- Email: [email protected]
Treatment failure due to induction of ciprofloxacin resistance during combination therapy with colistin and ciprofloxacin in multidrug-resistant Pseudomonas aeruginosa bacteraemia
Letters to the Editor / International Journal of Antimicrobial Agents 43 (2014) 383–393
the current study no qnr determinant was clearly outstanding. aac(6 )-Ib-cr was much more prevalent (70%) than any other PMQR determinant. Of the 20 PMQR-positive isolates, 9 (45%) had topoisomerase mutations. These mutations appeared only in E. coli [7/9 (77.8%) E. coli isolates] and K. pneumoniae [2/5 (40%) K. pneumoniae isolates]. Moreover, 55.6% (5/9) of E. coli isolates harboured four or even five mutations affecting gyrA, parC and parE. Most of them harboured ESBLs and aac(6 )-Ib-cr as the only PMQR mechanism. The remaining aac(6 )-Ib-cr genes were detected in K. pneumoniae strains that also harboured qnr genes and ESBLs. One K. pneumoniae isolate had a double Ser83 → Phe, Asp87 → Ala change in gyrA, without any parC mutation. Only three E. coli isolates showed clonality by rep-PCR (data not shown), confirmed by PFGE. Of the PMQR-positive isolates, 50% were quinolone-resistant, 80% of which also harboured topoisomerase mutations. No specific PMQR mechanisms were associated with higher minimum inhibitory concentrations (MICs) to fluoroquinolones. Most enterobacteria harbouring PMQR determinants, but not topoisomerase mutations, had ciprofloxacin MICs of ≤1 mg/L. Lavilla et al. [3] reported that 93.3% of qnr-positive isolates were ciprofloxacinsusceptible, and the highest MICs of ciprofloxacin appeared associated with QRDR mutations. Other authors [5] have found no association between PMQR genes and ciprofloxacin resistance. The current data confirm that the presence of PMQR determinants does not necessarily lead to quinolone resistance. Two K. pneumoniae isolates harbouring qnrB1 and aac(6 )-Ib-cr, but no topoisomerase mutations, were quinolone-resistant. These results suggest that the association of these two mechanisms may cause quinolone resistance in the absence of topoisomerase mutations. In summary, PMQR was much more frequent in ESBLharbouring enterobacteria. PMQR-harbouring, ESBL-positive enterobacteria are in most cases E. coli or K. pneumoniae harbouring qnr and/or aac(6 )-Ib-cr as well as multiple topoisomerase mutations and with high MICs of ciprofloxacin. In the absence of ESBLs, PMQR determinants appear in a wider group of species, qnr determinants are largely predominant, topoisomerase mutations are infrequent and isolates are usually ciprofloxacin-susceptible. PMQR determinants appear able to lead to quinolone resistance by themselves only when two different PMQR determinants appear combined in the same isolate. Funding: This study has been partially financed by the Gerencia Regional de Salud, Consejería de Sanidad, Junta de Castilla y León (Spain) [research grant BI-039-SA33-10]. Competing interests: None declared. Ethical approval: Not required. References [1] Strahilevitz J, Jacoby GA, Hooper DC, Robicsek A. Plasmid-mediated quinolone resistance: a multifaceted threat. Clin Microbiol Rev 2009;22: 664–89. [2] European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2011. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). ECDC: Stockholm, Sweden; 2012. [3] Lavilla S, González-López JJ, Sabaté M, García-Fernández A, Larrosa MN, Bartolomé RM, et al. Prevalence of qnr genes among extended-spectrum lactamase-producing enterobacterial isolates in Barcelona, Spain. J Antimicrob Chemother 2008;61:291–5. [4] Cano ME, Rodríguez-Martínez JM, Agüero J, Pascual A, Calvo J, García-Lobo JM, et al. Detection of plasmid-mediated quinolone resistance genes in clinical isolates of Enterobacter spp. in Spain. J Clin Microbiol 2009;47:2033–9. [5] Kim HB, Park CH, Kim CJ, Kim EC, Jacoby GA, Hooper DC. Prevalence of plasmidmediated quinolone resistance determinants over a 9-year period. Antimicrob Agents Chemother 2009;53:639–45.
