Wendy J. Munckhof

Antibiotic Choice May Not Explain Poorer Outcomes in Patients With Staphylococcus aureus Bacteremia and High Vancomycin Minimum Inhibitory Concentrations

BACKGROUND There are concerns about reduced efficacy of vancomycin in patients with Staphylococcus aureus bacteremia (SAB), especially when the minimum inhibitory concentration (MIC) nears the upper limit of the susceptible range. METHODS We examined the relationship between antibiotic treatment, 30-day mortality, and microbiologic parameters in a large Australasian cohort of patients with SAB. RESULTS We assessed 532 patients with SAB from 8 hospitals. All patients with methicillin-resistant S. aureus (MRSA) bacteremia were treated with vancomycin, and patients with methicillin-susceptible S. aureus (MSSA) bacteremia received either flucloxacillin or vancomycin. Increasing vancomycin MIC was associated with increased mortality in vancomycin-treated patients. However, even in patients with MSSA bacteremia treated with flucloxacillin, mortality was also higher if the vancomycin Etest MIC of their isolate was >1.5 μg/mL, compared with those with lower MIC isolates (26.8% vs 12.2%; P < .001). After adjustment in a multivariate model, age, hospital-onset SAB and vancomycin MIC were independently associated with mortality, but methicillin resistance and antibiotic choice were not. CONCLUSIONS We have confirmed an association between higher vancomycin MIC and increased mortality in patients with SAB, but surprisingly this relationship was not related to the antibiotic treatment received, suggesting that the use of vancomycin per se is not responsible for the poorer outcome.

Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia.

ABSTRACT A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥400 has been associated with clinical success when treating Staphylococcus aureus pneumonia, and this target was recommended by recently published vancomycin therapeutic monitoring consensus guidelines for treating all serious S. aureus infections. Here, vancomycin serum trough levels and vancomycin AUC/MIC were evaluated in a “real-world” context by following a cohort of 182 patients with S. aureus bacteremia (SAB) and analyzing these parameters within the critical first 96 h of vancomycin therapy. The median vancomycin trough level at this time point was 19.5 mg/liter. There was a significant difference in vancomycin AUC/MIC when using broth microdilution (BMD) compared with Etest MIC (medians of 436.1 and 271.5, respectively; P < 0.001). Obtaining the recommended vancomycin target AUC/MIC of ≥400 using BMD was not associated with lower 30-day all-cause or attributable mortality from SAB (P = 0.132 and P = 0.273, respectively). However, an alternative vancomycin AUC/MIC of >373, derived using classification and regression tree analysis, was associated with reduced mortality (P = 0.043) and remained significant in a multivariable model. This study demonstrated that we obtained vancomycin trough levels in the target therapeutic range early during the course of therapy and that obtaining a higher vancomycin AUC/MIC (in this case, >373) within 96 h was associated with reduced mortality. The MIC test method has a significant impact on vancomycin AUC/MIC estimation. Clinicians should be aware that the current target AUC/MIC of ≥400 was derived using the reference BMD method, so adjustments to this target need to be made when calculating AUC/MIC ratio using other MIC testing methods.

Life-threatening community-acquired methicillin-resistant Staphylococcus aureus infection in Australia

Eight patients with invasive bacteremic community-acquired methicillin-resistant Staphylococcus aureus infection in southeast Queensland, Australia, are reported. One patient died of septic shock. Haematogenous seeding to lungs, bone, and other sites was common. All isolates carried the virulence factor Panton-Valentine leukocidin and were either the southwest Pacific clone or the newly described Queensland clone. Clinicians should consider community-acquired methicillin-resistant Staphylococcus aureus infection in any patient presenting to hospital with severe staphylococcal sepsis or pneumonia.

Community-acquired methicillin-resistant Staphylococcus aureus causes severe disseminated infection and deep venous thrombosis in children : Literature review and recommendations for management

Abstract:  Community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA) infection in children is increasingly common and can be associated with dissemination and life‐threatening complications. Empiric therapy for presumed severe Staphylococcus aureus infection should be reviewed. Four children with severe invasive CA‐MRSA infection causing osteomyelitis and pneumonia complicated by pulmonary embolus and deep venous thrombosis are described. The literature is reviewed and recommendations for management are provided.

