Our study results show an association between the use of moxifloxacin in our healthcare system and an increase in fluoroquinolone resistance amongst Gram negative bacteria. The efficacy of moxifloxacin against S. pneumoniae has been documented in multiple studies across multiple patient populations [5–7]. Additionally, moxifloxacin has documented in vivo efficacy against Gram negative bacteria a variety of body tissues [8, 9]. In contrast, moxifloxacin is not FDA approved for the treatment of urinary tract infections, and no published clinical data exists on moxifloxacin's efficacy in urinary tract infections.
Fluoroquinolones exhibit concentration dependent bactericidal effects, and urine excretion of moxifloxacin is half that of the next closest fluroquinolone used in our healthcare system (ciprofloxacin at 43% [3]). Urine concentrations after a single dose of moxifloxacin in healthy volunteers have previously been found to be effective in vitro against levofloxacin susceptible and moderately susceptible strains of E. Coli, E. faecalis, and K. pneumoniae but not P. aeruginosa [10]. However, the relatively low excretion of moxifloxacin into the urine is particularly important due to the rising North American MIC90 of moxifloxacin against E. Coli. The TRUST 11 surveillance database demonstrated an MIC90 of 32 mcg/ml for moxifloxacin against E. Coli.
In addition, in vivo urine bactericidal concentrations may be much higher then in vitro due to biofilm [3] and pH effects [10]. Biofilms have been demonstrated to markedly increase needed minimum inhibitory concentrations (MICs) and a recent study by Rosen et al found filamentous bacteria were common even in healthy women with uncomplicated cystitis [11]. Additionally, fluoroquinolones have been shown to have be less active in acidic urine (pH 5) against E. Coli than in a broth medium [12]. As fluoroquinolone activity is concentration dependent, these factors may contribute to a differential in a sub-therapeutic exposure among urinary pathogens between moxifloxacin and other fluoroquinolones that are excreted in higher urinary concentrations. Sub-therapeutic exposure may result in selection of fluoroquinolone resistant among Gram negative bacteria dwelling in the urinary tract through previously established resistance mechanisms, such as mutations in DNA gyrase or development of efflux pumps [13].
An alternative mechanism for increasing resistance among Gram negative organisms was discussed by von Baum et al. [14] Their study found a doubling in the incidence of Gram negative bacteremia among patients given moxifloxacin as prophylaxis during neutropenia compared to historical controls given levofloxacin. It was proposed that this effect was due to moxifloxacin's superior efficacy against anaerobes. Elimination of native intestinal flora causesa loss of intestinal colonization resistance which may have favored colonization with fluoroquinolone resistant E. coli. Joris et al. [15] was able to show an increase in fluoroquinolone resistant Gram negative bacilli effect in healthy volunteers exposed to ciprofloxacin in combination with a drug with good efficacy against anaerobes, clindamycin. This increase was not seen in patients on ciprofloxacin alone.
In our health care system, ciprofloxacin is still a primary treatment for urinary tract infections. The increasing local resistance of Gram negative bacteria to ciprofloxacin has important consequences for empiric treatment of urosepsis and other Gram negative bacteremias. Further investigations should include microbiological investigation of the proposed mechanism of increasing resistance, as well as assessing the effect of outpatient fluoroquinolone prescriptions on resistance within the healthcare system.
Limitations
While our findings demonstrate an association between increased use of moxifloxacin and sensitivity of gram negative bacteria to fluoroquinolone, this was a retrospective review of antibiotic usage and microbial sensitivity. This study design is incapable of establishing a causal link between moxifloxacin usage and increasing fluoroquinolone resistance. Also, it is currently thought that fluoroquinolone resistance is not significantly influenced by other antimicrobial agents, and thus analysis was limited to the fluoroquinolone class. No formal microbiological studies were undertaken to demonstrate this property within our healthcare system. Finally, this study only considered inpatient antibiotic usage and inpatient blood cultures. It is possible that increases in non-moxifloxacin fluoroquinolone prescriptions to outpatients during the study period may be confounding the observed relationships.