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Letters to the Editor / International Journal of Antimicrobial Agents 45 (2015) 84–95

Evaluation of the efficiency of cefoxitin/cefepime combination against Enterobacteriaceae resistant to expanded-spectrum cephalosporins Keywords: Antibiotic resistance Gram-negative ESBL AmpC ␤-lactamase Cefoxitin Cefepime

Sir, Production of extended-spectrum ␤-lactamases (ESBLs) and overproduction of AmpC ␤-lactamases are the most frequent mechanisms by which antibiotic multiresistance occurs. Cephamycins such as cefoxitin have consistent activity in vitro against Enterobacteriaceae and exhibit good stability against hydrolysis by ESBLs [1]. Cefepime has intrinsic activity against AmpC-overproducing strains and has been used for the treatment of invasive infections due to AmpC ␤-lactamase-producing organisms [2]. Theoretically, the combination of cefoxitin with cefepime should cover most Enterobacteriaceae resistant to expanded-spectrum cephalosporins. Minimum inhibitory concentrations (MICs) of clinical strains, chosen to be representative of the dominant resistance groupings found in clinical samples (Table 1), were determined using a microdilution method and were interpreted according to the recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Unlike ESBL-producing strains (MICs of 2–128 mg/L), strains overproducing AmpC ␤-lactamases were susceptible to cefepime (0.125–1 mg/L). Conversely, no strain overproducing chromosomal or plasmid AmpC ␤-lactamases was susceptible to cefoxitin (MICs of 16 mg/L to ≥64 mg/L), whilst cefoxitin MICs were in the susceptible range for ESBL-producing strains,

except for the CTX-M-9/TEM-3-producing Escherichia coli strain, the CTX-M-15-producing Klebsiella pneumoniae strain and the TEM24-producing Enterobacter aerogenes strain (MICs of 16 mg/L to >64 mg/L). The in vitro efficacy of the cefoxitin/cefepime combination was assessed by the chequerboard method. With regard to ESBLproducing strains, the combination showed an additive effect against CTX-M-producing strains [fractional inhibitory concentration index (FICI) range 0.62–0.75] and a synergistic effect against TEM-producing strains (FICI = 0.31). In combination with 8 mg/L cefoxitin (susceptibility breakpoint), cefepime MICs, except for CTX-M-15 producing K. pneumoniae, decreased substantially, typically by 32-fold or more, and dropped into the susceptible range (MICs ≤ 0.5 mg/L). With regard to AmpC-producing strains, the combination revealed no antagonistic effect between cefoxitin and cefepime for AmpC enzymes (FICI range 0.75–2), suggesting that cefepime conserved activity against AmpC-producing strains. The efficacy of the cefoxitin/cefepime combination against a clinical CTX-M-14-producing E. coli and a clinical AmpCoverproducing Enterobacter cloacae was investigated in a mouse sepsis model. These strains are representative of those found in clinical laboratories in terms of epidemiology and MICs. Following infection of mice (OF1) by intraperitoneal administration, antibiotics were intraperitoneally administered at previously reported concentrations (50 mg/kg body weight dose of cefepime [3], 50 mg/kg dose of imipenem [4], 200 mg/kg dose of cefoxitin [1] and 50/200 mg/kg dose of cefoxitin/cefepime) combination at 0.5, 3 and 6 h post infection [4]. Survival of mice (eight animals per group) was monitored for 24 h post infection. Upon infection with CTX-M-14-producing E. coli, the survival rate of mice treated with the cefoxitin/cefepime combination (88%) was similar to that of the imipenem-treated group (88%), significantly higher than in mice receiving cefepime alone (25%) (P = 0.037) and different to that of the group with cefoxitin treatment (75%) (P > 0.05). Upon infection with AmpC-overproducing E. cloacae, only 50% of mice treated with cefoxitin or cefepime alone survived at 24 h post

Table 1 Fractional inhibitory concentration indexes (FICIs) and minimum inhibitory concentration (MICs) of cefoxitin (FOX) and cefepime (CEF) alone and in combination against clinical strains producing extended-spectrum ␤-lactamases and AmpC ␤-lactamases, and frequency of mutants resistant to FOX. Strain and ␤-lactamase(s)

Escherichia coli CTX-M-1 E. coli CTX-M-2 E. coli CTX-M-14 E. coli CTX-M-9/TEM-3 E. coli CTX-M-15 Enterobacter aerogenes TEM-24 Klebsiella pneumoniae CTX-M-15 E. coli AmpC E. coli AmpC E. coli AmpC DHA-1 E. coli AmpC CMY-2 Enterobacter cloacae AmpC E. aerogenes AmpC Citrobacter freundii AmpC K. pneumoniae AmpC DHA-1