Staphylococcus aureus Genotyping Using Novel Real-Time PCR Formats

ABSTRACT One approach to microbial genotyping is to make use of sets of single-nucleotide polymorphisms (SNPs) in combination with binary markers. Here we report the modification and automation of a SNP-plus-binary-marker-based approach to the genotyping of Staphylococcus aureus and its application to 391 S. aureus isolates from southeast Queensland, Australia. The SNPs used were arcC210, tpi243, arcC162, gmk318, pta294, tpi36, tpi241, and pta383. These provide a Simpsons index of diversity (D) of 0.95 with respect to the S. aureus multilocus sequence typing database and define 61 genotypes and the major clonal complexes. The binary markers used were pvl, cna, sdrE, pT181, and pUB110. Two novel real-time PCR formats for interrogating these markers were compared. One of these makes use of “light upon extension” (LUX) primers and biplexed reactions, while the other is a streamlined modification of kinetic PCR using SYBR green. The latter format proved to be more robust. In addition, automated methods for DNA template preparation, reaction setup, and data analysis were developed. A single SNP-based method for ST-93 (Queensland clone) identification was also devised. The genotyping revealed the numerical importance of the “South West Pacific” and “Queensland” community-acquired methicillin-resistant S. aureus (MRSA) clones and the clonal complex 239 “Aus-1/Aus-2” hospital-associated MRSA. There was a strong association between the community-acquired clones and pvl.

Once-Daily Intravenous Cefazolin Plus Oral Probenecid Is Equivalent to Once-Daily Intravenous Ceftriaxone Plus Oral Placebo for the Treatment of Moderate-to-Severe Cellulitis in Adults

A once-daily regimen of cefazolin (2 g intravenously [iv]) plus probenecid (1 g by mouth) was compared with a once-daily regimen of ceftriaxone (1 g iv) plus oral placebo in a randomized, double-blind equivalence trial of home-based therapy for moderate-to-severe cellulitis in adults. For the assessable recipients of cefazolin-probenecid (n=59) and ceftriaxone-placebo (n=57), clinical cure occurred at the end of treatment in 86% and 96% (P=.11), respectively, and was maintained at 1 month of follow-up in 96% and 91% (P=.55), respectively. The mean number of treatment doses (+/-standard deviation) given was similar in the 2 treatment arms (6.97+/-2.6 for cefazolin-probenecid and 6.12+/-2.1 for ceftriaxone-placebo; P=.06). The median antibiotic trough concentrations were 2.35 microgram/mL for cefazolin and 15.45 microgram/mL for ceftriaxone. Patients in the 2 treatment arms were similar with regard to overall rates of adverse reaction (P=.15), but nausea was more common among those in the cefazolin-probenecid arm (P=.048). The once-daily regimen of cefazolin-probenecid is a cheap, practical, and effective treatment option for moderate-to-severe cellulitis, and it avoids the need to use third-generation cephalosporins in most patients.

Cavernous sinus thrombosis and meningitis from community-acquired methicillin-resistant Staphylococcus aureus infection

Septic cavernous sinus thrombosis is an uncommon clinical syndrome with a high morbidity and mortality. The commonest bacterial pathogen is Staphylococcus aureus. We describe the study of a patient with cavernous sinus thrombosis and meningitis caused by community‐acquired methicillin‐resistant S. aureus (CA‐MRSA) infection. The isolate was genotyped as the ST93 (Queensland) clone of CA‐MRSA and carried the Panton‐Valentine leucocidin genes. Cure was obtained following prolonged antimicrobial therapy with vancomycin, rifampicin, cotrimoxazole and linezolid. Given the high morbidity and mortality of cavernous sinus thrombosis and the worldwide recent emergence of CA‐MRSA, clinicians treating patients with this infection should consider early empirical coverage for CA‐MRSA with an antimicrobial agent, such as vancomycin or linezolid, particularly in the presence of suspected facial staphylococcal skin infections. If vancomycin is used, we emphasize that high doses may be required to achieve even low levels in the cerebrospinal fluid.

Genetic and Molecular Predictors of High Vancomycin MIC in Staphylococcus aureus Bacteremia Isolates

ABSTRACT An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes.

Vancomycin minimum inhibitory concentration, host comorbidities and mortality in staphylococcus aureus bacteraemia

We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30-day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality.

Postantibiotic Suppression of Growth of Erythromycin A-Susceptible and -Resistant Gram-Positive Bacteria by the Ketolides Telithromycin (HMR 3647) and HMR 3004

ABSTRACT We investigated the in vitro postantibiotic effects (PAEs) of the ketolides telithromycin (HMR 3647) and HMR 3004 and analyzed the results using the sigmoid Emax model. Mean maximum telithromycin PAEs against erythromycin A-susceptible strains of Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae were 3.7, 8.9, and 9.7 h, respectively, while maximum PAEs for erythromycin A-resistant strains were much shorter. Mean maximum HMR 3004 PAEs were 3.2 to 4.4 h for all species.