Oral and Parenteral Therapeutic Options for Outpatient Urinary Infections Caused byEnterobacteriaceaeProducing CTX-M Extended-Spectrum β-Lactamases

Abstract

Effective therapeutic options are needed for community-onset urinary tract infections due to Escherichia coli strains that produce CTX-M extended-spectrum ␤-lactamases. We examined 46 urinary isolates producing CTX-M against several oral or long-acting parenteral antimicrobial agents. Approximately 90% were susceptible to fosfomycin and to a combination of cefdinir plus amoxicillin-clavulanate. All were susceptible to ertapenem.Since the early 1990s, Escherichia coli isolates that produce CTX-M extended-spectrum ␤-lactamases (ESBLs) have emerged as a serious cause of urinary tract infections (UTIs) in the community (18). Mortality in the more severe infections, particularly those progressing to bacteremia, is as high as 60.8% (14). Chances of survival increase with appropriate initial antibiotic coverage, while delay in proper therapy is associated with increased mortality (14). Empirical antibiotic therapy, particularly in the outpatient setting, is problematic as most of these organisms are resistant to fluoroquinolones, trimethoprim-sulfamethoxazole, oral cephalosporins, and amoxicillin-clavulanate (18,22). The primary goal of this investigation was to identify potential treatment options for outpatient UTIs with these organisms. We tested several candidate oral antibiotics and one long-acting parenteral agent against a collection of genetically characterized ESBL-producing isolates.The ESBLs produced by each isolate were characterized by PCR amplification followed by sequencing of PCR products as previously described (13). A total of 45 UTI isolates (predominantly E. coli) that produced a CTX-M alone (40 producing CTX-M15, three producing CTX-M16, and one each producing CTX-M8 and CTX-M14) and one isolate that produced a CTX-M15 and an SHV-2 ESBL were examined along with 11 isolates that produced only SHV (four producing SHV-12, three producing SHV-2, and three producing SHV-5) or TEM-10 ESBLs. All isolates were recovered between 2002 and 2008. Isolates were stored frozen at Ϫ70°C in skim milk and subcultured twice prior to susceptibility testing. Each isolate was tested for susceptibility to fosfomycin by the CLSI agar dilution method (4) and to ciprofloxacin, doxycycline, ertapenem, and nitrofurantoin and to a novel combination of cefdinir plus a fixed concentration of amoxicillin-clavulanate by the CLSI broth microdilution method (4). For testing the unique combination of cefdinir and amoxicillin-clavulanate, the cefdinir was diluted in the usual twofold dilution scheme in a fixed concentration of 8 g/ml amoxicillin and 4 g/ml clavulanate. Both cefdinir and amoxicillin-clavulanate were tested separately in the normal twofold dilution format to ascertain their activities when tested alone. The calculation of the percentage of isolates susceptible to the three-drug combination was based upon the cefdinir component and use of the approved cefdinir-susceptible breakpoint of Յ1 g/ml (5).Results are summarized in Table 1. Approximately 90% of urinary CTX-M ESBL-producing isolates were susceptible to the combina...

Fosfomycin and Its Application in the Treatment of Multidrug-Resistant Enterobacteriaceae Infections

“…Far from these descriptions, fosfomycin still exhibits good antibacterial activity, [12][13][14][15][16][17] mainly because its use has been limited in therapeutics. This underutilization was probably due to early problems in determining its true in vitro activity, 15 demonstrating its efficacy as a single agent, 15,18 and the resulting lack of inclination of pharmaceutical companies to perform clinical studies of fosfomycin in combination regimens.…”

The Changing Epidemiology of Extended Spectrum Beta-Lactamases (ESBL) Infections of the Urinary Tract Focusing on Clinical Resistance and Therapeutic Options

“…In the United States 90% of the isolates in one study were susceptible to fosfomycin and to a combination of cefdinir plus amoxicillin-clavulanate. (84,85) Pivmecillinam is a beta lactam antibiotic, which binds penicillin-binding protein 2 (PBP-2) and inhibits cell wall synthesis. This drug has been used in the treatment of cystitis due to Enterobacteriaceae.…”

<i>In vitro</i> activity of fosfomycin against uropathogen multi-drug resistant (MDR)<i> Pseudomonas aeruginosa</i> and <i>Acinetobacter baumannii</i>

“…Urinary infections (UTIs) due to multi-drug resistant Gram-negative bacilli (MDR-GNB) are an increasing clinical problem worldwide (1,2). The prevalence of multi-drug resistant (MDR) bacterial species of Pseudomonas aeruginosa and Acinetobacter baumannii has increased considerably since the introduction followed by arbitrary use of new generation extended spectrum antibiotics like third and fourth generation cephalosporins, carbapenems, monobactams, broad and extended spectrum penicillins etc (3).…”