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Review

Colistin resistance in Klebsiella pneumoniae Young-Mi Ah a , Ah-Jung Kim b , Ju-Yeun Lee a,∗ a College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-no, Sangnok-gu, Ansan, Gyeonggi-do 462-791, South Korea b Department of Pharmacy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea

a r t i c l e

i n f o

Article history: Received 17 December 2013 Accepted 27 February 2014 Keywords: Colistin Microbial resistance Klebsiella pneumoniae Epidemiology Multidrug resistance

a b s t r a c t Increasing use of colistin for multidrug-resistant Gram-negative bacterial infections has led to the emergence of colistin resistance in Klebsiella pneumoniae in several countries worldwide, including Europe (especially Greece), and colistin resistance rates are continually increasing. Heteroresistance rates, which were significantly higher than resistance rates, were found to be important. Although the mechanism underlying resistance is unclear, it has been suggested that it is related to lipopolysaccharide modification via diverse routes. Several factors have been reported as being associated with colistin resistance, with improper use and patient-to-patient transmission being most often cited. Total infections and infectionrelated mortality from colistin-resistant K. pneumoniae are high, but currently there are no established treatment regimens. However, several combination regimens that are mainly colistin-based have been found to be successful for treating such infections. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Klebsiella pneumoniae, a rod-shaped Gram-negative bacterium, is the most significant member of the Klebsiella genus of Enterobacteriaceae. It is an important pathogen in community- and hospital-acquired infections. Resistance to various ␤-lactam antibiotics was first found in K. pneumoniae in 1983, and this resistance was shown to derive from the production of extended-spectrum ␤-lactamases (ESBLs) by the pathogen [1]. The prevalence of ESBLproducing K. pneumoniae has greatly increased since that time, and ESBL production has hindered effective management of infection [2]. ESBL-producing K. pneumoniae are often reported to be resistant to various other antibiotics, including quinolones [3], which can lead to treatment failure. Carbapenems were used for infections caused by ESBLproducing pathogens, with carbapenem-resistant K. pneumoniae (CRKP) first emerging in 1993 [4]. The prevalence of CRKP has continued to increase globally, with such infections becoming a critical threat to human health and having a high mortality rate owing to the limited treatment options available [5,6]. Under these circumstances, tigecycline and colistin became the last-resort treatments for infections by multidrug-resistant (MDR) K. pneumoniae.

∗ Corresponding author. Tel.: +82 314005814; fax: +82 314005958. E-mail address: [email protected] (J.-Y. Lee).

Colistin (polymyxin E) is a polypeptide bactericidal agent and is one of the two clinically available forms of polymyxin agents (polymyxin B and polymyxin E). Colistin sulfate and colistimethate sodium are the commercially available forms. Colistimethate sodium, a prodrug that is hydrolysed to colistin sulfate, is administered parenterally and exerts a bactericidal effect by interacting with lipopolysaccharide (LPS) molecules in the outer membrane, leading to outer-membrane disruption [7]. Colistin had long been kept as a reserve agent because of serious nephrotoxicity and neurotoxicity issues and because of the introduction of less toxic antibiotics [8]. The rapid increase in the prevalence of Gram-negative pathogens that are resistant to fluoroquinolones and aminoglycosides as well as all ␤-lactams, including carbapenems, monobactam, cephalosporins and broad-spectrum penicillins, has prompted the reconsideration of colistin as a valid therapeutic option for critically ill patients [9]. With the current increase in the use of colistin for the treatment of MDR Gramnegative bacterial infections, the presence of colistin-resistant Acinetobacter spp., Pseudomonas spp., and Enterobacteriaceae has been reported worldwide. Infections involving pathogens such as Proteus and Serratia spp. that are intrinsically resistant to colistin have also been reported [10]. These infections are of concern because there are no suitable therapeutic agents available. Therefore, this article provides a comprehensive review of the prevalence of colistin-resistant K. pneumoniae (CoRKP) as well as the possible mechanisms underlying drug resistance and valid therapeutic options.

