Carbapenemaseproducing Klebsiella pneumoniae: (when) might we ...

REVIEW

10.1111/j.1469-0691.2011.03553.x

Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? G. L. Daikos1 and A. Markogiannakis2 1) First Department of Propaedeutic Medicine, University of Athens and 2) Department of Pharmacy, Laikon General Hospital, Athens, Greece

Abstract Infections caused by carbapenemase-producing Klebsiella pneumoniae (CPKP) are increasing in frequency worldwide. CPKP isolates exhibit extensive drug resistance phenotypes, complicate therapy, and limit treatment options. Although CPKP isolates are often highly resistant to carbapenems, a proportion of these have relatively low MICs for carbapenems, raising the question of whether this class of agents has any therapeutic potential against CPKP infections. Results from animal studies and patient outcome data indicate that carbapenems retain meaningful in vitro activity against CPKP isolates with carbapenem MICs of £4 mg/L. Accumulating clinical experience also suggests that the therapeutic efficacy of carbapenems against CPKP isolates with MICs of £4 mg/L is enhanced when these agents are administered in combination with another active antibiotic. The results of human pharmacokinetic/pharmacodynamic studies are in line with the above observations; it is highly probable that a high-dose/prolonged-infusion regimen of a carbapenem would attain a time above the MIC value of 50% for CPKP isolates with MICs up to 4 mg/L, ensuring acceptable drug exposure and favourable treatment outcome. The analyses summarized in this review support the notion that carbapenems have their place in the treatment of CPKP infections and that the currently proposed EUCAST clinical breakpoints could direct physicians in making treatment decisions. Keywords: Carbapenemases, carbapenems, Klebsiella pneumoniae, KPC and VIM b-lactamases, therapeutic efficacy Article published online: 25 April 2011 Clin Microbiol Infect 2011; 17: 1135–1141

Corresponding author: G. L. Daikos, First Department of Propaedeutic Medicine, Laikon General Hospital, Mikras Asias 75, Athens 115-26, Greece E-mail: [email protected]

Introduction Klebsiella pneumoniae is a notorious recipient of resistance genes, and over the last two decades a number of resistance mechanisms have accumulated in this pathogen. Resistance to b-lactams is mainly mediated by extendedspectrum b-lactamases, with the TEM, SHV and CTX-M types being predominant [1]. More recently, resistance to carbapenems, mediated by b-lactamases with carbapenemhydrolysing activity (carbapenemases), has emerged. The most prevalent among these enzymes are the serine carbapenemases KPC and OXA-48, and the metallo-b-lactamases VIM, IMP, and NDM [2,3]. Carbapenemase-producing K. pneumoniae (CPKP) isolates have undergone extensive dissemination in many countries, and continues to spread in

new geographical locations, indicating an ongoing dynamic process [4–7]. Certain types of carbapenemases show geographical associations. KPC-producing K. pneumoniae isolates were first found in North Carolina, and subsequently emerged in Europe, Latin America, and China [7–9]. In countries such as Greece and Israel, and in the eastern USA, KPC-producing K. pneumoniae isolates have become endemic [8–10]. The metallo-b-lactamases VIM and IMP are scattered globally, with VIM predominating in southern Europe and IMP in the Far East, and NDM being widespread in India and Pakistan [3,11,12]. OXA-48-producing K. pneumoniae isolates were first described in Turkey, and subsequently emerged in the Middle East, India, Europe, and North Africa [7,13]. CPKP isolates affect mainly hospitalized patients with underlying diseases and poor functional status [14–16].

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases

1136

Clinical Microbiology and Infection, Volume 17 Number 8, August 2011

They often exhibit extensive drug resistance phenotypes, complicate therapy, and limit treatment options [15–21]. These organisms generally have elevated carbapenem MICs, but, for some isolates, routine susceptibility testing may show low MIC values (£4 mg/L) despite the production of a carbapenemase [16,22–25]. This phenomenon has important implications for reporting susceptibility results, and raises the fundamental question of whether carbapenems can still be used in the treatment of infections caused by CPKP isolates with low MICs. In this report, we review the relevant literature and attempt to give a clinical perspective on the issue.

