Cefazolin high-inoculum effect in methicillin-susceptible Staphylococcus aureus from South American hospitals

100

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.

Section: Discussionmentioning

confidence: 99%

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

Echevarria

Hughes

et al. 2014

100

“…Another group reported a rate of only 4% of this type of strains among bloodstream MSSA isolates recovered in the United States during 2010 (47). More recently, these strains were found in 36% of 357 MSSA strains isolated from patients with osteomyelitis and bloodstream infections in Colombia, Ecuador, Colombia, Peru, and Venezuela (48). Again, however, it should be emphasized that the number of situations in which the inoculum effect might have a clinical impact is surely much lower.…”

Section: Figmentioning

confidence: 99%

In Vivo Effects of Cefazolin, Daptomycin, and Nafcillin in Experimental Endocarditis with a Methicillin-Susceptible Staphylococcus aureus Strain Showing an Inoculum Effect against Cefazolin

Nannini

Singh

Arias

et al. 2013

Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log 10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P ‫؍‬ 0.005; daptomycin versus nafcillin, P ‫؍‬ 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log 10 reduction of 1.4 versus 5.5, respectively; P ‫؍‬ 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity. Staphylococcus aureus continues to be an important pathogen causing invasive infections associated with significant morbidity and mortality. These infections include endocarditis, pneumonia, bacteremia, infections of prosthetic devices and catheters, complicated abscesses, osteomyelitis, and other deep-seeded infections, and methicillin-susceptible S. aureus (MSSA) strains still cause a significant proportion of these infections. Currently, more than 90% of S. aureus isolates produce ␤-lactamase (Bla), and four different variants of this enzyme (A, B, C, and D) have been identified by different methods (1-4). The type A Bla was shown to have a higher rate of hydrolysis of cefazolin (5), and several cases of cefazolin clinical failures have been reported in patients with endocarditis caused by MSSA strains showing an inoculum effect against this cephalosporin (6-9). These strains typically display an MIC of cefazolin of greater than 50 g/ml when tested at a high inoculum, associated with cefazolin degradation (7,8). The clinical impact of S. aureus strains showing an inoculum effect against cefazolin on treatment outcome is of potential concern since (i) cefazolin is an option for the treatment of MSSA endocarditis in patients with non-immediate-type hypersensitivity to penicillin (10, 11), (ii) many physicians discharge patients to complete a course of home...

“…Isolates of MSSA often harbor one of four different variants of ␤la (types A, B, C, and D) capable of hydrolyzing penicillins, except isoxazolyl-penicillins (5,6,(9)(10)(11)(12)(13). Among the ␤-lactamase types, ␤la type A has been associated with clinical failures in patients with endocarditis treated with CFZ (5,(14)(15)(16).…”

mentioning

confidence: 99%

“…Among the ␤-lactamase types, ␤la type A has been associated with clinical failures in patients with endocarditis treated with CFZ (5,(14)(15)(16). When available, isolates recovered from these infections often exhibit the cefazolin InE, which can be detected by a marked increase (Ն4-fold) in the MIC of CFZ when a large inoculum is used (10 7 CFU/ml compared to the standard 10 5 CFU/ml) (5,6,16). The inoculum effect is of potential concern, since CFZ is recommended as an option for the treatment of MSSA endocarditis in patients with non-immediate-type hypersensitivity to penicillin (15).…”

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confidence: 99%

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