Morbidity from in-hospital complications is greater than treatment failure in patients with Staphylococcus aureus bacteraemia.

BACKGROUND: Various studies have identified numerous factors associated with poor clinical outcomes in patients with Staphylococcus aureus bacteraemia (SAB). A new study was created to provide deeper insight into in-hospital complications and risk factors for treatment failure. METHODS: Adult patients hospitalised with Staphylococcus aureus bacteraemia (SAB) were recruited prospectively into a multi-centre cohort. The primary outcome was treatment failure at 30 days (composite of all-cause mortality, persistent bacteraemia, or recurrent bacteraemia), and secondary measures included in-hospital complications and mortality at 6- and 12-months. Data were available for 222 patients recruited from February 2011 to December 2012. RESULTS: Treatment failure at 30-days was recorded in 14.4% of patients (30-day mortality 9.5%). Multivariable analysis predictors of treatment failure included age > 70 years, Pitt bacteraemia score ≥ 2, CRP at onset of SAB > 250 mg/L, and persistent fevers after SAB onset; serum albumin at onset of SAB, receipt of appropriate empiric treatment, recent healthcare attendance, and performing echocardiography were protective. 6-month and 12-month mortality were 19.1% and 24.2% respectively. 45% experienced at least one in-hospital complication, including nephrotoxicity in 19.5%. CONCLUSIONS: This study demonstrates significant improvements in 30-day outcomes in SAB in Australia. However, we have identified important areas to improve outcomes from SAB, particularly reducing renal dysfunction and in-hospital treatment-related complications.

Genetic and molecular predictors of high vancomycin MIC in Staphylococcus aureus bacteremia isolates.

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

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.

First report of probable neurobrucellosis in Australia.

We report the first known Australian case of probable neurobrucellosis, in a young feral-pig shooter who presented with episodic left-sided visual loss and left-sided numbness and headache. Treatment with intravenous ceftriaxone and oral rifampicin, doxycycline and trimethoprim­sulfamethoxazole resulted in a good clinical response.

Community-associated methicillin-resistant Staphylococcus aureus endocarditis 'down under': case series and literature review.

Infective endocarditis is a common complication of Staphylococcus aureus bacteraemia, but literature reports of community-associated methicillin-resistant S. aureus (CA-MRSA) endocarditis are relatively uncommon and mostly comprise intravenous drug users (IVDUs) with the USA300 strain. We report 5 cases of CA-MRSA endocarditis in previously healthy young Australian adults, 4 in IVDUs. Morbidity was high with frequent septic emboli; 3 patients required cardiac surgery and 1 patient died. Typing revealed the 2 most common Australian strains, the Panton-Valentine leukocidin (PVL)-positive ST93 (Queensland) strain and the PVL-negative ST1 (WA-MRSA-1) strain.

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.

First case report of cerebral abscess from Nocardia terpenica and literature review.

Nocardia is a Gram-positive weakly acid-fast bacterium that is ubiquitous in the environment. It represents a rare cause of infection in humans and typically causes pulmonary, cutaneous, or central nervous system (CNS) infections. CNS nocardiosis has very poor prognosis, especially in immunocompromised hosts. Nocardia terpenica is a species of Nocardia consisting of two strains that were reclassified from Nocardia brasiliensis in 2007. We report the second case of CNS Nocardia terpenica infection, and the first case of cerebral abscess from Nocardia terpenica. This report raises the index of suspicion for nocardiosis when evaluating contrast-enhancing CNS lesions, points out the capability of this species for CNS spread, and shares our experience regarding management and prognosis.

Retrospective review of CT-guided intervertebral disc biopsies performed at a tertiary referral centre for suspected osteodiscitis.