Variation of in vitro Susceptibilities of CPKP Isolates to Carbapenems Carbapenem MICs for CPKP isolates may vary within a broad range of values, from 0.12 to >256 mg/L [16,22–25]. This variation depends on both the geographical origin of the bacterial isolates and the type of carbapenemase produced [8]. Surprisingly, although VIM enzymes have strong carbapenem-hydrolytic activity, a proportion of VIM-producing K. pneumoniaeisolates have low carbapenem MICs [24–26]. In a previous report from Greece on 67 VIM-producing K. pneumoniae isolates, not only did their carbapenem MICs range from 0.12 to 32 mg/L, but, notably, 53 (79%) isolates had an MIC of £4 mg/L for at least one carbapenem [26]. Similarly, IMP-producing K. pneumoniae isolates may show only a small reduction in carbapenem susceptibility. For example, 15 of 17 IMP-producing K. pneumoniae isolates from Taiwan had meropenem MICs of £1 mg/L [11]. In contrast, isolates producing the NDM metallo-b-lactamase have higher carbapenem MICs, only 3% of those described having meropenem MICs of £2 mg/L [12]. A wide variation in carbapenem MICs has also been observed among KPC-producing K. pneumoniae isolates. More specifically, among 42 contemporary KPC-producing K. pneumoniae isolates from the eastern USA, one had a meropenem MIC of 1 mg/L, eight had a meropenem MIC of 2 mg/L, and the remaining 33 had higher MICs [27]. On the other hand, in a Chinese study, all 95 KPC-producing K. pneumoniae isolates had carbapenem MICs ranging from 3 to ‡32 mg/L [9]. In our geographical region (Athens, Greece), the MICs for a significant proportion (32%) of KPC-producing K. pneumoniae isolates remain below 4 mg/L. Indeed, among 150 contemporary KPC-producing K. pneumoniae blood isolates tested in our laboratory, 41 had MICs for meropenem of £2 mg/L and seven had MICs of £1 mg/L (range: 0.12 to ‡32 mg/L). Similar MICs were

CMI

observed for imipenem and doripenem (G. L. Daikos, unpublished data).

Revision of Carbapenem Breakpoints and Unresolved Issues Following the evaluation of MIC distributions of contemporary carbapenemase-producing isolates, pharmacokinetic (PK)/pharmacodynamic (PD) properties, and limited clinical outcome data, both the EUCAST and the CLSI in the USA revised their susceptibility breakpoints for carbapenems. First, the EUCAST decided to set its clinical breakpoints to £2 mg/L for imipenem and meropenem, £1 mg/L for doripenem, and £0.5 mg/L for ertapenem [28]. More recently, the CLSI reduced its previous breakpoint values to £1 mg/L for imipenem, meropenem, and doripenem, and to £0.25 mg/L for ertapenem [29,30]. Both committees intended the revised breakpoints to improve the ability of microbiological laboratories to detect carbapenemase-producing organisms by routine susceptibility testing without the performance of additional confirmatory tests, while at the same time obtaining clinically meaningful results to guide physicians in making decisions on treatment. In these schemes, the presence or absence of a carbapenemase does not in itself influence the categorization of susceptibility, so isolates that produce carbapenemases but have MICs below the breakpoints are reported as tested. However, even with these recent modifications of breakpoints, several issues remain unresolved. On the one hand, a proportion of isolates will be reported as susceptible to carbapenems, despite the presence of carbapenemases, depending on the geographical region and the type of carbapenemase. Thus, a number of patients infected with such isolates may receive a carbapenem for treatment, a therapeutic approach that is not considered appropriate by some experts [20,31]. On the other hand, by lowering the breakpoints and reporting as resistant a larger proportion of CPKP isolates, we decrease the opportunities for some patients to obain the potential therapeutic benefit of carbapenems. For example, there are carbapenemase-producing isolates with carbapenem MICs of 4 or 8 mg/L (reported as resistant on the basis of the revised interpretive criteria) that cause infections for which there is no other therapeutic option, or for which the efficacy of alternative treatments (tigecycline or colistin) is very doubtful [15]. A notable example is the questionable efficacy of colistin or gentamicin monotherapy in neutropenic patients [32]. Such therapeutic dilemmas arise often in areas where carbapenemase-producing organisms are endemic. In the absence of controlled

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 1135–1141

CMI

Daikos and Markogiannakis

comparative trials, therefore, critical interpretation of data from animal infection models and PK/PD studies, and continuing appraisal of our clinical experience, may provide selection criteria for ‘when to give or not to give’ carbapenems in infections caused by carbapenemase-producing organisms.

