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.
87
[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
88
Letters to the Editor / International Journal of Antimicrobial Agents 45 (2015) 84–95
Table 1 Results of Monte Carlo simulation using population mean pharmacokinetic parameters of teicoplanin for five loading dose regimens (A–E).a Probability of achievement (%)
Ctrough (mg/L) 20 mg/L for treating severe infections [5]. The probability of achieving a Ctrough within 20–30 mg/L for each regimen was as follows: A, 0.0%; B, 0.0%; C, 20.6%; D, 65.6%; and E, 81.3% (Table 1). Following a LD of 1200 mg/day, a MD of 600 mg might be necessary for administration over 2 days to obtain a Ctrough of ≥15 mg/L with probability of >80% and 13.3 mg/kg per dose. Furthermore, a LD of 1600 mg/day and MD of 800 mg are necessary for severe infection to obtain a Ctrough of ≥20 mg/kg with probability of >80% and 17.7 mg/kg per dose. Rapid achievement of an effective therapeutic range requires accurate and quick determination of the LD and MD. Treatment options are limited when determination of adequate doses of an antibiotic is difficult. These results indicate that both a LD and MD are required to reach optimal Ctrough in clinical settings. This study might help to characterise the LD and MD of TEIC for the treatment of infections. Funding: No funding sources. Competing interests: None declared. Ethical approval: None required. References [1] Brink AJ, Richards GA, Cummins RR, Lambson J. Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients treated for sepsis. Int J Antimicrob Agents 2008;32:455–8. [2] Nakayama K, Gemma H, Kaibara A, Niwa T. Population pharmacokinetics of teicoplanin in adult patients. Jpn J Chemother 2006;54:1–6. [3] Gould FK, Brindle R, Chadwick PR, Fraise AP, Hill S, Nathwani D, et al.; MRSA Working Party of the British Society for Antimicrobial Chemotherapy. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococ-
cus aureus (MRSA) infections in the United Kingdom. J Antimicrob Chemother 2009;63:849–61. [4] Ueda T, Takesue Y, Nakajima K, Ichki K, Wada Y, Tsuchida T, et al. Evaluation of teicoplanin dosing designs to achieve a new target trough concentration. J Infect Chemother 2012;18:296–302. [5] Pea F, Viale P, Candoni A, Pavan F, Pagani L, Damiani D, et al. Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population benefiting from higher dosages. Clin Pharmacokinet 2004;43:405–15.
Yoichi Hiraki ∗ Naoko Yasumori Masahisa Nagano Daisuke Inoue Department of Pharmacy, National Hospital Organization Kumamoto Medical Center, 1-5 Ninomaru, Kumamoto City, Kumamoto 860-0008, Japan Yasuhiro Tsuji Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama City, Toyama 930-0194, Japan Hidetoshi Kamimura Yoshiharu Karube Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan ∗ Corresponding
author. Tel.: +81 96 353 6501; fax: +81 96 325 2519. E-mail address: [email protected] (Y. Hiraki) 24 September 2014
http://dx.doi.org/10.1016/j.ijantimicag.2014.09.014
Plasmid-mediated quinolone resistance in isolates of Salmonella enterica serotype Typhi, USA Sir, Salmonella enterica serotype Typhi is the causative agent of typhoid fever, a severe, systemic, febrile illness. The infection is usually acquired through consumption of water or food contaminated with human faecal material and is therefore more common in areas with poor sanitation and crowding. Typhoid fever was estimated to cause 11.9 million illnesses and 129 000 deaths in 2010 [1]. A large proportion of typhoid fever occurs among infants and children in South-Central and Southeast Asia. Typhoid fever in the USA is often associated with international travel. Timely treatment with appropriate antimicrobial agents is critical for optimal management of typhoid fever. However, resistance to traditional first-line antimicrobial agents (chloramphenicol, ampicillin and trimethoprim/sulfamethoxazole) is common and has prompted the use of other drugs such as fluoroquinolones (e.g. ciprofloxacin) [2]. In the USA, antimicrobial susceptibility among S. Typhi is monitored by the National Antimicrobial Resistance Monitoring System (NARMS) at the US Centers for Disease Control and Prevention (CDC). Fluoroquinolone resistance among S. enterica has traditionally been associated with point mutations in the topoisomerase genes gyrA/B and parC/E. However, during the last decade, plasmidmediated quinolone resistance (PMQR) mechanisms have emerged in nontyphoidal serotypes of Salmonella [3] and were recently described among S. Typhi from South India [4]. In 2011, 384 isolates of S. Typhi were submitted to NARMS. Antimicrobial susceptibility testing using 15 agents was performed by broth microdilution (Sensititre® ; Trek Diagnostics, Thermo Fisher Scientific, Oakwood Village, OH). When available, Clinical and Laboratory Standards Institute (CLSI) guidelines were
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.