391
M. Albert ∗ G. Yagüe ∗ Department of Microbiology, Hospital Universitario Virgen de la Arrixaca, University of Murcia, Madrid – Cartagena Road, s/n 30120, El Palmar, Murcia, Spain M. Fernández Department of Microbiology, Complejo Hospitalario de León, León, Spain ˜ L. Vinuela Department of Microbiology, Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain M. Segovia Department of Microbiology, Hospital Universitario Virgen de la Arrixaca, University of Murcia, Madrid – Cartagena Road, s/n 30120, El Palmar, Murcia, Spain
a
˜ a,b J.L. Munoz Department of Microbiology, Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain b Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
∗ Corresponding authors. Tel.: +34 968 395 372. E-mail addresses: [email protected] (M. Albert), [email protected] (G. Yagüe)
5 August 2013 http://dx.doi.org/10.1016/j.ijantimicag.2014.01.019
Treatment failure due to induction of ciprofloxacin resistance during combination therapy with colistin and ciprofloxacin in multidrug-resistant Pseudomonas aeruginosa bacteraemia Sir, Nosocomial infections caused by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa strains compromise the selection of appropriate antibiotics. Although combination therapy has been considered for severely ill patients as well as for MDR/XDR infections, the benefit may not justify it as a general practice [1]. Here we report on an immunocompromised patient with skin and soft-tissue infection caused by MDR P. aeruginosa who experienced treatment failure due to induction of ciprofloxacin (CIP) resistance during combination therapy with colistin (COL) and CIP. A 36-year-old woman was admitted to Samsung Medical Center (Seoul, South Korea) with neutropenic fever following induction chemotherapy for acute myeloid leukaemia. After 2 days of empirical antibiotic therapy with cefepime, a new skin rash appeared on her left thigh. Blood cultures produced no microbial growth. Since the skin lesion was gradually deteriorating, the tissue was incised and drained, and antibiotics were changed to meropenem. Although a P. aeruginosa strain susceptible to carbapenems was isolated from tissues surgically obtained and cultured, her skin lesion was aggravated. On the 9th post-operative day, an episode of sepsis occurred, with carbapenem-resistant P. aeruginosa bacteraemia (isolate 1). Combination therapy with COL [150 mg intravenous (i.v.) twice daily] and CIP (400 mg i.v. twice daily) was administered based on antimicrobial susceptibility results, and the patient underwent a second operation. However, a second episode of sepsis
392
Letters to the Editor / International Journal of Antimicrobial Agents 43 (2014) 383–393
Fig. 1. (a) Clinical course of treatment in a patient with Pseudomonas aeruginosa bacteraemia. *Colistin, 150 mg intravenous twice daily without a loading dose, CIP: ciprofloxacin. (b) Pulsed-field gel electrophoresis (PFGE) analysis of genomic DNA from ciprofloxacin-resistant P. aeruginosa amplified by PCR. *M: marker; lane 1: Isolate 1; lane 2: Isolate 2; lane 3: P. aeruginosa ATCC 27853. (c) mRNA level of four efflux pump genes by quantitative reverse transcription PCR.