Animal Infection Models Several investigators have examined the efficacy of carbapenems against CPKP isolates in animal infection models [33–35] (Craig et al., 48th ICAAC, 2008, Abstract A-029). Daikos et al. [33] assessed the activity of imipenem against VIM-1producing K. pneumoniae (VPKP) isolates in the neutropenic murine thigh infection model. Animals were infected with three VPKP isolates (with imipenem MICs of 2, 4 and 32 mg/ L, respectively) and a susceptible clinical isolate (MIC of 0.125 mg/L) that did not produce any b-lactamase with broad-spectrum activity. The bactericidal effect was greatest against the susceptible non-VIM-1-producing isolate, intermediate against the ‘susceptible’ VPKP isolates (imipenem MICs of 2 and 4 mg/L), and minimal against the resistant VPKP isolate (imipenem MIC of 32 mg/L). With administration of higher doses of imipenem and attainment of a drug exposure of approximately 40% time above MIC (T > MIC) an appreciable effect against the VIM-1-producing isolates with low imipenem MICs (2–4 mg/L) was achieved. Similar results were obtained by Souli et al. [34] in a rabbit model of peritoneal abscess, using a carbapenem-susceptible (meropenem MIC of 1 mg/L) VIM-producing Escherichia coli isolate as the infecting organism; carbapenems produced a statistically significant reduction of bacterial colony forming units as compared with the untreated controls, and this reduction was comparable to that achieved by aztreonam, to which the infecting organism was susceptible. More importantly, the mortality rate in the control group (11 of 16; 68.8%) was higher than that in the imipenem-treated group (five of 15; 33.3%, p 0.003), the meropenem-treated group (two of 15; 13.3%, p 0.003), the ertapenem-treated group (three of 16; 18.8%, p 0.01), and the aztreonam-treated group (0 of 15; p MIC) must be 20–30% for bacteriostatic activity and 40–50% for bactericidal activity [36]. Craig et al. (48th ICAAC, 2008, Abstract A-029), using the mouse thigh infection model, compared the activity of carbapenems

Carbapenemase-producing Klebsiella pneumoniae

1137

against wild-type Enterobacteriaceae and strains with KPC exhibiting carbapenem MICs between 1 and 16 mg/L. The authors demonstrated that the presence of KPC in Enterobacteriaceae had no impact on the PD (%T > MIC) necessary for bacteriostasis by imipenem, meropenem, or doripenem. Similarly, in an in vitro model simulating human pharmacokinetics, Bulik et al. [37] showed that a high dose of meropenem (2 g every 8 h) infused over 3 h was bactericidal against KPC-producing K. pneumoniae isolates with MICs of 2 mg/L. Although the targeted 40% T > MIC exposure was achieved by this dosing regimen against KPC-producing K. pneumoniae isolates with meropenem MICs up to 16 mg/L, this drug was not able to produce a reliable reduction in the bacterial density in two of three KPC-producing K. pneumoniae isolates with MICs of 8 mg/L. In another study, the same group of investigators evaluated the efficacy of 1-g and 2-g doses, and prolonged infusions, of doripenem against KPC-producing K. pneumoniae isolates with MICs ranging from 4 to 32 mg/L, in both immunocompetent and neutropenic mice [35]. The 1-g dose was able to produce only a bacteriostatic response for the KPCproducing K. pneumoniae isolates with MICs of 4 and 8 mg/L, whereas the 2-g dose achieved a similar effect for isolates with MICs up to 16 mg/L. Relative to neutropenic mice, in the immunocompetent animals a significant reduction in bacterial density was observed, with overall decreases of up to 1 log, with either the 1-g or the 2-g doripenem dose. A critical interpretation of the animal infection model data just summarized suggests that high-dose, prolonged-infusion regimens of carbapenems are able to achieve at least a bacteriostatic effect in severely compromised hosts and a modest bactericidal effect in immunocompetent animals infected with KPC-producing K. pneumoniae isolates with MICs up to 8 mg/L. Moreover, Bulik and Nicolau [38], exploiting the high affinity of the KPC enzyme for ertapenem, demonstrated that the efficacy of doripenem against KPC-producing K. pneumoniae isolates is enhanced when it is administered in combination with ertapenem, suggesting the potential utility of double-carbapenem therapy against this pathogen.