INTRODUCTION: Patients with osteodiscitis are often prescribed antibiotics prior to biopsy. There is controversy in the literature about whether antibiotic pre-treatment prior to CT-guided biopsy decreases the microbiological culture yield. Conclusions from previous studies are influenced by sample size error and selection bias. Our study, conducted in a large number of patients over a 10-year period, clarifies this issue so that best clinical practice is assured. METHODS: We performed a retrospective audit of the clinical, radiological and microbiological features of adult patients who underwent CT-guided biopsies for suspected osteodiscitis at a tertiary institution. Patients who had received intravenous antibiotic therapy in the month prior to biopsy or oral antibiotics 2 weeks prior to biopsy were considered as having had antecedent treatment. RESULTS: We initially found no significant difference in the likelihood of a positive culture between patients who had received antecedent treatment and those who had not. However, when we performed a subgroup analysis, we found that using multiple antibiotics influenced the likelihood of a positive culture. A second subgroup analysis demonstrated that pre-treatment reduced the likelihood of a positive culture. This discrepancy arose from the match between the antecedent antibiotics and the organisms' antibiotic sensitivity profile. CONCLUSION: Antibiotic treatment preceding CT-guided biopsy reduces the likelihood of a positive microbiological culture results. However, due to the often poor match, between the pre-treatment antibiotic and the organisms' antibiotic sensitivity profile, this is often not clinically apparent. Furthermore, positive cultures sensitive to the pre-treatment antibiotics can still be obtained.

Methicillin-resistant Staphylococcus aureus genotyping using a small set of polymorphisms.

The aim of this study was to identify a set of genetic polymorphisms that efficiently divides methicillin-resistant Staphylococcus aureus (MRSA) strains into groups consistent with the population structure. The rationale was that such polymorphisms could underpin rapid real-time PCR or low-density array-based methods for monitoring MRSA dissemination in a cost-effective manner. Previously, the authors devised a computerized method for identifying sets of single nucleotide polymorphisms (SNPs) with high resolving power that are defined by multilocus sequence typing (MLST) databases, and also developed a real-time PCR method for interrogating a seven-member SNP set for genotyping S. aureus. Here, it is shown that these seven SNPs efficiently resolve the major MRSA lineages and define 27 genotypes. The SNP-based genotypes are consistent with the MRSA population structure as defined by eBURST analysis. The capacity of binary markers to improve resolution was tested using 107 diverse MRSA isolates of Australian origin that encompass nine SNP-based genotypes. The addition of the virulence-associated genes cna, pvl and bbp/sdrE, and the integrated plasmids pT181, pI258 and pUB110, resolved the nine SNP-based genotypes into 21 combinatorial genotypes. Subtyping of the SCCmec locus revealed new SCCmec types and increased the number of combinatorial genotypes to 24. It was concluded that these polymorphisms provide a facile means of assigning MRSA isolates into well-recognized lineages.

In vitro exposure of community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains to vancomycin: does vancomycin resistance occur?

Vancomycin is the preferred parenteral antibiotic for the treatment of all methicillin-resistant Staphylococcus aureus (MRSA) infections, including the newly emerging community-associated MRSA (CA-MRSA) infections. Vancomycin-intermediate nosocomial MRSA strains have developed in vitro and in vivo after exposure to vancomycin. The aim of this study was to determine whether daily serial passage of CA-MRSA strains onto vancomycin-supplemented agar selects for the development of vancomycin resistance. Twelve clinical isolates of the six commonest Australian and US strains of CA-MRSA were serially passaged daily for 25 days onto brain-heart infusion agar plates supplemented with 4 microg/mL vancomycin and then subcultured for a further 15 days onto antibiotic-free agar to assess the stability of the resistance phenotype. Minimum inhibitory concentrations (MICs) were determined by standard Etest every 5 days from day 0 to day 40. Serial passaging resulted in increased MICs in all strains but the rises were modest, with an increase of < 2 doubling dilutions. All strains remained vancomycin susceptible throughout the experiment according to Clinical Laboratory Standards Institute criteria.

Scedosporium prolificans: an uncommon cause of septic arthritis.

Septic arthritis due to fungal infection is uncommon, but when it does occur it can have a devastating effect. Scedosporium prolificans is an emerging fungal pathogen that appears to have a predilection for bone and cartilaginous surfaces. This fungus is resistant to most commonly prescribed antifungal agents. We report the successful treatment of Scedosporium prolificans septic arthritis with a combination of surgery and new antifungal agents.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics.

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.

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.

Resistance development in community-acquired strains of methicillin-resistant Staphylococcus aureus: an in vitro study.