FICIa

0.62 0.62 0.75 0.31 0.62 0.31 0.62 0.75 0.75 1.5 1.1 2 2 1.2 2

MIC (mg/L)

Frequency of mutants resistant to FOX (×10−8 )

FOXb

FOX with CEFc (1 mg/L)

FOX with CEFd (4 mg/L)

CEFe

CEF with FOXf (1 mg/L)

CEF with FOXg (8 mg/L)

FOX 8 mg/L

FOX 8 mg/L with CEF 1 mg/L

2 8 2 16 2 128 16 64 64 16 64 64 64 256 64

1 8 0.5 8 0.5 ≤0.015 16 0.50 0.50 0.50 0.125 64 0.25 64 0.125

0.50 2 ≤0.015 0.25 ≤0.015 ≤0.015 16 0.50 0.50 ≤0.015 ≤0.015 0.25 ≤0.015 0.25 ≤0.015

4 16 2 16 2 2 128 0.50 0.25 0.25 0.25 1 0.25 1 0.25

1 8 0.25 8 0.25 0.5 32 0.50 0.25 0.5 1 2 0.5 2 0.5

≤0.015 0.5 ≤0.015 ≤0.015 ≤0.015 0.5 16 0.50 0.25 0.25 1 2 0.5 2 0.5

5.8 (±3.6) 60 (±17) 2.4 (±1.3) NR h 1.5 ± 1.0 NR NR NR NR NR NR NR NR NR NR

2. b Breakpoints of FOX: S ≤ 8 mg/L; R > 32 mg/L. c MIC of FOX in combination with CEF at fixed concentration of 1 mg/L. d MIC of FOX in combination with CEF at fixed concentration of 4 mg/L. e Breakpoints of CEF: S ≤ 1 mg/L; R > 4 mg/L. f MIC of CEF in combination with FOX at fixed concentration of 1 mg/L. g MIC of CEF in combination with FOX at fixed concentration of 8 mg/L. h NR, non-realisable (strain MIC was greater than FOX concentration used).

Letters to the Editor / International Journal of Antimicrobial Agents 45 (2015) 84–95

infection. In contrast, combined cefoxitin/cefepime and imipenem rescued all animals. To complete these data, bacterial loads in the blood, kidney, liver and spleen of treated mice (five to eight mice per group) were determined at 0.5, 3, 6 and 24 h post infection (Supplementary Fig. S1). The cefoxitin/cefepime combination was significantly more effective against the two clinical strains than cefoxitin or cefepime alone in the blood, spleen and liver (P = 0.004–0.008 vs. cefoxitin and P ≤ 0.008 vs. cefepime). However, the efficacy of the cefoxitin/cefepime combination in eliminating CTX-M-14-producing E. coli from the kidneys (P = 0.092) was comparable with that of cefoxitin, probably because of the high urinary concentrations observed with this antibiotic. The effectiveness of the cefoxitin/cefepime combination was confirmed by a rapid and significant decrease in bacterial blood counts (≥3 log in 6 h). Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijantimicag. 2014.10.001. The emergence of clinical isolates resistant to cefoxitin by depletion or loss of porins has been observed in E. coli [5]. The frequency of mutations conferring cefoxitin resistance to ESBL-producing strains was investigated in vitro at a cefoxitin concentration of 8 mg/L (susceptibility breakpoint) and varied from 1.5 × 10−8 to 6.0 × 10−7 . When 1 mg/L cefepime (susceptibility breakpoint) was added, this frequency decreased substantially (>100 fold) (Table 1). The cefoxitin/cefepime combination therefore prevented the appearance of cefoxitin-resistant mutants in CTX-M-producing E. coli strains at clinically relevant concentrations. In conclusion, cefoxitin and cefepime in combination improve antibacterial activity against E. coli and E. aerogenes strains producing ESBLs and is effective against AmpC-overproducing strains but not against CTX-M-15-producing Klebsiella. This combination also prevented the appearance of mutants resistant to cefoxitin in CTXM-producing E. coli strains and may therefore be used to treat E. coli and Enterobacter infections as an alternative to carbapenems, which are considered as last-line agents. These results are promising but need to be backed up by additional studies, in particular with other strains and other ESBLs. Acknowledgments The authors thank Marlene Jan for technical assistance and would like to thank H. N’Guyen for reading and commenting on the manuscript. Funding: This work was supported by the Ministère Franc¸ais de l’Éducation Nationale, de la Recherche et de la Technologie, l’Institut national de la santé et de la recherche médicale (INSERM U1071), and l’Institut National de la Recherche Agronomique (USC2018). This work was also supported by the Centre Hospitalier Régional Universitaire de Clermont-Ferrand (Clermont-Ferrand, France). Competing interests: None declared. Ethical approval: The animal protocol was approved by the Committee for Research and Ethical Issues of the Department of Auvergne (CEMEA Auvergne) following international directive 86/609/CEE [n◦ CE16-09]. References [1] Lepeule R, Ruppé E, Le P, Massias L, Chau F, Nucci A, et al. 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 ␤-lactamase. Antimicrob Agents Chemother 2012;56:1376–81. [2] Tamma PD, Girdwood SCT, Gopaul R, Tekle T, Roberts AA, Harris AD, et al. The use of cefepime for treating AmpC ␤-lactamase-producing Enterobacteriaceae. Clin Infect Dis 2013;57:781–8. [3] Pechère J-C, Vladoianu IR. Development of resistance during ceftazidime and cefepime therapy in a murine peritonitis model. J Antimicrob Chemother 1992;29:563–73.