Outcome of Patients Infected with CPKP Isolates and Clinical Experience with Carbapenem Treatment Clinical experience in the treatment and outcome of patients infected with CPKP isolates is limited to case reports, case series, retrospective studies, and one prospective observational study (Table 1). Several investigators from the USA, Israel, Taiwan and Greece have reported mortality rates


1138


CMI

TABLE 1. Clinical studies, antimicrobial therapies and outcomes of patients infected with carbapenemase-producing Klebsiella pneumoniae

References

First author (year of publication)

42 22 43 17 52 41 53 14 54 11

Villegas (2004) Lomaestro (2006) Wei (2007) Daly (2007) Mendes (2008) Endimiani (2008) Marschall (2009) Mathers (2009) Benenson (2009) Yan (2001)

39 55

Lee (2004) Bradford (2004)

10 24

Bratu (2005) Daikos (2007)

18

Outcome (no. of successes/ no. of failures)

Study design

No. of patients

Carbapenemase (no. of isolates)

Treatment (no. of patients)

Case reports

11

KPC (11) IMP (1)

Carbapenem (4) Carbapenem combined with another agent (1) Other treatment (6)

5/6

Case series

16

IMP (16)

3 4

IMP (3) KPC (4)

Retrospective Retrospective

58 28

KPC (29) VIM (28)

Souli (2008)

Case series

17

VIM (17)

23

Weisenberg (2009)

Case series

21

KPC (21)

56

Maltezou (2010)

Case series

22

KPC (22)

57

Endimiani (2009)

Case series

7

KPC (7)

58 25

Nadkarni (2009) Daikos (2009)

Case series Prospective observational

6 67

KPC (6) VIM (67)

59

Souli (2010)

Case series

18

KPC (18)

15

Mouloudi (2010)

Case control

37

VIM (18) KPC (19)

Carbapenem (3) Other treatment (13) Carbapenem (3) Carbapenem combined with another therapy (3) Other treatment (1) No precise information on treatment (58) Carbapenem (11) Carbapenem combined with another agent (13) Other treatment (4) Carbapenem combined with another agent (9) Other treatment (8) Carbapenem (11) Carbapenem combined with another agent (1) Other treatment (9) Carbapenem combined with another agent (1) Other treatment (13) No information on treatment (8) Carbapenem combined with another agent (1) Other treatment (1) No information on treatment (5) Other treatment Carbapenem (14) Carbapenem combined with another agent (12) Other treatment (41) Carbapenem (1) Carbapenem combined with another agent (11) Other treatment (6) Other treatment (37)

9/7

Case series Case series

ranging from 24% to 65% in patients infected with CPKP isolates [5,10,15,24,25,39]. Resistance to carbapenems, older age and severity of underlying disease have been shown to be independent predictors of death in these patients [25,40]. Given that CPKP isolates exhibit an extensive drug-resistant phenotype, an additional factor contributing to adverse outcome in these infections may be the delay in initiating appropriate empirical therapy. Over the last five years, the development of resistance to colistin and/or tigecycline, the ‘last-resort’ treatments for these infections, has further compromised the therapeutic options [19–21]. Currently, in our geographical region, approximately 20% of CPKP isolates are resistant to colistin, and 5% of these organisms are pan-drug-resistant, exhibiting resistance to both colistin and tigecycline. In the absence of alternative treatments, and in light of the aforementioned animal model experiments, we therefore need to examine the utility of carbapenems against CPKP isolates, and particularly against those that have low carbapenem MICs. In order to address this issue, we performed a search of MEDLINE, including the terms: carbapenemase-Klebsiella, VIM-Klebsiella,

3/0 3/1 9/20 9/19

14/3 8/13

11/3

4/3

2/4 16/51

11/7

21/16

KPC-Klebsiella, IMP-Klebsiella, and NDM-Klebsiella. We compiled data from the published reports that provided the necessary information to examine the efficacy of carbapenems in relation to carbapenemase production and to the MIC for the infecting organisms (Table 1). We were able to extract data from 44 patients infected with CPKP isolates, all of whom had received carbapenem monotherapy [11,14,22– 25,39,41–43]. Among these patients, 32 were infected with CPKP isolates for which carbapenem MICs were £4 mg/L, five with CPKP isolates for which the MICs were 8 mg/L, and seven with CPKP isolates organisms for which the MICs were >8 mg/L. For comparison, we evaluated 22 patients infected with non-carbapenemase-producing K. pneumoniae isolates with carbapenem MICs of £0.5 mg/L, all of whom had received carbapenem monotherapy (data on file [25]). By analysing these data, we observed that, for CPKP infections, the therapeutic efficacy of carbapenems increases from 29% for an MIC of >8 mg/L, to 60% for an MIC of 8 mg/L, and to 69% for an MIC of 4 mg/L or less. Although the comparison between the groups was not statistically significant, it is worth noting that the efficacy of carbapenems in the last



