXO, CP, TCL, EGM, SYCT. Methodology - SWXO, CP, TCL, EGM, SYCT, DN. Software - CP, SWXO. Validation - CP, DN, SWXO. Formal Analysis - CP, SWXO. Investigation - CP, DN, SWXO. Resources - SWXO, TCL, EGM, SYCT. Data Curation - CP, DN. Writing Original Draft - All authors. Writing Review and Editing - All authors. Visualization - CP, SWXO. Supervision - SWXO, TCL, EGM, SYCT. Project administration - CP, SWXO, TCL, EGM, SYCT. SUPPLEMENTAL FIGURES Download figure Open in new tab Supplemental Figure 1. Forest plot of 30-day all-cause mortality for cefazolin vs. antistaphylococcal penicillins (ASP) excluding studies at high risk of bias. Download figure Open in new tab Supplemental Figure 2. Forest plot of 30-day all-cause mortality for cefazolin vs. antistaphylococcal penicillins (ASP) in patients with IE. Download figure Open in new tab Supplemental Figure 3. Funnel plot of 30-day all-cause mortality for cefazolin vs. antistaphylococcal penicillins (ASP). Download figure Open in new tab Supplemental Figure 4. Funnel plot of 90-day all-cause mortality for cefazolin vs. antistaphylococcal penicillins. Download figure Open in new tab Supplemental Figure 5. Funnel plot of treatment-related adverse events for cefazolin vs. antistaphylococcal penicillins. Download figure Open in new tab Supplemental Figure 6. Funnel plot of discontinuation due to toxicity for cefazolin vs. antistaphylococcal penicillins. Egger’s test was not performed because there were <10 studies reporting outcome. Download figure Open in new tab Supplemental Figure 7. Funnel plot of nephrotoxicity for cefazolin vs. antistaphylococcal penicillins. Download figure Open in new tab Supplemental Figure 8. Leave-one-out meta-analysis of 30-day all-cause mortality for cefazolin vs. antistaphylococcal penicillins. Download figure Open in new tab Supplemental Figure 9. Leave-one-out meta-analysis of 90-day all-cause mortality for cefazolin vs. antistaphylococcal penicillins. Download figure Open in new tab Supplemental Figure 10. Leave-one-out meta-analysis of treatment-related adverse events for cefazolin vs. antistaphylococcal penicillins. Download figure Open in new tab Supplemental Figure 11. Leave-one-out meta-analysis of discontinuation due to toxicity for cefazolin vs. antistaphylococcal penicillins. Download figure Open in new tab Supplemental Figure 12. Leave-one-out meta-analysis of nephrotoxicity for cefazolin vs. antistaphylococcal penicillins. ACKNOWLEDGEMENTS The authors have no acknowledgements. Footnotes Funding: This project received no funding. Conflicts of Interest: TCL, ND, JSD, NGLJ, NGZ, ALG, AJK, IK, BJM, EGM, SYCT, and SWXO are investigators for the Staphylococcus aureus Network Adaptive Platform trial. The remaining authors have no conflicts of interest to declare. REFERENCES 1. ↵ Hindy J-R , Quintero-Martinez JA , Lee AT , et al. Incidence Trends and Epidemiology of Staphylococcus aureus Bacteremia: A Systematic Review of Population-Based Studies . Cureus 14 : e25460 . 2. ↵ Bai AD , Lo CKL , Komorowski AS , et al. Staphylococcus aureus bacteraemia mortality: a systematic review and meta-analysis . Clin Microbiol Infect 2022 ; 28 : 1076 – 1084 . OpenUrl CrossRef PubMed 3. ↵ Westgeest AC , Buis DTP , Sigaloff KCE , et al. 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Population pharmacokinetics of unbound cefazolin in infected hospitalized patients requiring intermittent high-flux haemodialysis: can a three-times-weekly post-dialysis dosing regimen provide optimal treatment? J Antimicrob Chemother 2024 ; : dkae318 . View the discussion thread. Back to top Previous Next Posted February 21, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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