87
[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
88
Letters to the Editor / International Journal of Antimicrobial Agents 45 (2015) 84–95
Table 1 Results of Monte Carlo simulation using population mean pharmacokinetic parameters of teicoplanin for five loading dose regimens (A–E).a Probability of achievement (%)
Ctrough (mg/L) 20 mg/L for treating severe infections [5]. The probability of achieving a Ctrough within 20–30 mg/L for each regimen was as follows: A, 0.0%; B, 0.0%; C, 20.6%; D, 65.6%; and E, 81.3% (Table 1). Following a LD of 1200 mg/day, a MD of 600 mg might be necessary for administration over 2 days to obtain a Ctrough of ≥15 mg/L with probability of >80% and 13.3 mg/kg per dose. Furthermore, a LD of 1600 mg/day and MD of 800 mg are necessary for severe infection to obtain a Ctrough of ≥20 mg/kg with probability of >80% and 17.7 mg/kg per dose. Rapid achievement of an effective therapeutic range requires accurate and quick determination of the LD and MD. Treatment options are limited when determination of adequate doses of an antibiotic is difficult. These results indicate that both a LD and MD are required to reach optimal Ctrough in clinical settings. This study might help to characterise the LD and MD of TEIC for the treatment of infections. Funding: No funding sources. Competing interests: None declared. Ethical approval: None required. References [1] Brink AJ, Richards GA, Cummins RR, Lambson J. Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients treated for sepsis. Int J Antimicrob Agents 2008;32:455–8. [2] Nakayama K, Gemma H, Kaibara A, Niwa T. Population pharmacokinetics of teicoplanin in adult patients. Jpn J Chemother 2006;54:1–6. [3] Gould FK, Brindle R, Chadwick PR, Fraise AP, Hill S, Nathwani D, et al.; MRSA Working Party of the British Society for Antimicrobial Chemotherapy. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococ-
cus aureus (MRSA) infections in the United Kingdom. J Antimicrob Chemother 2009;63:849–61. [4] Ueda T, Takesue Y, Nakajima K, Ichki K, Wada Y, Tsuchida T, et al. Evaluation of teicoplanin dosing designs to achieve a new target trough concentration. J Infect Chemother 2012;18:296–302. [5] Pea F, Viale P, Candoni A, Pavan F, Pagani L, Damiani D, et al. Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population benefiting from higher dosages. Clin Pharmacokinet 2004;43:405–15.
Yoichi Hiraki ∗ Naoko Yasumori Masahisa Nagano Daisuke Inoue Department of Pharmacy, National Hospital Organization Kumamoto Medical Center, 1-5 Ninomaru, Kumamoto City, Kumamoto 860-0008, Japan Yasuhiro Tsuji Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama City, Toyama 930-0194, Japan Hidetoshi Kamimura Yoshiharu Karube Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan ∗ Corresponding
author. Tel.: +81 96 353 6501; fax: +81 96 325 2519. E-mail address: [email protected] (Y. Hiraki) 24 September 2014
http://dx.doi.org/10.1016/j.ijantimicag.2014.09.014
Plasmid-mediated quinolone resistance in isolates of Salmonella enterica serotype Typhi, USA Sir, Salmonella enterica serotype Typhi is the causative agent of typhoid fever, a severe, systemic, febrile illness. The infection is usually acquired through consumption of water or food contaminated with human faecal material and is therefore more common in areas with poor sanitation and crowding. Typhoid fever was estimated to cause 11.9 million illnesses and 129 000 deaths in 2010 [1]. A large proportion of typhoid fever occurs among infants and children in South-Central and Southeast Asia. Typhoid fever in the USA is often associated with international travel. Timely treatment with appropriate antimicrobial agents is critical for optimal management of typhoid fever. However, resistance to traditional first-line antimicrobial agents (chloramphenicol, ampicillin and trimethoprim/sulfamethoxazole) is common and has prompted the use of other drugs such as fluoroquinolones (e.g. ciprofloxacin) [2]. In the USA, antimicrobial susceptibility among S. Typhi is monitored by the National Antimicrobial Resistance Monitoring System (NARMS) at the US Centers for Disease Control and Prevention (CDC). Fluoroquinolone resistance among S. enterica has traditionally been associated with point mutations in the topoisomerase genes gyrA/B and parC/E. However, during the last decade, plasmidmediated quinolone resistance (PMQR) mechanisms have emerged in nontyphoidal serotypes of Salmonella [3] and were recently described among S. Typhi from South India [4]. In 2011, 384 isolates of S. Typhi were submitted to NARMS. Antimicrobial susceptibility testing using 15 agents was performed by broth microdilution (Sensititre® ; Trek Diagnostics, Thermo Fisher Scientific, Oakwood Village, OH). When available, Clinical and Laboratory Standards Institute (CLSI) guidelines were