CMI

group was similar to that observed in patients infected with non-carbapenemase-producing K. pneumoniae (73%). In addition, we analyzed data from 138 patients who had received appropriate treatment other than carbapenem monotherapy [15,17,18,23,24,25,58,59]. The lowest mortality rate (only three of 26 died) was observed among those patients who received combination therapy with two active drugs, one of which was a carbapenem (when its MIC was £4 mg/L) and the other of which was an aminoglycoside (11 patients), or colistin (14 patients), or tigecycline (one patient), as compared with that observed in patients who received other active drug(s) besides carbapenems (46 of 112 patients had adverse outcome; OR 5.3, 95% CI 1.5–18.9, p 0.006, Fisher’s exact test). These data indicate that carbapenems provide some therapeutic benefit against CPKP isolates when the MIC is £4 mg/L. Therefore, for clinical purposes, the carbapenem MICs should be reported as tested, and the presence or absence of a carbapenemase should not in itself influence the categorization of the isolates as resistant or susceptible.

Human PK and PD Studies The aforementioned experimental and clinical outcome data are supported by human PK/PD studies. Carbapenems are known to display time-dependent bactericidal killing when free drug concentrations remain above the MIC for approximately 40–50% of the time between dosing intervals. Previous reports have provided PK data for several dosing regimens of meropenem; in particular, the traditional 30-min infusion of 1 g every 8 h (1 g TI every 8 h), the prolonged 3-h infusion of 1 g every 8 h (1 g PI every 8 h), and the high-dose/prolonged 3-h infusion of 2 g every 8 h (2 g PI every 8 h) [36,44–48]. As shown in Fig. 1, when the traditional 1 g TI every 8 h regimen was


1139

used, the serum meropenem concentration fell below 2 mg/L (EUCAST breakpoint) 5 h after administration. In contrast, prolonging the infusion time to 3 h (1 g PI every 8 h) resulted in serum concentrations above 2 mg/L for the whole time interval between dosages, which were further increased to concentrations above 4 mg/L when the meropenem dose was doubled (2 g PI every 8 h). Moreover, Monte Carlo simulation models of different dosing regimens of carbapenems indicate that prolonging the infusion time from 30 min to 3 h increases the probability of bactericidal target attainment at each MIC value. As shown in Fig. 2, the probabilities of attaining T > MIC targets for at least 50% of the dosing intervals for an MIC of 4 mg/L were 69%, 93% and 100% for the 1 g TI every 8 h, 1 g PI every 8 h and 2 g PI every 8 h dosing regimens, respectively. For an MIC of 8 mg/L, only the high-dose/prolonged-infusion regimen displayed a relatively high probability (85%) of bactericidal target attainment [36]. Considering these observations in combination with the MIC distributions of CPKP isolates, the high-dose/prolonged-infusion regimen of meropenem achieves the bactericidal PK/PD targets with a high degree of certainty for carbapenemase-producing Enterobacteriacae that have MICs of £4 mg/L. An additional factor that should be taken into consideration is the fact that CPKP isolates affect mainly critically ill and immunocompromised patients, as there is evidence that the probability of clinical response as a function of %T > MIC may be different in this population. Therefore, it is preferable to use the high-dose/prolongedinfusion regimen of carbapenems in CPKP infections, in order to achieve drug exposure for at least 75% T > MIC [49]. Moreover, depending on the severity of infection and the immune status of the host, the therapeutic efficacy of carbapenems against CPKP infections could be enhanced by adding another active agent, as discussed above. It is

FIG. 2. Simulated target attainment probabilities for 50% time above FIG. 1. Simulated concentration–time profiles of three different dos-

the MIC (50% T > MIC) of three different regiments of meropenem.

ing regimens of meropenem. TI, traditional 30-min infusion; PI, pro-

TI, traditional 30-min infusion; PI, prolonged 3-h infusion. Adapted

longed 3-h infusion. Adapted from [35,45,47].

from [36].


1140


important to note that, before adopting high-dose and extended-infusion regimens, consideration should be given to the safety and stability of the compounds used. For example, imipenem is not likely to be considered for this therapeutic strategy, in view of its lower stability at elevated room temperatures and its lower tolerability when administered in higher dosages [50,51]. In addition, we need to monitor renal function regularly and adjust the carbapenem dose as required, particularly for the high-dose regimens, as the majority of the patients infected with CPKP isolates are critically ill and have altered renal function.