http://dx.doi.org/10.1016/j.ijantimicag.2014.02.016 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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2. Epidemiology Colistin resistance in K. pneumoniae has been reported in surveillance studies as well as clinical case reports. The resistance rates measured may depend on susceptibility test methods [11,12] and susceptibility breakpoint criteria recommended by the different committees setting testing standards. Consequently, results of the various studies cannot be directly compared. Therefore, in this review we have presented prevalence data as they were reported by the respective studies (Table 1). Colistin resistance in K. pneumoniae has been reported from numerous regions, including Europe, North America, South America, Asia and South Africa. The highest overall colistin resistance rate in clinically isolated K. pneumoniae strains was reported in Greece at 10.5–20% [15,16], followed by South Korea (6.8%) [17], Singapore (6.3%) [18] and Canada (2.9%) [19], illustrating that Greece is a hotspot for resistance to antibiotics. Data from the global SENTRY Antimicrobial Surveillance Program (2006–09), which includes different centres in North America, Europe, Latin America and the Asia-Pacific region, revealed that the overall colistin resistance rate in K. pneumoniae was 1.5% [20]. It was the highest in Latin America (2.1%) followed by North America (1.8%). Colistin resistance in Latin America gradually increased from 1.3% (2006) to 3.0% (2009); significantly, this was accompanied by a reduction in imipenem susceptibility [20]. Several studies reported rates of colistin resistance among MDR isolates [21–23], ESBL-producing isolates [24,25] and carbapenem-resistant or carbapenemase-producing isolates [11,26–30]. According to these studies, colistin resistance rates (4.4–85.7%) for these subpopulations were higher than those reported in studies evaluating overall colistin resistance in K. pneumoniae isolates (Table 1). Particularly high colistin resistance rates (20–55.2%) have been reported in intensive care unit patients [16,24,25]. Trends in the prevalence of colistin resistance were reported in three studies [15,20,31], all of which showed increases in resistance. In one centre in Greece, the overall rate of colistin resistance among K. pneumoniae isolates in 2005–2008 was 10.5%, although no resistance was observed during 1996–1998. It was reported that colistin resistance had risen at an alarming rate, that is from 1% in 2005 to 19% in 2008. It was also shown that colistin resistance among isolates that were non-susceptible to imipenem had risen from 14% in 2005 to 34% in 2008 [15]. An epidemiological study of K. pneumoniae resistance to colistin in one region of Tunisia showed that rates increased from 0.4% in 2005 to 1.9% in 2009 [31]. Trends towards increased colistin resistance were also confirmed in the report of the worldwide SENTRY Antimicrobial Surveillance Program, that is from 1.2% in 2006 to 1.8% in 2009 [20]. Four studies reported the overall prevalence of colistin resistance in Gram-negative bacilli in various clinical isolates [16,18–20]. In three of the studies, the colistin resistance rate was higher in K. pneumoniae (1.5–20%) than in Acinetobacter baumannii (0–6.45%) and Pseudomonas aeruginosa (0.4–1%) [16,19,20]. However, an earlier report from a single institution showed the colistin resistance rate in P. aeruginosa (33%) to be higher than that in K. pneumoniae or A. baumannii [18] (Table 1). A further consideration is the issue of heteroresistance, which is defined as resistance to certain antibiotics expressed by a subset of a microbial population that as a whole would be classed as susceptible using traditional in vitro sensitivity testing [32]. Heteroresistance has been reported by only a limited number of studies because it cannot be assessed with ordinary minimum inhibitory concentration (MIC) testing methods. The rates of heteroresistance in K. pneumoniae reported in two studies [11,21] were markedly higher than those for resistance, indicating that CoRKP is more prevalent than indicated by the results of susceptibility tests. Detection of heteroresistant isolates can be considered a warning that