with CIP-resistant P. aeruginosa bacteraemia (isolate 2) recurred on the 10th day of combination therapy. On revision of antibiotics to COL and tobramycin, the patient’s condition began to improve and, with wound care, continued to improve for an additional 2 months (Fig. 1a). Phenotypic and genotypic analyses of two consecutive isolates of carbapenem-resistant P. aeruginosa obtained from blood culture of this patient were performed to identify CIP resistance mechanisms. The two isolates were resistant to all antipseudomonal agents except for COL, to aminoglycosides and to CIP by the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. However, the second isolate (isolate 2) obtained from blood during combination therapy with COL and CIP exhibited 16- and 128-fold higher resistance to levofloxacin [minimum inhibitory concentration (MIC) >32 g/mL] and CIP (MIC = 32 g/mL), respectively, compared with the first isolate (isolate 1; levofloxacin MIC = 2 g/mL; CIP MIC = 0.25 g/mL). Both isolates displayed the same pulsotype on pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) revealed that they were clonally related (ST1248) (Fig. 1b). Analysis of quinolone resistance-determining regions (QRDRs) by PCR showed no amino acid substitution in the gyrA and parC genes. However, the level of mexF gene transcription in isolate 2 was 210 times that of isolate 1 by quantitative reverse transcription PCR. This suggested that the MexEF–OprN efflux pump system might be involved in the clinical P. aeruginosa strain’s high-level resistance to CIP (Fig. 1c). Several studies have raised doubts about the clinical effectiveness of using combination therapy. Recent studies found no survival
benefit from combination therapy compared with monotherapy in patients receiving adequate empirical and definitive antibiotics [2]. In particular, there was no reduction of mortality in critically ill patients receiving combination therapy. However, clinical data for the treatment of MDR P. aeruginosa bacteraemia are more limited [3]. We noted that although combination therapy with COL and CIP was administered as a treatment for MDR P. aeruginosa bacteraemia, induction of CIP resistance during combination therapy led to treatment failure. Selection of appropriate antibiotics is complicated by the potential for development of antimicrobial drug resistance. Therefore, combination antibiotic therapy for P. aeruginosa is often selected in order to reduce the risk of resistance developing during antibiotic treatment. Clinical isolate 2 in the present case showed an increased MIC for fluoroquinolones during combination therapy. It did not present mutations in the QRDRs of gyrA or parC but did show overexpression of the mexF gene that encodes a component of the MexEF–OprN efflux system conferring cross-resistance or reduced susceptibility to multiple antibiotic classes through complex interactions among the regulatory genes [4]. Although high-level resistance to fluoroquinolones occurs during combination therapy, suboptimal dosing with COL may have contributed to the induction of fluoroquinolone resistance and treatment failure in the patient described here. The current dosing recommendations for COL may be inadequate to provide optimal activity, promoting the development of resistance [5]. In conclusion, we report on the emergence of resistance to fluoroquinolones during combination therapy with COL and CIP in a patient with MDR P. aeruginosa bacteraemia. Treatment failure
Letters to the Editor / International Journal of Antimicrobial Agents 43 (2014) 383–393
in this patient suggests that addition of active CIP to COL therapy may not effectively prevent the induction of fluoroquinolone resistance in MDR P. aeruginosa bacteraemia. Induction of antimicrobial resistance is worrisome because treatment options for MDR/XDR P. aeruginosa infection are severely limited. Funding: This study was supported by a Samsung Biomedical Research Institute grant [#SBRI GL1-B2-031-1]. Competing interests: None declared. Ethical approval: Not required. References [1] Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with Gram-negative bacteria. Clin Microbiol Rev 2012;25: 450–70. ˜ C, Suarez C, Ocampo-Sosa A, Murillas J, Almirante B, Pomar V, et al. Effect [2] Pena of adequate single-drug vs. combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections: a post hoc analysis of a prospective cohort. Clin Infect Dis 2013;57:208–16. [3] Marcus R, Paul M, Elphick H, Leibovici L. Clinical implications of lactam–aminoglycoside synergism: systematic review of randomised trials. Int J Antimicrob Agents 2011;37:491–503. [4] Llanes C, Köhler T, Patry I, Dehecq B, van Delden C, Plésiat P. Role of the MexEF–OprN efflux system in low-level resistance of Pseudomonas aeruginosa to ciprofloxacin. Antimicrob Agents Chemother 2011;55: 5676–84. [5] Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose and microbiologic outcomes in patients with multidrug-resistant Gram-negative bacteremia. Clin Infect Dis 2013;56:398–404.
