Vancomycin ANZCOSS substudy

Monash Infectious Diseases is participating in this multicentre study, the Vancomycin Sub-Study of the Australia New Zealand Cooperative On Outcomes in Staphylococcal Sepsis, which is a retrospective study evaluating outcomes of vancomycin treatment for methicillin-susceptible and methicillin-resistant Staphylococus aureus bacteraemia.

Study Coordinator: Dr Natasha Holmes

Participating Sites

• Auckland District Health
• Austin Health
• Ipswich Hospital
• Monash Infectious Diseases
• Princess Alexandra Hospital
• Royal Perth Hospital
• Royal Hobart Hospital
• Westmead Hospital

Journal Articles

Vancomycin AUC/MIC and 30-day mortality in patients with Staphylococcus aureus bacteremia.
Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O’Sullivan MV, Anderson TL, Roberts SA, Warren SJ, Gao W, Howden BP, Johnson PD.
Antimicrob Agents Chemother. 2013 Apr;57(4):1654-63. doi: 10.1128/AAC.01485-12. Epub 2013 Jan 18.
PMID: 23335735 [PubMed – as supplied by publisher]
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

Vancomycin minimum inhibitory concentration, host comorbidities and mortality in Staphylococcus aureus bacteraemia.
Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O’Sullivan MV, Anderson TL, Roberts SA, Warren SJ, Gao W, Johnson PD, Howden BP.
Clin Microbiol Infect 2013 Feb 26. doi: 10.1111/1469-0691.12168. [Epub ahead of print]
Abstract: 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.

Antibiotic choice may not explain poorer outcomes in patients with high vancomycin MIC Staphylococcus aureus bacteremia.
Holmes NE. Turnidge JD. Munchkof WJ. Robinson JO. Korman TM. O’Sullivan MVN. Anderson TL. Roberts SA. Gao W. Christiansen KJ. Coombs GW. Johnson PDR. Howden BP.
J Infect Dis. 2011 Aug;204(3):340-7.
PMID: 21742831 [PubMed – in process]
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.

Accompanying editorial:
Vancomycin Minimum Inhibitory Concentration and Outcome in Patients With Staphylococcus aureus Bacteremia: Pearl or Pellet?
Holland TL, Fowler VG Jr.
J Infect Dis. 2011 Aug;204(3):329-31. No abstract available.
PMID: 21742827 [PubMed – in process]
Full Text

Conference Abstracts
Searching for organism factors that may explain the association between elevated vancomycin minimum inhibitory concentration and mortality in Staphylococcus aureus bacteraemia.
Holmes NE. Turnidge JD. Munchkof WJ. Robinson JO. Korman TM. O’Sullivan MVN. Anderson TL. Roberts SA. Coombs G. Gao W. Johnson PDR. Howden BP.
Antimicrobials. 2012.

Vancomycin Pharmacodynamics in Staphylococcus aureus Bacteremia (SAB).
Holmes NE. Turnidge JD. Munchkof WJ. Robinson JO. Korman TM. O’Sullivan MVN. Anderson TL. Roberts SA. Gao W. Johnson PDR. Howden BP.
International Conference on Antimicrobial Agents and Chemotherapy. 2011.

Increased Mortality in Patients with S. aureus Bacteremia Isolates with Elevated Vancomycin Minimum Inhibitory Concentration (MIC) Persists After Adjustment for Comorbidities.
Holmes NE. Turnidge JD. Munchkof WJ. Robinson JO. Korman TM. O’Sullivan MVN. Anderson TL. Roberts SA. Gao W. Howden BP. Johnson PDR.
International Conference on Antimicrobials Agents and Chemotherapy. 2011.

Vancomycin use itself does not cause poor outcome in Staphylococcus aureus bacteraemia (SAB)?
Holmes NE. Turnidge JD. Munchkof WJ. Robinson JO. Korman TM. O’Sullivan MVN. Anderson TL. Roberts SA. Gao W. Howden BP. Johnson PDR.
Antimicrobials. 2011.

Increased mortality in patients with Staphylococcus aureus bacteraemia (SAB) with elevated vancomycin MIC regardless of antibiotic treatment.
Holmes NE. Turnidge JD. Munchkof WJ. Robinson JO. Korman TM. O’Sullivan MVN. Anderson TL. Roberts SA. Gao W. Howden BP. Johnson PDR.
International Symposium on Staphylococci and Staphylococcal Infections. 2011.

Vancomycin Minimum Inhibitory Concentration (MIC) in Australasian Staphylococcus aureus Bacteraemia (SAB) – an Australian and New Zealand Co-operative on Outcomes in Staphylococcal Sepsis (ANZCOSS) Substudy.
Holmes NE. Turnidge JD. Korman TM. Munchkof WJ.O’Sullivan MVN. Robinson JO. Anderson TL. Roberts SA. Gao W. Johnson PDR. Howden BP.
Antimicrobials. 2010