there is potential for rapid development of colistin resistance and therapeutic failure, as has occurred with other antibiotics in other strains [32]. 3. Risk factors The fact that development of colistin resistance in K. pneumoniae is related to colistin use was well demonstrated in an in vitro study [33]. Furthermore, the use of colistin was found to be an independent risk factor for the occurrence of resistance in Gram-negative bacteria in a clinical setting [34]. In many studies, colonisation or infection by colistin-resistant isolates was found to be associated with previous colistin use, and acquired resistance developed in some patients during colistin therapy [35,36]. Moreover, three studies revealed that treatments including colistin for selective decontamination of the digestive tract (SDD) not only failed to prevent colonisation by ESBL-producing Enterobacteriaceae but also led to colistin resistance [24,25,37]. Colistin resistance rates were significantly increased from 0–6% to 55–69% by the SDD regimen [24,25]. Another cohort study involving critically ill patients identified colistin treatment as a main risk factor for colonisation by CoRKP [16]. The available evidence suggests that inappropriate use of colistin, such as suboptimal dosing or prolonged monotherapy, may itself contribute to the emergence of colistin resistance [21,38–41]. Regrowth phenomena were observed after initial bacterial killing with colistin monotherapy, even with pathogens initially susceptible to colistin [21,40–42]. An in vitro pharmacodynamic study by Poudyal et al. showed that colistin has a very modest postantibiotic effect against MDR K. pneumoniae isolates, even at clinically unachievable high concentrations (64× MIC) [21]. In an in vitro pharmacokinetic/pharmacodynamic study that involved P. aeruginosa and compared colistin regimens, the same daily dosage of colistin was administered at 8-, 12- or 24-h intervals. There was no significant difference in bactericidal effect regardless of the colistin dosing regimen, but the occurrence of colistin resistance was most effectively prevented by the 8-h dosing interval [42]. Another possibility was revealed by considering the occurrence of colistin resistance in colistin-naïve patients [27,29,43,44]. These studies reported sequence analyses of isolates and showed that horizontal transmission was as important a cause of colistin resistance acquisition as selective pressure. Furthermore, Arduino et al. reported that colistin resistance spread was related to horizontal gene transfer factors such as transposons and integrons [45]. In a matched case–control study in Greece, admissions from other institutions and the use of a ␤-lactam/␤-lactamase inhibitor for longer periods were associated with the detection of colistin-resistant K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae [46]. However, the total duration of colistin treatment was not related to the emergence of colistin resistance. In case reports in the USA, CoRKP isolated from older patients had higher MICs against imipenem than colistin-susceptible pathogens from a different patient group [44]. Generally, infection control methods such as hand sanitisation and isolation of patients infected or colonised by resistant isolates are important for preventing patient-to-patient transmission. In one study, adoption of strict infection control methods prevented further outbreaks of CoRKP [44], but this approach was unsuccessful in another study [47]. 4. Mechanisms underlying colistin resistance Colistin is positively charged and thus readily binds to the outer membrane of Gram-negative bacteria. After binding, colistin

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Table 1 Reports of colistin resistance in Klebsiella pneumoniae. Study year

Country

Setting

Test method

Studies reporting colistin resistance rates, overall clinical isolates 2006–2009 Worldwideb Worldwide BMD surveillance 1996–1998 Greece Single centre Disc diffusion 2005–2008 Greece Single centre Disc diffusion or VITEK 2d 2003–2006 Greece Single centre, Disc diffusion only ICU and Etest 2005–2010 Tunisia Single centre Disc diffusion and Etest 2007–2008 Canada National BMD 2004–2005 Singapore Single centre Agar dilution 2006–2007 South Korea National BMD

Breakpoint criteria

Total isolates

N (%)

Reference

ESBL(+)

Carbapenemase(+)

Colistin resistanta

Heteroresistant

9774

N/A

N/A

(1.5)

N/A

[20]

N/Ac N/Ac

345 959

N/A N/A

N/A N/A

0 (0) 101 (10.5)

N/A N/A

[15] [15]

EUCAST

150e

N/A

N/A

30 (20.0)e

N/A

[16]

4548

N/A

N/A

56 (1.2)

N/A

[31]

515 16 221

N/A N/A N/A

N/A N/A N/A

15 (2.9)f 1 (6.3) 15 (6.8)

N/A N/A N/A

[19] [18] [17]

N/A 14 (100) 50 (100) 20 (100) 51 (78.5) 92 (94.8)

6 (28.6) 2 (14.3) (14) 4 (20.0) 16 (24.6) (36.1)

14 (66.7) N/A N/A 12 (60.0) N/A N/A

[21] [26] [28] [11] [22] [30]

41 (100)i N/A

15 (36.6) 10 (47.6)

N/A N/A

[23] [24]

N/A

74 (55.2)

N/A

[25]