Conclusion When faced with the daily challenge of managing critically ill patients, we should try to reduce the gap between the available medical evidence for using carbapenems against CPKP infections and the dearth of alternative therapeutic options, some of which have not been satisfactorily investigated and/or whose efficacy in certain situations remains questionable. Whether we can use carbapenems in the presence of a carbapenemase is an issue on which divergent opinions have been expressed by several experts. The data analyses presented herein support the notion that carbapenems may be a reasonable treatment option against CPKP, provided that: (i) the carbapenem MIC for the infecting organism is £4 mg/L; (ii) a high-dose prolonged-infusion regimen is administered to drive the PK/PD profile to acceptable exposures; and (iii) this class of agent is administered in combination with another active compound. Finally, the data summarized in this review indicate that the EUCAST clinical breakpoints (susceptible, £2 mg/L; intermediate, 4 mg/L) can direct physicians in making treatment decisions. In the absence of control trials, the continued appraisal of clinical experience will provide further important information on the utility of carbapenems against CPKP.

Transparency Declaration Conflicts of interest: nothing to declare.

References 1. Coque TM, Baquero F, Canton R. Increasing prevalence of ESBL-producing Enterobacteriaceae in Europe. Euro Surveil 2008; 13: pii: 19044. Available at: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19044 (last accessed 12 May 2011). 2. Bush K. Alarming b-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol 2010; 13: 558–564.

CMI

3. Quenan EM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev 2007; 20: 440–458. 4. Vatopoulos A. High rates of metallo-betalactamase-producing Klebsiella pneumoniae in Greece—a review of the current evidence. Euro Surveil 2008; 13: pii: 8023. Available at: http://www.eurosurveillance.org/ ViewArticle.aspx?ArticleId=8023 (last accessed 12 May 2011). 5. Schwaber MJ, Carmeli Y. Carbapenem-resistant Enterobacteriaceae: a potential threat. JAMA 2008; 300: 2911–2913. 6. Nordmann P, Cuzon G, Nas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 2009; 9: 228–236. 7. Gundmann H, Livermore DM, Giske GG et al. Carbapenem non-susceptible Enterobacteriaceae in Europe: conclusions from a meeting of national experts. Euro Surveil 2010; 15: pii: 19711. Available at: http:// www.eurosurveillance.org/Viearticle.aspx?Articleld=19711 (last accessed 12 May 2011). 8. Cuzon G, Naas T, Truong H et al. Worldwide diversity of Klebsiella pneumoniae that produces b-lactamase blaKPC-2 gene. Emerg Infect Dis 2010; 16: 1349–1356. 9. Qi Y, Wei Z, Li S et al. ST1, the dominant clone of KPC-producing Klebsiella pneumoniae in China. J Antimicrob Chemother 2010; 66: 307–312. 10. Bratu S, Landman D, Haag R et al. Rapid spread of carbapenem-resistant Klebsiella pneumoniae in New York city: a new threat to our antibiotic armamentarium. Arch Intern Med 2005; 165: 1430–1435. 11. Yan J-J, Ko W-C, Tsai S-H. Outbreak of infection with multidrugresistant Klebsiella pneumoniae carrying blaIMP-8 in a university medical center in Taiwan. J Clin Microbiol 2001; 39: 4433–4439. 12. Kurnarasamy KK, Toleman MA, Walsh TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan and the UK: a molecular, biological and epidemiological study. Lancet Infect Dis 2010; 10: 597–602. 13. Poirel L, Heritier C, Tolun V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem Klebsiella pneumoniae. Antimicrob Agents Chemother 2004; 48: 15–22. 14. Mathers AJ, Cox HL, Bonatti H et al. Fatal cross infection by carbapenem-resistant Klebsiella in two liver transplant recipients. Transpl Infect Dis 2009; 11: 257–265. 15. Mouloudi E, Protonariou E, Zagorianou A et al. Bloodstream infections caused by metallo-b-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patient in Greece: risk factors for infection and impact of type of resistance on outcomes. Infect Control Hosp Epidemiol 2010; 31: 1250–1256. 16. Hirsch EB, Tam VH. Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): an emerging cause of multidrugresistant infection. J Antimicrob Chemother 2010; 65: 1119–1126. 17. Daly MW, Riddle DJ, Ledeboer NA et al. Tigecycline for treatment of pneumonia and empyema caused by carbapenemase-producing Klebsiella pneumoniae. Pharmacotherapy 2007; 27: 1052–1057. 18. Souli M, Kontopidou FV, Papadomichelakis E et al. Clinical experience of serious infections caused by Enterobacteriaceae producing VIM-1 metallo-b-lactamase in a Greek university hospital. Clin Infect Dis 2008; 46: 847–854. 19. Antoniadou A, Kontopidou F, Poulakou F et al. Colistin-resistant Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multinational cluster. J Antimicrob Chemother 2007; 59: 786–790. 20. Elemam A, Rahimian J, Mandell W. Infection with panresistant Klebsiella pneumoniae: a report of 2 cases and a brief review of the literature. Clin Infect Dis 2009; 49: 271–274. 21. Kontopoulou K, Protonariou E, Vasilakos K et al. Hospital outbreak caused by Klebsiella pneumoniae producing KPC-2 b-lactamase resistant to colistin. J Hosp Infect 2010; 76: 70–73. 22. Lomaestro BM, Tobin EH, Shang W, Gootz T. The spread of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae to upstate New York. Clin Infect Dis 2006; 43: e26–e28.