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[4] Eidam O, Romagnoli C, Dalmasso G, Barelier S, Caselli E, Bonnet R, et al. Fragmentguided design of subnanomolar ␤-lactamase inhibitors active in vivo. Proc Natl Acad Sci U S A 2012;109:17448–53. [5] Martínez-Martínez L. Extended-spectrum ␤-lactamases and the permeability barrier. Clin Microbiol Infect 2008;14(Suppl. 1):82–9. Erratum in: Clin Microbiol Infect 2008;14(Suppl. 5):21–4.

Arnaud Serres Laboratoire de Bactériologie, Centre Hospitalo-Universitaire Clermont-Ferrand, Clermont-Ferrand, France Lucie Gibold a,b Laboratoire de Bactériologie, Centre Hospitalo-Universitaire Clermont-Ferrand, Clermont-Ferrand, France b Microbes, Intestins, Inflammation et Susceptibilité de l’Hôte, INSERM U1071, INRA USC2018, Université d’Auvergne, Clermont-Ferrand, France a

Guillaume Dalmasso Microbes, Intestins, Inflammation et Susceptibilité de l’Hôte, INSERM U1071, INRA USC2018, Université d’Auvergne, Clermont-Ferrand, France Frédéric Robin a,b Richard Bonnet a,b Julien Delmas a,b,∗ a Laboratoire de Bactériologie, Centre Hospitalo-Universitaire Clermont-Ferrand, Clermont-Ferrand, France b Microbes, Intestins, Inflammation et Susceptibilité de l’Hôte, INSERM U1071, INRA USC2018, Université d’Auvergne, Clermont-Ferrand, France ∗ Corresponding

author at: Laboratoire de Bactériologie, CHU Clermont-Ferrand, 58 rue Montalembert, 63003 Clermont-Ferrand, France. Tel.: +33 4 7375 4920; fax: +33 4 7375 4922. E-mail address: [email protected] (J. Delmas) 22 September 2014

http://dx.doi.org/10.1016/j.ijantimicag.2014.10.001

Optimal loading regimen and achievement of trough concentrations for teicoplanin using Japanese population parameters Sir, Teicoplanin (TEIC) is an effective glycopeptide antibiotic against infections with Gram-positive cocci. As TEIC has a long half-life, large volume of distribution and low clearance, the blood concentration requires time to achieve the therapeutic range at steady state. A loading dose (LD) is therefore administered on Day 1 for a rapid therapeutic response [1]. However, as the LD of TEIC is decided by the physician, the probability of achieving an optimal LD regimen remains unclear. We investigated the optimal LD and maintenance dose (MD) as well as the probability of achieving the therapeutic range at steady state using a Monte Carlo simulation. The pseudorandom number of the pharmacokinetic (PK) parameters for 30 000 virtual patients according to a normal distribution was estimated using R software v.3.0.2 (R Core Team, Vienna, Austria; http://www.R-project.org/) with the rnorm function, which was based on and consistent with previously reported population PK parameters in Japan [2]. The trough concentration (Ctrough ) of TEIC was calculated using a twocompartment model with the PK parameters obtained in the Monte Carlo simulation. Of the 30 000 virtual patients, 14 959 were male and 15 041 were female, with a mean ± standard deviation age of 75.5 ± 11.6

cefepime combination against Enterobacteriaceae resistant to expanded-spectrum cephalosporins.

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