(85.7)e

N/A N/A

[29] [27]

EUCAST

CA-SFM N/Ac ≥4 ␮g/mL BSAC

Studies reporting colistin resistance rates among MDR, ESBL-producing or carbapenem-resistant isolates Worldwideh – BMD ≥4 ␮g/mL 21 N/A 2008g 2003–2006 Greece Single centre Etest BSAC 14 13 (92.9) 2007–2008 Greece Single centre Etest EUCAST 50 50 (100) 2009 Greece Single centre BMD EUCAST 20 N/A 2009–2010 Greece Single centre Etest EUCAST 65 14 (21.5) 2010–2011 Italy Multicentre VITEK 2 and EUCAST 97 5 (5.2) microdilution c 2010–2013 Italy Multicentre VITEK 2 N/A 41 – >2 ␮g/mL 2005–2007 Austria Single centre, 21 21 (100) VITEK 2, disc only NICU diffusion and Etest 2001–2008 The Single centre, EUCAST 134 134 (100) Etest Netherlands only ICU e 2008–2009 Hungary Multicentre Etest EUCAST 7 7 (100)e 2009–2010 China Single centre Agar dilution EUCAST 68 N/Aj Study year

Country

Setting

Case series reports of colistin-resistant isolates Single centre, 2000–2004 Greece only ICU 2004–2005 Greece Single centre, only ICU 2002–2007 Greece Single centre 2006–2007 Greece Single centre 2006–2007 2008–2008

Greece Greece

2008–2009 2010 2011–2012 2004–2005

Greece Italy Italy Slovakia

2009

Czech Republic

Single centre Single centre, only ICU Single centre Two centres Single centre Single centre, only ICU Single centre

2009

USA

2010 2010 2005–2009

USA USA Argentina

Two hospitals and one LTAC facility Two centres Single centre Three centres

2010–2011

South Africa

Single centre

(100)e

7 N/Aj

6 3 (4.4)

Test method

Breakpoint criteria

Total isolates

Characteristics of isolates

Reference

Disc diffusion and Etest Etest

≥4 ␮g/mL

2

[53]

BSAC

18

Resistant to 7 antipseudomonal antibiotic agentsk including colistin 83% ESBL(+), 72% MBL(+), 61% both(+)

Etest Etest

N/A BSAC

22 23

[13] [56]

Etest Etest

≥2 ␮g/mL ≥4 ␮g/mL

33 7

MDR pathogensl Resistant to 7 antipseudomonal antibiotic agentsk including colistin N/A MDR pathogens,l all ESBL(+), carbapenemase(+)

BMD Microdilution VITEK 2, Etest N/A

EUCAST EUCAST EUCAST N/A

13 8 28 4

[46] [52] [47] [54]

Microdilution method Etest

N/A

1

All carbapenemase(+) MDR pathogens,l all carbapenemase(+) All ESBL(+), 86% carbapenemase(+) 3 of 4 isolates were resistant to all antibiotics tested and 1 isolate was susceptible to amikacin MDR pathogen,l carbapenemase(+)

Agar dilution BMD Etest and microdilution Etest

pathogens,l

80% carbapenemase(+)

[55]

[34] [57]

[35]

EUCAST

5

MDR

[44]

N/A N/Ac >4 ␮g/mL

5 1 14

All carbapenemase(+) MDR pathogen,l carbapenemase(+) MDR pathogens,l 43% ESBL(+), 29% carbapenemase(+)

[36] [58] [45]

EUCAST

1

ESBL(+), carbapenemase(+)

[37]

