Factors influencing time to vancomycin-induced clearance of nonendocarditis methicillin-resistant Staphylococcus aureus bacteremia: role of platelet microbicidal protein killing and agr genotypes

Abstract

Background: Vancomycin susceptibility, the accessory gene global regulator (agr) genotype and function, staphylococcal cassette chromosome (SCC) mec type, and susceptibility to cationic thrombin-induced platelet microbicidal protein 1 (tPMP-1) have been individually predictive of duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. This investigation evaluated the interrelationship of these factors with time to clearance of MRSA bacteremia during vancomycin therapy in patients without endocarditis.

Methods: Vancomycin minimum inhibitory concentration and in vitro killing, agr function (delta-hemolysin activity), agr group, SCCmec type, and survival in tPMP-1 killing assays were determined for 29 MRSA bacteremia isolates.

Results: Increased resistance to tPMP-1 killing was observed with agr group III MRSA (P = .025) and MRSA with reduced or absent agr function (P = .023). The median time to clearance of MRSA bacteremia was earlier for agr group III (3 days) versus group I (10.5 days) or II (15 days) (P = .001). In multivariate analysis, agr group II, reduced tPMP-1 killing in vitro, and prior vancomycin exposure were significant independent predictors of longer MRSA bacteremia duration.

Conclusions: Specific genotypic, phenotypic, and clinical parameters appear to correlate with persistent MRSA bacteremia. The interrelationship of these and other factors probably contributes to vancomycin-mediated clearance of MRSA bacteremia.

Figure 1

Median time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia by accessory gene global regulator (agr) specificity group. The median time to clearance was earlier for agr group III MRSA (3 days) (dashed line) than for group I (10.5 days) (dotted line) or group II (15 days) (solid line) MRSA (P =.001).

Figure 2

Kaplan-Meier analysis of time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia by vancomycin in vitro killing activity. Upper (dotted) line represents 16 patients whose MRSA isolates demonstrated a reduction of <3.0 log₁₀ colony-forming units per mL at 24 h; lower (solid) line represents 13 patients whose MRSA isolates demonstrated a reduction of ≥3.0 log₁₀ colony-forming units per mL (P =.001).

Figure 3

Kaplan-Meier analysis of time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia by thrombin-induced platelet microbicidal protein 1 (tPMP-1) activity. Upper (dotted) line represents 23 patients whose MRSA isolates demonstrated ≥15% MRSA survival at 2 h with exposure to 1 mg/L tPMP-1; lower (solid) line represents 6 patients whose MRSA isolates demonstrated <15% MRSA survival for the same exposure (P =.046).

Figure 4

Kaplan-Meier analysis of time to clearance of methicillin-resistant Staphylococcus aureus bacteremia by previous vancomycin use within 30 days of methicillin-resistant S. aureus bacteremia. Upper (dotted) line represents 12 patients who had received vancomycin previously; lower (solid) line represents 17 patients who had not received vancomycin previously (P =.020).