Jungok Kim Division of Infectious Diseases, Sejong General Hospital, Seoul, Republic of Korea Cheol-In Kang ∗ Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea Jin Yang Baek Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea
393
Sun Young Cho Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea So Hyun Kim Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea Kwan Soo Ko Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
a
b
Doo Ryeon Chung a,b Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea
Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea Kyong Ran Peck Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea
Jae-Hoon Song a,b Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea b Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea a
∗ Corresponding
author. Tel.: +82 2 3410 0324; fax: +82 2 3410 0064. E-mail address: [email protected] (C.-I. Kang) 27 January 2014 27 January 2014 http://dx.doi.org/10.1016/j.ijantimicag.2014.01.020
the current study no qnr determinant was clearly outstanding. aac(6 )-Ib-cr was much more prevalent (70%) than any other PMQR determinant. Of the 20 PMQR-positive isolates, 9 (45%) had topoisomerase mutations. These mutations appeared only in E. coli [7/9 (77.8%) E. coli isolates] and K. pneumoniae [2/5 (40%) K. pneumoniae isolates]. Moreover, 55.6% (5/9) of E. coli isolates harboured four or even five mutations affecting gyrA, parC and parE. Most of them harboured ESBLs and aac(6 )-Ib-cr as the only PMQR mechanism. The remaining aac(6 )-Ib-cr genes were detected in K. pneumoniae strains that also harboured qnr genes and ESBLs. One K. pneumoniae isolate had a double Ser83 → Phe, Asp87 → Ala change in gyrA, without any parC mutation. Only three E. coli isolates showed clonality by rep-PCR (data not shown), confirmed by PFGE. Of the PMQR-positive isolates, 50% were quinolone-resistant, 80% of which also harboured topoisomerase mutations. No specific PMQR mechanisms were associated with higher minimum inhibitory concentrations (MICs) to fluoroquinolones. Most enterobacteria harbouring PMQR determinants, but not topoisomerase mutations, had ciprofloxacin MICs of ≤1 mg/L. Lavilla et al. [3] reported that 93.3% of qnr-positive isolates were ciprofloxacinsusceptible, and the highest MICs of ciprofloxacin appeared associated with QRDR mutations. Other authors [5] have found no association between PMQR genes and ciprofloxacin resistance. The current data confirm that the presence of PMQR determinants does not necessarily lead to quinolone resistance. Two K. pneumoniae isolates harbouring qnrB1 and aac(6 )-Ib-cr, but no topoisomerase mutations, were quinolone-resistant. These results suggest that the association of these two mechanisms may cause quinolone resistance in the absence of topoisomerase mutations. In summary, PMQR was much more frequent in ESBLharbouring enterobacteria. PMQR-harbouring, ESBL-positive enterobacteria are in most cases E. coli or K. pneumoniae harbouring qnr and/or aac(6 )-Ib-cr as well as multiple topoisomerase mutations and with high MICs of ciprofloxacin. In the absence of ESBLs, PMQR determinants appear in a wider group of species, qnr determinants are largely predominant, topoisomerase mutations are infrequent and isolates are usually ciprofloxacin-susceptible. PMQR determinants appear able to lead to quinolone resistance by themselves only when two different PMQR determinants appear combined in the same isolate. Funding: This study has been partially financed by the Gerencia Regional de Salud, Consejería de Sanidad, Junta de Castilla y León (Spain) [research grant BI-039-SA33-10]. Competing interests: None declared. Ethical approval: Not required. References [1] Strahilevitz J, Jacoby GA, Hooper DC, Robicsek A. Plasmid-mediated quinolone resistance: a multifaceted threat. Clin Microbiol Rev 2009;22: 664–89. [2] European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2011. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). ECDC: Stockholm, Sweden; 2012. [3] Lavilla S, González-López JJ, Sabaté M, García-Fernández A, Larrosa MN, Bartolomé RM, et al. Prevalence of qnr genes among extended-spectrum lactamase-producing enterobacterial isolates in Barcelona, Spain. J Antimicrob Chemother 2008;61:291–5. [4] Cano ME, Rodríguez-Martínez JM, Agüero J, Pascual A, Calvo J, García-Lobo JM, et al. Detection of plasmid-mediated quinolone resistance genes in clinical isolates of Enterobacter spp. in Spain. J Clin Microbiol 2009;47:2033–9. [5] Kim HB, Park CH, Kim CJ, Kim EC, Jacoby GA, Hooper DC. Prevalence of plasmidmediated quinolone resistance determinants over a 9-year period. Antimicrob Agents Chemother 2009;53:639–45.