ESBL, extended-spectrum ␤-lactamase; BMD, broth microdilution; EUCAST, European Committee on Antimicrobial Susceptibility Testing; N/A, not available; ICU, intensive care unit; CA-SFM, Comité de l’Antibiogramme de la Société Franc¸aise de Microbiologie; BSAC, British Society for Antimicrobial Chemotherapy; MDR, multidrug-resistant; NICU, neonatal intensive care unit; MBL, metallo-␤-lactamase; LTAC, long-term acute care. a Colistin resistance rates of K. pneumoniae were calculated by the number of colistin-resistant isolates divided by the total number of isolates in each study. b SENTRY surveillance programme; North America (USA only), Europe (14 countries), Latin America (4 countries), Asia-Pacific (12 countries). c Clinical and Laboratory Standards Institute (CLSI) standards were used as antimicrobial susceptibility criteria. However, CLSI standards do not define criteria for colistin. d Because the VITEK 2 system was not introduced until 2006, susceptibility testing before 2006 was performed using disc diffusion. e Resistance rates were calculated from the number of patients, not isolates. f In this study, only the minimum inhibitory concentration (MIC) distribution for colistin was reported; therefore, EUCAST criteria (>2 ␮g/mL, Enterobacteriaceae) were applied for calculation of colistin resistance rates. g This research was reported in 2008. h Australia, Asia-Pacific (from SENTRY surveillance programme), Slovak Republic and France. i Of the patients infected with carbapenemase-producing K. pneumoniae, only those treated with fosfomycin were included. j Two of three colistin-resistant K. pneumoniae isolates produced ESBL and carbapenemase. k Seven antipseudomonal antibiotics included antipseudomonal penicillins, cephalosporins, carbapenems, monobactams, quinolones, aminoglycosides, and colistin. l Susceptibility data presented in the reports were used and isolates were redefined as MDR using the resistance classification reported by Magiorakos et al. [14].

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displaces divalent cations such as Ca2+ and Mg2+ from the phosphate groups of lipid A. As a result, colistin changes the permeability of the bacterial cell membrane, thereby causing leakage of cell contents and finally cell death [48]. The primary cause of colistin resistance is change in the negative charge of the outer membrane. The overall negative charge is weakened by changing the phosphate groups of lipid A to 4-amino4-deoxy-l-arabinose and/or phosphoethanolamine. Intrinsically colistin-resistant pathogens such as Proteus, Providencia, Serratia, Brucella, Neisseria, Chromobacterium and Burkholderia spp. have lower colistin binding affinity due to LPS modification. Although the mechanism underlying resistance is currently unclear, recent genomic analyses have suggested that insertional inactivation of

the mgrB gene, upregulation of the PhoP/PhoQ signalling system [49], activation of the PmrA-regulated pmrHFIJKLM operon [50], and the presence of ArnB [51] eventually lead to LPS modifications related to colistin resistance in several pathogens, including K. pneumoniae. 5. Clinical outcomes of infection A number of case series and case reports have described clinical outcomes in patients infected by CoRKP [16,23,26,29,36,44,46,52–57]. One case series from Italy reported eight patients with CRKP and CoRKP that were susceptible to gentamicin and tigecycline. All patients were treated and cured with

Table 2 Antibiotic treatment regimen used for COL-resistant Klebsiella pneumoniae and treatment success rate. Infection or isolation site (no. of patients)

COL-based regimens Tip of the CVC (1) Bronchial (1), catheter (1), ascites (1), blood (1), pus (1) Blood (1) UTI (1), VAP (1), CR-BSI (1) Blood (1) Bronchial secretion (1) Pus (1) Blood (1) Catheter (1) Bronchial (1) Meningitis (1) IAI + bacteraemia (1) CR-BSI (2) Bacteraemia (1)

Blood (5), CVC tip (1), gallbladder drainage (1) IAI + bacteraemia (1) Urine (1) Pus (1) Catheter (1) CR-BSI (1), bacteraemia (1) Pus (1), catheter (1), blood (1) TIG-based regimens Blood (3), urine (1), sputum (1), CVC (1), bronchial aspirate (1), abdominal drainage (1) Bacteraemia (1), VAP + empyema (1) Bacteraemia (1) Bacteraemia (1) STI and bacteraemia (1) Other regimens Bacteraemia (1), VAP (1) Bacteraemia (1) Trauma (1) VAP (1) Bacteraemia (1), STI (1) Catheter (1) Urine (1)

Prior COL (days)

COL MIC (␮g/mL)

Susceptible antibacterial (N)

Treatment

Reference

Antibiotics (dosage)

Duration (days)

Treatment success (%)

Death (%)

33 0–43

N/A N/A

N/A N/A

COLa + MER COL + MER

N/A 5–32

1/1 (100) 5/5 (100)

0/1 (0) 0/5 (0)

[53] [56]