CMI


23. Weisenberg SA, Morgan DJ, Espinal-Witter R, Larone DH. Clinical outcomes of patients with KPC-producing Klebsiella pneumoniae following treatment with imipenem or meropenem. Diagn Microbiol Infect Dis 2009; 64: 233–235. 24. Daikos GL, Karabinis A, Paramithiotou E et al. VIM-1 producing Klebsiella pneumoniae bloodstream infections: analysis of 28 cases. Int J Antimicrob Agents 2007; 29: 471–483. 25. Daikos GL, Petrikkos P, Psichogiou M et al. Prospective observational study of the impact of VIM-1 metallo-b-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother 2009; 53: 1868–1873. 26. Psichogiou M, Tassios PT, Avlamis A et al. Ongoing epidemic of blaVIM-1 positive Klebsiella pneumoniae in Athens, Greece: a prospective survey. J Antimicrob Chemother 2008; 61: 59–63. 27. Endimiani A, Hujer AM, Perez F. Characterization of bla-KPC containing Klebsiella pneumoniae isolates detected in different institutions in eastern United States. J Antimicrob Chemother 2009; 63: 427–437. 28. EUCAST. EUCAST Clinical Breakpoint Table v. 1.1 1010-4-27, Enterobacteriaceae, 2010.Available at: http://eucast.org./fileadmin/src/ media/PDFs/EUCAST_files/Disk_test_documents/EUCAST_breakpoints_v1.1.xl (last accessed 10 October 2010). 29. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing M02-A10 and M07-A8. M100-S21-U. Volume 31 No. 1. January 2010. Wayne, PA: CLSI, 2010. 30. Clinical and Laboratory Standards Institute. M100-S20-U. Performance standards for antimicrobial susceptibility testing: 20th informational supplement (June 2010 Update). Wayne, PA: CLSI, 2010. 31. Endimiani A, Perez F, Bajaksouzian S et al. Evaluation of updated interpretative criteria for categorizing Klebsiella pneumoniae with reduced carbapenem susceptibility. J Clin Microbiol 2010; 48: 4417–4425. 32. Bodey GP, Middleman E, Umsawadi T, Rodriguez V. Infections in cancer patients. Results with gentamicin sulfate therapy. Cancer 1972; 29: 1697–1701. 33. Daikos GL, Panagiotakopoulou A, Tzelepi E et al. Activity of imipenem against VIM-1 metallo-b-lactamase-producing Klebsiella pneumoniae in the murine thigh infection model. Clin Microbiol Infect 2007; 13: 196–215. 34. Souli M, Konstantinidou E, Tzelepi E et al. Efficacy of carbapenems against a metallo-b-lactamase-producing Escherichia coli clinical isolate in a rabbit intra-abdominal abscess model. J Antimicrob Chemother 2010; 66: 611–617. 35. Bulik CC, Nicolau DP. In vivo efficacy of simulated human dosing regiments of prolonged-infusion doripenem against carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother 2010; 54: 4112–4115. 36. Kuti JL, Dandekar P, Nightgale CH, Nicolau DP. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J Clin Pharmacol 2003; 43: 1116–1123. 37. Bulik CC, Christensen H, Li P et al. Comparison of activity of a human simulated, high-dose, prolonged infusion of meropenem against Klebsiella pneumoniae producing the KPC carbapenemase versus that against Pseudomonas aeruginosa in a in vitro pharmacodynamic model. Antimicrob Agents Chemother 2010; 54: 804–810. 38. Bulik CC, Nicolau DP. Double carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother, in press. doi: 10.1128/AAC.01420-10. 39. Lee N-Y, Lee H-C, Liu K-H. Clinical experiences of bacteremia caused by metallo-b-lactamase-producing gram-negative organisms. J Microbiol Immunol Infect 2004; 37: 343–349. 40. Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S et al. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality. Antimicrob Agents Chemother 2008; 52: 1028–1033. 41. Endimiani A, Carias LL, Hujer AM et al. Presence of plasmid-mediated quinolone resistance in Klebsiella pneumoniae isolates possessing

42.