391
M. Albert ∗ G. Yagüe ∗ Department of Microbiology, Hospital Universitario Virgen de la Arrixaca, University of Murcia, Madrid – Cartagena Road, s/n 30120, El Palmar, Murcia, Spain M. Fernández Department of Microbiology, Complejo Hospitalario de León, León, Spain ˜ L. Vinuela Department of Microbiology, Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain M. Segovia Department of Microbiology, Hospital Universitario Virgen de la Arrixaca, University of Murcia, Madrid – Cartagena Road, s/n 30120, El Palmar, Murcia, Spain
a
˜ a,b J.L. Munoz Department of Microbiology, Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain b Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
∗ Corresponding authors. Tel.: +34 968 395 372. E-mail addresses: [email protected] (M. Albert), [email protected] (G. Yagüe)
5 August 2013 http://dx.doi.org/10.1016/j.ijantimicag.2014.01.019
Treatment failure due to induction of ciprofloxacin resistance during combination therapy with colistin and ciprofloxacin in multidrug-resistant Pseudomonas aeruginosa bacteraemia Sir, Nosocomial infections caused by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa strains compromise the selection of appropriate antibiotics. Although combination therapy has been considered for severely ill patients as well as for MDR/XDR infections, the benefit may not justify it as a general practice [1]. Here we report on an immunocompromised patient with skin and soft-tissue infection caused by MDR P. aeruginosa who experienced treatment failure due to induction of ciprofloxacin (CIP) resistance during combination therapy with colistin (COL) and CIP. A 36-year-old woman was admitted to Samsung Medical Center (Seoul, South Korea) with neutropenic fever following induction chemotherapy for acute myeloid leukaemia. After 2 days of empirical antibiotic therapy with cefepime, a new skin rash appeared on her left thigh. Blood cultures produced no microbial growth. Since the skin lesion was gradually deteriorating, the tissue was incised and drained, and antibiotics were changed to meropenem. Although a P. aeruginosa strain susceptible to carbapenems was isolated from tissues surgically obtained and cultured, her skin lesion was aggravated. On the 9th post-operative day, an episode of sepsis occurred, with carbapenem-resistant P. aeruginosa bacteraemia (isolate 1). Combination therapy with COL [150 mg intravenous (i.v.) twice daily] and CIP (400 mg i.v. twice daily) was administered based on antimicrobial susceptibility results, and the patient underwent a second operation. However, a second episode of sepsis
392
Letters to the Editor / International Journal of Antimicrobial Agents 43 (2014) 383–393
Fig. 1. (a) Clinical course of treatment in a patient with Pseudomonas aeruginosa bacteraemia. *Colistin, 150 mg intravenous twice daily without a loading dose, CIP: ciprofloxacin. (b) Pulsed-field gel electrophoresis (PFGE) analysis of genomic DNA from ciprofloxacin-resistant P. aeruginosa amplified by PCR. *M: marker; lane 1: Isolate 1; lane 2: Isolate 2; lane 3: P. aeruginosa ATCC 27853. (c) mRNA level of four efflux pump genes by quantitative reverse transcription PCR.