0 N/A 0 31

N/A N/A N/A N/A

N/A FOS N/A N/A

4 N/A 12 N/A

0/1 (0) 1/3 (33)b 1/1 (100) 0/1 (0)

1/1 (100) 1/3 (33) 0/1 (0) 1/1 (100)

[56] [23] [56] [53]

26 3 32 13 N/A N/A N/A –

N/A N/A N/A N/A N/A N/A N/A >8

N/A N/A N/A N/A FOS FOS FOS TIG, FOS

12 + 4 10 + 3 19 + 9 + 8 13 + 17 + 5 N/A N/A N/A 3

0/1 (0) 1/1 (100) 1/1 (100) 1/1 (100) 1/1 (100)b 0/1 (0)b 1/2 (50)b 1/1 (100)

1/1 (100) 0/1 (0) 0/1 (0) 0/1 (0) 0/1 (0) 1/1 (100) 1/2 (50) 0/1 (0)

[56] [56] [56] [56] [23] [23] [23] [58]

N/A

12–128

TIG (2)

N/A

N/A

5/7 (71)

[57]

N/A 55 7 101 N/A 0–36

N/A N/A N/A N/A N/A N/A

FOS N/A N/A N/A FOS N/A

COL + MER + CIP COL + MER + FOS COL + IPM COL (1,000,000 IU q8h) + SAM + SXT COL + SAM COL + TZP COL + TZP + SXT COL + TZP + CHL COL + TZP + FOS COL + TZP + TIG + FOS COL + TIG + FOS COL i.v. (350 mg/day) and inhaled (150 mg/day) + highdose TIG (200 mg/day) + AMK (1000 mg/day) COL (1,000,000 IU q4h) + TIG ± AGs COL + GEN + FOS COL + RIF COL + SXT COL + ATM COL + FOS COL

N/A 10 + 17 6+3 7+5 N/A 8–32

1/1 (100)b 0/1 (0) 0/1 (0) 0/1 (0) 1/2 (50)b 2/3 (67)

1/1 (100) 1/1 (100) 1/1 (100) 1/1 (100) 1/2 (50) 1/3 (33)

[23] [56] [56] [56] [23] [56]

N/A

8–64

TIG, GEN

TIG + GEN ± CBM ± anti-G(+) drug

N/A

8/8 (100)

1/8 (12.5)

[52]

N/A N/A – 45

N/A N/A 128 64–128

FOS FOS GEN, TIG N/A

TIG + FOS TIG + GEN + FOS TIG IPM → TIG

N/A N/A N/A N/A

1/2 (50)b 1/1 (100)b 0/1 (0) 0/1 (0)

0/2 (0) 0/1 (0) 1/1 (100) 1/1 (100)

[23] [23] [26] [55]

N/A N/A 0 4 27, 29 0 47

N/A 96 N/A 96 64, 96 N/A N/A

FOS GEN, TIG N/A N/A N/A N/A N/A

GEN + FOS MER + GEN + DOX TZP → MER IPM i.v. TET CTRX NIT

N/A N/A 6→5 N/A N/A 3 16

2/2 (100)b 1/1 (100) 0/1 (0) 1/1 (100) 2/2 (100) 0/1 (0) 1/1 (100)

1/2 (50) 1/1 (100) 1/1 (100) 1/1 (100) 2/2 (100) 1/1 (100) 0/1 (0)

[23] [26] [56] [55] [55] [56] [56]

COL, colistin; MIC, minimum inhibitory concentration; CVC, central venous catheter; N/A, not available; MER, meropenem; CIP, ciprofloxacin; UTI, urinary tract infection; VAP, ventilator-associated pneumonia; CR-BSI, catheter-related bloodstream infection; FOS, fosfomycin; IPM, imipenem; IU, international units; q8h, every 8 h; SAM, ampicillin/sulbactam; SXT, trimethoprim/sulfamethoxazole; TZP, piperacillin/tazobactam; CHL, chloramphenicol; IAI, intra-abdominal infection; TIG, tigecycline; i.v., intravenous; AMK, amikacin; q4h, every 4 h; AGs, aminoglycosides; GEN, gentamicin; RIF, rifampicin; ATM, aztreonam; CBM, carbapenems; anti-G(+), anti-Gram-positive; STI, soft-tissue infection; DOX, doxycycline; TET, tetracycline; CTRX, ceftriaxone; NIT, nitrofurantoin. a 2,000,000 IU q8h for 16 days + 1,000,000 IU q8h for 12 days + 1,000,000 IU every 12 h for 19 days. b Microbiological eradication was considered treatment success.

