Prevalence of
            <i>blaZ</i>
            Gene Types and the Inoculum Effect with Cefazolin among Bloodstream Isolates of Methicillin-Susceptible Staphylococcus aureus

Despite the rise and impact of methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus (MSSA) continues to contribute to the overall burden of S. aureus infections, representing Ն50% of clinical S. aureus strains (1-3) with known appreciable mortality outcomes (4, 5). Prevailing evidence supports the use of semisynthetic penicillins, such as oxacillin or nafcillin, or the first-generation cephalosporin cefazolin in preference to vancomycin as optimal therapy for MSSA bloodstream infections (BSI) (6-11). Moreover, an early switch from vancomycin to either nafcillin or cefazolin with definitive MSSA identification was associated with a 69% risk reduction in 30-day in-hospital mortality in a recent retrospective cohort study (11).Cefazolin offers a convenient dosing scheme with a favorable adverse event profile, allowing many institutions to consider its use in the management of MSSA infections (12). However, deepseated infections with a high burden of S. aureus have been shown to overproduce certain types of ␤-lactamases, rendering cefazolin inactive and thus resulting in possible treatment failure (13-15). Furthermore, current practice guidelines, such as those for infective endocarditis, suggest reserving the use of cefazolin for patients with nonanaphylactoid-type penicillin allergies (7). As a result, clinician preference for either nafcillin or oxacillin for more severe or deep-seated MSSA infection has evolved in practice, while the use of cefazolin in this setting remains controversial (12,16,17). The purpose of this study was to evaluate and compare treatment outcomes using cefazolin or oxacillin for MSSA BSI, including deep-seated sources of infection.(Portions of this paper were presented as a poster at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, 5 to 9 September 2014, Washington, DC.) MATERIALS AND METHODS Study design.From January 2010 to April 2013, a retrospective cohort study was conducted at Rush University Medical Center (RUMC) and Northwestern Memorial Hospital (NMH), two tertiary care academic medical centers in Chicago, IL. The study methods were reviewed and approved by the institutional review boards at RUMC, NMH, and Midwestern University. Adult patients who received in-hospital definitive treatment with cefazolin or oxacillin within 48 h of finalized blood cultures with MSSA were eligible for inclusion in the study. Patients were included only once, and only the first (index) in-hospital admission during the study period was evaluated. The index blood culture was the first blood culture growing MSSA during the index admission. Patients were excluded if they (i) were Ͻ18 years of age, (ii) received antibiotics other than cefazolin or oxacillin for definitive treatment of an MSSA BSI, (iii) received Ն5 days of an empirical antibiotic agent active against MSSA prior to definitive treatment with cefazolin or oxacillin, (iv) had a docu-

Section: Discussioncontrasting

confidence: 55%

mentioning

confidence: 99%

Treatment Outcomes with Cefazolin versus Oxacillin for Deep-Seated Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections

Rao

Rhodes

Lee

et al. 2015

“…The efficacy of CFZ in vivo was restored when the strain was cured of ␤-lactamase (TX0117c) (21). The results of the current work reiterate that the CFZ InE can influence the efficacy of CFZ in vivo (4,5). While the percentage of MSSA infections in which the InE may have a clinical effect appears to be quite small, it nonetheless is of concern when the inoculum is large, such as a large vegetation or an undrained abscess.…”

Section: Discussionmentioning

confidence: 61%

“…There are published reports (including from our group) that correlate the CFZ inoculum effect with clinical failure (4,5,7,14,16). These reports have shown that, in the majority of the strains, an increase in the CFZ MICs (tested at high inoculum) was associated with the presence of type A ␤-lactamase (4, 5, 7).…”

Section: Discussionmentioning

confidence: 91%

Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis

Singh

Tran

Nannini

et al. 2017

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in highinoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A ␤-lactamase (␤la)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its ␤la-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to Ն128 g/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log 10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log 10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P ϭ 0.001; CPT versus NAF, P ϭ 0.9830). Both CFZ and CPT were efficacious against the ␤la-cured derivative, TX0117c, compared to time zero (t 0 ) (P ϭ Ͻ0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for highinoculum infections caused by MSSA exhibiting the CFZ InE.KEYWORDS ␤-lactamase, Staphylococcus aureus, ceftaroline, endocarditis S taphylococcus aureus continues to be a leading cause of bacterial infections worldwide, including skin and soft tissue infections, bacteremia, pneumonia, endocarditis, septic arthritis, and osteomyelitis (1-3). The prevalence of methicillin-susceptible S. aureus (MSSA) isolates exhibiting the cefazolin (CFZ) inoculum effect (InE) in the United States has been reported to range from 19% to 27% (4, 5). Besides the United States, the overall prevalence of the cefazolin InE was reported to be 36% in South America (Colombia, Ecuador, Peru, and Venezuela), where MSSA ␤-lactamase (␤la) type A and type C were 66% and 31%, respectively (6). In South Korea, the blaZ gene was detected in 92% of 220 MSSA isolates studied, and a pronounced cefazolin InE was observed in 13%, most of which (79%) expressed type A ␤-lactamase (7). More recently, a study

“…Type A beta-lactamases, in particular, have been hypothesized to contribute to cefazolin treatment failure since they efficiently hydrolyze cefazolin. These reports have demonstrated an increase in MICs for high inocula of MSSA isolates that produce type A beta-lactamases (6,7). However, only isolated case reports have described clinical failures with cefazolin therapy for MSSA endocarditis, and the clinical relevance of this in vitro phenomenon is unclear.…”

mentioning

confidence: 96%

Comparison of Cefazolin versus Oxacillin for Treatment of Complicated Bacteremia Caused by Methicillin-Susceptible Staphylococcus aureus

Echevarria

Hughes

et al. 2014

e Contrary to prior case reports that described occasional clinical failures with cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infections, recent studies have demonstrated no difference in outcomes between cefazolin and antistaphylococcal penicillins for the treatment of MSSA bacteremia. While promising, these studies described low frequencies of high-inoculum infections, such as endocarditis. This retrospective study compares clinical outcomes of cefazolin versus oxacillin for complicated MSSA bacteremia at two tertiary care hospitals between January 2008 and June 2012. Fifty-nine patients treated with cefazolin and 34 patients treated with oxacillin were included. Osteoarticular (41%) and endovascular (20%) sources were the predominant sites of infection. The rates of clinical cure at the end of therapy were similar between cefazolin and oxacillin (95% versus 88%; P ‫؍‬ 0.25), but overall failure at 90 days was higher in the oxacillin arm (47% versus 24%; P ‫؍‬ 0.04). Failures were more likely to have received surgical interventions (63% versus 40%; P ‫؍‬ 0.05) and to have an osteoarticular source (57% versus 33%; P ‫؍‬ 0.04). Failures also had a longer duration of bacteremia (7 versus 3 days; P ‫؍‬ 0.0002), which was the only predictor of failure. Antibiotic selection was not predictive of failure. Rates of adverse drug events were higher in the oxacillin arm (30% versus 3%; P ‫؍‬ 0.0006), and oxacillin was more frequently discontinued due to adverse drug events (21% versus 3%; P ‫؍‬ 0.01). Cefazolin appears similar to oxacillin for the treatment of complicated MSSA bacteremia but with significantly improved safety. The higher rates of failure with oxacillin may have been confounded by other patient factors and warrant further investigation.