43.

44.

45.

46.

47.

48.

49.

50. 51.

52.

53.

54.

55.

56.

57.

58.

59.


1141

blaKPC in the United States. Antimicrob Agents Chemother 2008; 52: 2680–2682. Villegas MV, Lolans K, Corre A et al. First detection of the plasmidmediated class A carbapenemase KPC-2 in clinical isolates of Klebsiella pneumoniae from South America. Antimicrob Agents Chemother 2006; 50: 2880–2882. Wei Z-Q, Du X-X, Yu Y-S et al. Plasmid-mediated KPC-2 in a Klebsiella pneumoniae isolate form China. Antimicrob Agents Chemother 2007; 51: 763–765. Dandekar PK, Maglio D, Sutherland CA et al. Pharmacokinetics of meropenem 0.5 g and 2 g every 8 h administered as 3 h infusion. Pharmacotherapy 2003; 23: 988–991. Li C, Kuti JL, Nightgale CH, Nicolau DP. Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients. J Clin Pharmacol 2006; 46: 1171–1178. Jaruratanasirikul S, Sriwiriyajan S. Comparison of the pharmacodynamics of meropenem in healthy volunteers following administration by intermittent infusion or bolus injection. J Antimicrob Chemother 2003; 52: 518–521. Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated pneumonia following administration by 3-hour infusion or bolus injection. Antimicrob Agents Chemother 2006; 49: 1337–1339. Perrott J, Mabasa VH, Ensom MH. Comparing outcomes of meropenem administration strategies based on pharmacokinetic and pharmacodynamic principles: a qualitative systematic review. Ann Pharmacother 2010; 44: 557–564. Ariano RE, Nyhlen A, Donelly JP et al. Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann Pharmacother 2005; 39: 32–38. Rodloff AC, Goldstein EJC, Torres A. Two decades of imipenem therapy. J Antimicrob Chemother 2006; 58: 916–929. Keel RA, Sutherland CA, Crandon JL, Nicolau DP. Stability of doripenem, imipenem and meropenem at elevated room temperatures. Int J Antimicrob Ag 2011; 37: 174–185. Mendes RE, Bell JM, Yang Q et al. Carbapenem-resistant isolates of Klebsiella pneumoniae in China and detection of a conjugative plasmid (blaKPC-2 plus qnrB4) and blaIMP-4 gene. Antimicrob Agents Chemother 2008; 52: 798–799. Marschall J, Tibbets RJ, Dunne WM et al. Presence of KPC carbapenemase gene in Enterobacteriaceae causing bacteremia and its correlation with in vitro carbapenem susceptibility. J Clin Microbiol 2009; 47: 239–241. Benenson S, Navon-Venezia S, Carmeli Y. Carbapenem-resistant Klebsiella pneumoniae endocarditis in a young adult: successful treatment with gentamicin and colistin. Int J Infect Dis 2009; 13: e295–e298. Bradford PA, Bratu S, Urban C et al. Emergence of carbapenem-resistant Klebsiella species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor resistant TEM-30 b-lactamases in New York City. Clin Infect Dis 2004; 39: 55–60. Maltezou HC, Giakkoupi P, Maragos A et al. Outbreak of infections due to KPC-2-producing Klebsiella pneumoniae in a hospital of Crete (Greece). J Infect 2009; 58: 213–219. Endimiani A, DePasquale JM, Forero S et al. Emergence of blaKPCcontaining Klebsiella pneumoniae in a long-term acute care hospital: a new challenge to our healthcare system. J Antimicrob Chemother 2009; 64: 1102–1110. Nadkarni AS, Schliep T, Khan L et al. Cluster of bloodstream infections caused by KPC-2 carbapenemase-producing Klebsiella pneumoniae in Manhattan. Am J Infect Control 2009; 37: 121–126. Souli M, Galani I, Antoniadou A et al. An outbreak of infection due to b-lactamase Klebsiella pneumoniae carbapenemase-2-producing K. pneumoniae in a Greek university hospital: molecular characterization, epidemiology and outcomes. Clin Infect Dis 2010; 50: 364–373.
