Antibiotic combinations significantly more active than monotherapy in an in vitro infection model of Stenotrophomonas maltophilia

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Abstract

The goal of this study was to investigate clinical doses of trimethoprim–sulfamethoxazole (TMP–SMX) alone and in combination against Stenotrophomonas maltophilia in an in vitro pharmacodynamic infection model. A 1-compartment model was established using 4 clinical isolates of S. maltophilia susceptible to TMP–SMX and susceptible or intermediately susceptible to at least one other agent (ie, ceftazidime, ciprofloxacin, gentamicin, tobramycin). Antibiotics alone and in combination were tested by simulating unbound serum concentration profiles achieved with multiple-dose regimens in humans. Despite susceptible minimum inhibitory concentrations, TMP–SMX alone was bacteriostatic at best against all isolates. All antibiotic combinations were more active than monotherapy as determined by bacterial reductions at both 24 and 48 h (P < 0.0001). Significant benefit was observed even with agents inactive alone or only intermediately susceptible based on minimum inhibitory concentrations. These preclinical data support further investigation of antibiotic combinations in the management of serious S. maltophilia infections.

Introduction

Historically, the taxonomy of Stenotrophomonas maltophilia has evolved from previous genus classifications as Pseudomonas and Xanthomonas (Denton & Kerr, 1998). Theories regarding the organism's route of acquisition and virulence have been equally controversial. Over the past decade, however, S. maltophilia has emerged as an important nosocomial pathogen (Calza et al, 2003, Denton & Kerr, 1998) with patient morbidity and mortality similar to that observed with other Gram-negative infections (Hanes et al, 2002, Morrison et al, 1986, Senol et al, 2002). S. maltophilia infections including pneumonia, bacteremia, and urinary tract are associated with intensive care unit admission, mechanical ventilation, central venous catheterization, immunosuppression, and broad-spectrum antibiotic therapy (Denton & Kerr, 1998).

With few clinical studies and limited knowledge related to antibiotic pharmacodynamics against S. maltophilia, the management of clinical infection relies largely on minimum inhibitory concentrations (MIC) testing. Antibiotic selection is further complicated by high rates of resistance to antibiotics including β-lactams (eg, piperacillin–tazobactam, 40%; ceftazidime, 40%), fluoroquinolones (eg, ciprofloxacin, 53%), and aminoglycosides (eg, tobramycin, 81%) (Gales et al, 2001). In clinical practice, trimethoprim–sulfamethoxazole (TMP–SMX), which demonstrates relatively low rates of resistance (ie, <5%), has become a common treatment of choice. Notably, several recent studies have demonstrated the importance of appropriate antibiotic selection on patient outcome, including survival (Friedman et al, 2002, Hanes et al, 2002, Senol et al, 2002). As one author suggested “patients do not die as a result of S. maltophilia pneumonia but, rather, as a result of the lack of adequate empiric antibiotic therapy” (Hanes et al, 2002).

The goal of this study was to investigate clinical doses of TMP–SMX alone and in combination against S. maltophilia in an in vitro pharmacodynamic model (IPDM). The intention was to generate data to assist therapeutic decisions in the management of serious S. maltophilia infections.

Section snippets

Isolates, antibiotics, and media

Clinical S. maltophilia isolates were identified using a microbiology laboratory database (Microscan®, Dade Diagnostics, Mississauga, ON) of records between 2000 and 2002. Four isolates associated with clinical infection were selected including a peritoneal fluid isolate from a dialysis outpatient in October 2001 (isolate 828), a blood isolate from a hemodialysis outpatient in September 2001 (isolate 503), an endobronchial fluid isolate from a medical intensive care patient in May 2002 (isolate

Results

In static kill curve studies, only ceftazidime alone against isolate 229 produced bacterial kill at 24 h compared with the initial inocula. However, all antibiotic combinations produced net bacterial kill including TMP–SMX plus ceftazidime against isolate 828, TMP–SMX plus ciprofloxacin against isolate 503, TMP–SMX plus gentamicin against isolate 233, and TMP–SMX plus ceftazidime, TMP–SMX plus ciprofloxacin, TMP–SMX plus tobramycin, ceftazidime plus ciprofloxacin, ceftazidime plus tobramycin,

Discussion

There is mounting evidence that clinical outcome is critically dependent on antibiotic selection in the management of S. maltophilia infection. Recent studies have reported significantly lower death rates in patients with bloodstream (Friedman et al, 2002, Senol et al, 2002) and respiratory tract infections (Hanes et al, 2002) treated with appropriate antibiotic therapy. Unfortunately, the challenge of antibiotic selection in clinical practice relies largely on MICs, observational studies, and

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