Cefoxitin as an Alternative to Carbapenems in a Murine Model of Urinary Tract Infection Due to Escherichia coli Harboring CTX-M-15-Type Extended-Spectrum β-Lactamase

Abstract

We investigated the efficiency of the cephamycin cefoxitin as an alternative to carbapenems for the treatment of urinary tract infections (UTIs) due to Escherichia coli producing CTX-M-type extended-spectrum ␤-lactamases. The susceptible, UTIinducing E. coli CFT073-RR strain and its transconjugant CFT073-RR Tc (pbla CTX-M-15 ), harboring a bla CTX-M-15 carryingplasmid, were used for all experiments. MICs of cefoxitin (FOX), ceftriaxone (CRO), imipenem (IMP), and ertapenem (ETP) for CFT073-RR and CFT073-RR Tc (pbla CTX-M-15 ) were 4 and 4, 0.125 and 512, 0.5 and 0.5, and 0.016 and 0.032 g/ml, respectively. Bactericidal activity was similarly achieved in vitro against the two strains after 3 h of exposure to concentrations of FOX, IMI, and ETP that were 2 times the MIC, whereas CRO was not bactericidal against CFT073-RR Tc (pbla CTX-M-15 ). The frequencies of spontaneous mutants of the 2 strains were not higher for FOX than for IMP or ETP. In the murine model of UTIs, mice infected for 5 days were treated over 24 h. Therapeutic regimens in mice (200 mg/kg of body weight every 3 h or 4 h for FOX, 70 mg/kg every 6 h for CRO, 100 mg/kg every 2 h for IMP, and 100 mg/kg every 4 h for ETP) were chosen in order to reproduce the percentage of time that free-drug concentrations above the MIC are obtained in humans with standard regimens. All antibiotic regimens produced a significant reduction in bacterial counts (greater than 2 log 10 CFU) in kidneys and bladders for both strains (P < 0.001) without selecting resistant mutants in vivo, but the reduction obtained with CRO against CFT073-RR Tc (pbla CTX-M-15 ) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producing E. coli. Over the last decade, resistance to ␤-lactams among Enterobacteriaceae has emerged as a major public health threat. This is mostly due to proliferation of extended-spectrum ␤-lactamases (ESBLs), especially of the CTX-M-type, which have spread worldwide both in hospitals and the community (9). Escherichia coli isolates that produce CTX-M (especially CTX-M-15 in Western countries) are currently a serious cause of urinary tract infections (UTIs) in the community (36). Mortality in the most severe infections, particularly those evolving into bacteremia, is as high as 60% (27). In addition, associated resistance to other classes of antimicrobial agents is often observed in CTX-M producers, limiting the availability of therapeutic options. Carbapenems are widely regarded as the drug of choice for parenchymal infections due to ESBL-producing Enterobacteriaceae (35). However, several reports have described the emergence of resistance to carbapenems in Enterobacteriaceae by two mechanisms: (i) in vivo selection of porin-deficient mutants under therapy with carbapenems (11,20) and (ii) emergence of carbapenemases, reported extensively in Klebsiella pneumoniae (18, 30) and more recently in E. coli (18,29). The rise of ESBLs h...

Pharmacological Study of Cefoxitin as an Alternative Antibiotic Therapy to Carbapenems in Treatment of Urinary Tract Infections Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli

“…Alternatives to carbapenems are urgently needed. As cephamycins demonstrate in vitro activity against ESBL-PE, some authors suggest that this class of antibiotics could be used in ESBL-producing E. coli (ESBL-EC) infections (6,7). However, data concerning the use of cefoxitin for the treatment of ESBL-PE infections are scarce, and pharmacodynamic target attainment probabilities in pyelonephritis have not been studied so far.…”

Clinical spectrum of urine cultures positive for ESBL-producing Escherichia coli in hospitalized patients and impact on antibiotic use

“…Cefepime could have been used for 1 patient for [17]. Finally, all but 4 strains were susceptible to cefoxitin, a cephamycin effective for the treatment of UTIs caused by ESBL-producing E. coli in a murine UTI model [18] and in recent retrospective studies [19][20][21]. Our results stress the need to improve the prescribers' awareness of carbapenem alternatives.…”

Cefotaxime and Amoxicillin-Clavulanate Synergism against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Murine Model of Urinary Tract Infection

“…Looking at E. coli, MICs of temocillin and cefoxitin against ESBL-producing E. coli are higher than those of the CTX-CLA combination. Previous reports from our team found a MIC of temocillin against CFT073-RR Tc bla CTX-M-15 between 8 and 32 mg/liter (according to the method used-agar or macrodilution, respectively) and a MIC of cefoxitin of 4 mg/liter (agar dilution) versus a MIC of 0.125 mg/liter for CTX plus CLA (macrodilution) (11,23). This better in vitro efficacy, associated with our in vivo data, suggests that CTX and AMC 5:1 combination may play a leading role among possible alternatives to carbapenems.…”

“…For IMP (100 mg/kg), data from a previous study from our laboratory were used (11). After centrifugation, concentrations were determined by high-performance liquid chromatography with UV detection at 237 nm.…”

“…75-861). The ascending, unobstructed UTI mouse model was used as previously described (11,24). Eight-week-old immunocompetent CBA female mice (weight, 20 to 23 g) were used.…”