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targeted combination therapies, including gentamicin plus tigecycline and/or carbapenems and/or an anti-Gram-positive drug [52]. In most other case series, CoRKP isolation has been associated with overall death rates ranging from 20% to 100% and infection-related deaths ranging from 25% to 71% [16,23,26,29,36,44,46,53–57]. Even allowing that most patients were critically ill, the mortality rates for infections by CoRKP were high. This was supported in a study by Capone et al. showing that infection by CRKP and CoRKP was an independent risk factor for mortality [30]. 6. Antimicrobial strategies No well-designed clinical trials have been performed to evaluate antibiotic regimens for treating infections caused by CoRKP. Only a few case series have reported the antibiotic regimen and treatment outcomes for infections by CoRKP [23,26,52,53,55–58] (Table 2). It is not possible to evaluate the adequacy of the treatment regimens in these cases because of variations in the antibiotic

5

susceptibility of each colistin-resistant strain and in sites of infection, co-infection status and co-morbidities. The optimal treatment options for CoRKP infections therefore remain undefined at this time. However, the antibiotic regimens used in clinical cases can be categorised as follows: (a) colistin-based monotherapy or combination therapy; (b) tigecycline-based monotherapy or combination therapy; (c) combination regimen not including colistin or tigecycline; and (d) monotherapy (tetracycline, imipenem, ceftriaxone or nitrofurantoin). Colistin-based monotherapy or combination regimens were reviewed in clinical case reports and in vitro studies. Colistin combination therapy was suggested because a bacterial regrowth phenomenon was observed after an initially rapid killing effect of colistin in many studies [21,40–42,59]. In 2005 and 2008, Falagas et al. reported a study involving 22 patients who were infected by pandrug-resistant (including colistin-resistant) K. pneumoniae [53,56]. In these studies, six of seven patients who received colistin plus meropenem (one of them additionally received ciprofloxacin)

Table 3 In vitro microbiological studies of colistin-resistant or heteroresistant Klebsiella pneumoniae. No. of isolates

Method (inoculum, CFU/mL)

Drug 1 (concentration in ␮g/mL)

Drug 2 (concentration in ␮g/mL)

Bactericidal [N (%)]

Synergy [N (%)]

Antagonism [N (%)]

Reference

18

Time–kill assaya (N/A)

Colistin (5)

Imipenem (10)

2 (11)

2 (11)

10 (56)

[62]

3b

Time–kill assayc (ca. 106 and ca. 108 )

Colistin (0.5) Colistin (0.5) Colistin (2) Colistin (2)

Doripenem (2.5) Doripenem (25) Doripenem (2.5) Doripenem (25)

N/A N/A N/A N/A

2 (67)d 3 (100)d 3 (100)d 3 (100)d

N/A N/A N/A N/A

[41]

10

Time–kill assaya (1 × 106 )

Colistin (1) Colistin (1) Colistin (1) Doripenem (8) Doripenem (8) Gentamicin (2)

Doripenem (8) Gentamicin (2) Doxycycline (2) Gentamicin (2) Doxycycline (2) Doxycycline (2)

7 (70) 5 (50) 0 (0) 2 (20) 1 (10) 2 (10)

6 (60) 2 (20) 1 (10) 1 (10) 3 (30) 4 (40)

0 (0) 0 (0) 3 (30) 2 (20) 2 (20) 2 (20)

[61]

1

Time–kill assaya (ca. 105 –106 )

Colistin (0.25–0.5 × MIC)e Colistin (0.25–0.5 × MIC)e Colistin (0.25–0.5 × MIC)e

Vancomycin(0.25–0.5 × MIC)e

1 (100)

1 (100)

0 (0)

[65]

Trimethoprim (0.25–0.5 × MIC)e SXT (0.25–0.5 × MIC)e

1 (100)

1 (100)

0 (0)