with CIP-resistant P. aeruginosa bacteraemia (isolate 2) recurred on the 10th day of combination therapy. On revision of antibiotics to COL and tobramycin, the patient’s condition began to improve and, with wound care, continued to improve for an additional 2 months (Fig. 1a). Phenotypic and genotypic analyses of two consecutive isolates of carbapenem-resistant P. aeruginosa obtained from blood culture of this patient were performed to identify CIP resistance mechanisms. The two isolates were resistant to all antipseudomonal agents except for COL, to aminoglycosides and to CIP by the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. However, the second isolate (isolate 2) obtained from blood during combination therapy with COL and CIP exhibited 16- and 128-fold higher resistance to levofloxacin [minimum inhibitory concentration (MIC) >32 g/mL] and CIP (MIC = 32 g/mL), respectively, compared with the first isolate (isolate 1; levofloxacin MIC = 2 g/mL; CIP MIC = 0.25 g/mL). Both isolates displayed the same pulsotype on pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) revealed that they were clonally related (ST1248) (Fig. 1b). Analysis of quinolone resistance-determining regions (QRDRs) by PCR showed no amino acid substitution in the gyrA and parC genes. However, the level of mexF gene transcription in isolate 2 was 210 times that of isolate 1 by quantitative reverse transcription PCR. This suggested that the MexEF–OprN efflux pump system might be involved in the clinical P. aeruginosa strain’s high-level resistance to CIP (Fig. 1c). Several studies have raised doubts about the clinical effectiveness of using combination therapy. Recent studies found no survival
benefit from combination therapy compared with monotherapy in patients receiving adequate empirical and definitive antibiotics [2]. In particular, there was no reduction of mortality in critically ill patients receiving combination therapy. However, clinical data for the treatment of MDR P. aeruginosa bacteraemia are more limited [3]. We noted that although combination therapy with COL and CIP was administered as a treatment for MDR P. aeruginosa bacteraemia, induction of CIP resistance during combination therapy led to treatment failure. Selection of appropriate antibiotics is complicated by the potential for development of antimicrobial drug resistance. Therefore, combination antibiotic therapy for P. aeruginosa is often selected in order to reduce the risk of resistance developing during antibiotic treatment. Clinical isolate 2 in the present case showed an increased MIC for fluoroquinolones during combination therapy. It did not present mutations in the QRDRs of gyrA or parC but did show overexpression of the mexF gene that encodes a component of the MexEF–OprN efflux system conferring cross-resistance or reduced susceptibility to multiple antibiotic classes through complex interactions among the regulatory genes [4]. Although high-level resistance to fluoroquinolones occurs during combination therapy, suboptimal dosing with COL may have contributed to the induction of fluoroquinolone resistance and treatment failure in the patient described here. The current dosing recommendations for COL may be inadequate to provide optimal activity, promoting the development of resistance [5]. In conclusion, we report on the emergence of resistance to fluoroquinolones during combination therapy with COL and CIP in a patient with MDR P. aeruginosa bacteraemia. Treatment failure
Letters to the Editor / International Journal of Antimicrobial Agents 43 (2014) 383–393
in this patient suggests that addition of active CIP to COL therapy may not effectively prevent the induction of fluoroquinolone resistance in MDR P. aeruginosa bacteraemia. Induction of antimicrobial resistance is worrisome because treatment options for MDR/XDR P. aeruginosa infection are severely limited. Funding: This study was supported by a Samsung Biomedical Research Institute grant [#SBRI GL1-B2-031-1]. Competing interests: None declared. Ethical approval: Not required. References [1] Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with Gram-negative bacteria. Clin Microbiol Rev 2012;25: 450–70. ˜ C, Suarez C, Ocampo-Sosa A, Murillas J, Almirante B, Pomar V, et al. Effect [2] Pena of adequate single-drug vs. combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections: a post hoc analysis of a prospective cohort. Clin Infect Dis 2013;57:208–16. [3] Marcus R, Paul M, Elphick H, Leibovici L. Clinical implications of lactam–aminoglycoside synergism: systematic review of randomised trials. Int J Antimicrob Agents 2011;37:491–503. [4] Llanes C, Köhler T, Patry I, Dehecq B, van Delden C, Plésiat P. Role of the MexEF–OprN efflux system in low-level resistance of Pseudomonas aeruginosa to ciprofloxacin. Antimicrob Agents Chemother 2011;55: 5676–84. [5] Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose and microbiologic outcomes in patients with multidrug-resistant Gram-negative bacteremia. Clin Infect Dis 2013;56:398–404.
Jungok Kim Division of Infectious Diseases, Sejong General Hospital, Seoul, Republic of Korea Cheol-In Kang ∗ Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea Jin Yang Baek Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea
393
Sun Young Cho Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea So Hyun Kim Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea Kwan Soo Ko Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
a
b
Doo Ryeon Chung a,b Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea
Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea Kyong Ran Peck Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea
Jae-Hoon Song a,b Division of Infectious Diseases, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Republic of Korea b Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Republic of Korea a
∗ Corresponding
author. Tel.: +82 2 3410 0324; fax: +82 2 3410 0064. E-mail address: [email protected] (C.-I. Kang) 27 January 2014 27 January 2014 http://dx.doi.org/10.1016/j.ijantimicag.2014.01.020