This study compares in vitro antimicrobial resistance development between strains of Staphylococcus aureus including newly described community-acquired methicillin-resistant strains (CA-MRSA). High-level resistance developed in all strains of S. aureus after exposure to rifampicin and gentamicin and in some strains after fusidic acid exposure, independent of methicillin resistance phenotype. Resistance did not develop after exposure to clindamycin, cotrimoxazole, ciprofloxacin, linezolid, or vancomycin. These results have important implications for therapy of CA-MRSA infections.

Emergence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infection in Queensland, Australia.

OBJECTIVES: To investigate the incidence and epidemiology of non-multiresistant methicillin-resistant Staphylococcus aureus (nmMRSA) infection in south-east Queensland, Australia. STUDY DESIGN: A retrospective survey was done of hospital records of all patients who had non-multiresistant MRSA isolated at Ipswich Hospital (a 250-bed general hospital, 40 km south-west of Brisbane, Queensland, Australia) between March 2000 and June 2001. Laboratory typing of these isolates was done with antibiogram, pulsed-field gel electrophoresis, bacteriophage typing and coagulase gene typing. RESULTS: There were 44 infections caused by nmMRSA. Seventeen infections (39%) occurred in patients from the south-west Pacific Islands (predominantly Samoa, Tonga and New Zealand). Laboratory typing showed that the isolates in Pacific Islanders were Pacific Island strains, and 16/17 of these infections were community acquired. Twenty-three infections (52%) occurred in Caucasians. Eleven of the isolates from Caucasians (48%) were a new predominantly community-acquired strain that we have termed the 'R' pulsotype, nine (39%) were Pacific Island strains, and three (13%) were health care institution-associated strains. Four infections occurred in patients who were not Caucasians or Pacific Islanders. Overall, 34 of all 44 infections (77%) were community acquired. CONCLUSIONS: Non-multiresistant MRSA infection, relatively frequently observed in Pacific Islanders in south-east Queensland, is now a risk for Caucasians as well, and is usually community acquired. Clinicians should consider taking microbiological specimens for culture and antimicrobial susceptibility testing in patients with suspected staphylococcal infections who are not responding to empirical therapy with beta-lactam antibiotics.

Staphylococcus aureus bacteraemia: a major cause of mortality in Australia and New Zealand.

OBJECTIVE: To document the types of, and mortality from, Staphylococcus aureus bacteraemia in Australia and New Zealand, and determine factors associated with mortality. DESIGN AND SETTING: Prospective observational study in 27 independent or hospital pathology laboratories in Australia (24) and New Zealand (3), employing a web-based database to prospectively record demographic features, selected risk factors, principal antibiotic treatment and mortality data on all patients with positive blood cultures for S. aureus from June 2007 to May 2008. MAIN OUTCOME MEASURE: 30-day all-cause mortality. RESULTS: 1994 episodes of S. aureus bacteraemia were identified, and complete 30-day follow-up data were available for 1865. Most episodes had their onset in the community (60.8%; 95% CI, 58.7%-63.0%). Methicillin-resistant S. aureus (MRSA) caused 450 episodes (24.1%; 95% CI, 22.2%-25.9%), and 123 of these (27.3%) had a susceptibility profile consistent with community-associated MRSA. All-cause mortality at 30 days was 20.6% (95% CI, 18.8%-22.5%). On univariate analysis, increased mortality was significantly associated with older age, European ethnicity, MRSA infection, infections not originating from a medical device, sepsis syndrome, pneumonia/empyema, and treatment with a glycopeptide or other non-beta-lactam antibiotic. On multivariable analysis, independent predictors of mortality were age, sepsis syndrome, pneumonia/empyema, device-associated infection with a secondary focus, left-sided endocarditis, and treatment with a glycopeptide such as vancomycin, but not MRSA infection. CONCLUSIONS: S. aureus bacteraemia is a common infection in both the community and hospitals in Australia and New Zealand, and is associated with appreciable mortality. Invasive MRSA infection may be more life-threatening, partly because of the inferior efficacy of the standard treatment, vancomycin. National web-based surveillance of S. aureus bacteraemia and its outcomes is not only important but also easily achievable.

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

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.