1 (100)

1 (100)

0 (0)

14

Etest

Colistin

Fosfomycin

N/A

5 (35.7)f

0 (0)

[22]

8

Time–kill assaya (N/A)

Fosfomycin (100) Fosfomycin (100) Fosfomycin (100)

Meropenem (10) Colistin (5) Gentamicin (5)

N/Ag N/Ah N/A

5 (62.5) 2 (25) 0 (0)

N/A N/A N/A

[63]

13

Checkerboard assay (2.5 × 105 )

Colistin Colistin Colistin Colistin Colistin Tigecycline Tigecycline Tigecycline Imipenem Meropenem

Rifampicin Imipenem Meropenem Tigecycline Gentamicin Imipenem Meropenem Gentamicin Gentamicin Gentamicin

N/Ai N/A N/A N/A N/A N/A N/A N/A N/A N/A

13 (100) 5 (38.5) 5 (38.5) 5 (38.5) 5 (38.5) 0 (0) 0 (0) 0 (0) 3 (23.1) 5 (38.5)

0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

[64]

In the checkerboard and Etest assays, synergy was defined as a fractional inhibitory concentration index (FICI) of ≤0.5 and antagonism as a FICI of >4. In time–kill assays, a bactericidal effect was defined as a ≥3 log10 decrease from the starting inoculum. Synergy means a ≥2 log10 greater reduction for the combination treatments than the single agents. Antagonism was defined as a ≥2 log10 lesser reduction for the combination treatments than the single agents. N/A, not available; MIC, minimum inhibitory concentration; SXT, trimethoprim/sulfamethoxazole. a 24-h incubation. b Two heteroresistant and one resistant to colistin. c The incubation period was 72 h; however, data at 24 h were used. d When synergy effects were observed at low inoculum (∼106 CFU/mL) or at high inoculum (∼108 CFU/mL) at 24 h, we consider that the antimicrobial combination had a synergistic effect. Synergistic effects were seen for colistin-heteroresistant isolates with combinations of colistin (2 ␮g/mL) and doripenem (2.5 ␮g/mL or 25 ␮g/mL) at high inoculum. e MIC > 128 ␮g/mL was considered 128 ␮g/mL. f Synergistic effect of the combination was not different from that against colistin-susceptible carbapenemase-producing K. pneumoniae (36.1%). g Bactericidal effects were seen against 12 (70.6%) of the 17 isolates including 9 colistin-susceptible K. pneumoniae. h Bactericidal effects were seen against 11 (64.7%) of the 17 isolates including 9 colistin-susceptible K. pneumoniae.

Please cite this article in press as: Ah Y-M, et al. Colistin resistance in Klebsiella pneumoniae. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.02.016

G Model ANTAGE-4294; No. of Pages 8 6

ARTICLE IN PRESS Y.-M. Ah et al. / International Journal of Antimicrobial Agents xxx (2014) xxx–xxx

were cured or improved. In addition, a recent systematic review showed that polymyxins and carbapenems in combination had a synergistic effect on most colistin-susceptible Gram-negative bacteria, with doripenem combinations having the strongest effect [60]. The synergistic effect (60–100%) of doripenem was also observed on CoRKP in an in vitro study [41,61] (Table 3). Combinations with imipenem, however, showed a high antagonism rate (56%) [62] (Table 3). Although the use of doripenem and colistin combinations for the treatment of CoRKP has not been reported in clinical cases, this combination regimen appears promising. Four of five patients who received colistin plus piperacillin/tazobactam [four of them additionally received trimethoprim/sulfamethoxazole (SXT), chloramphenicol, fosfomycin, or tigecycline + fosfomycin, respectively] showed improvement [23,56]. This combination may therefore be another option to consider for the treatment of CoRKP [23,56]. As reported by Falagas et al., although two of three patients receiving colistin monotherapy were cured or showed improvement [56], in vitro studies and clinical case reports raise many concerns about colistin monotherapy, even for the treatment of colistin-susceptible isolates [21,40]. Colistin combination therapy rather than colistin monotherapy should therefore be considered for the control of CoRKP in clinical practice. In vitro combinations of colistin with fosfomycin, gentamicin or doxycycline exhibited synergic effects of