Bacterial resistance to multiple classes of antibiotics is an increasing global problem. The worldwide dissemination of multidrug-resistant (MDR) pathogens, especially in intensive care units (ICUs), has become a major cause of concern for medical and scientific community, as well as for the whole society. Infections caused by MDR isolates are associated with increased costs, length of hospitalization, and especially morbidity and mortality rates (1, 2). An area of particular concern involves gram-negative pathogens, where few therapeutic agents remain effective or are in late stage of development. In addition, it has been reported that hospital-acquired infections caused by resistant gram-negative organisms had higher median hospital costs ($80,500 vs. $29,604, P < 0.0001) and median antibiotic costs ($2,607 vs. $758, P < 0.0001) and had longer median hospital length of stay (29 vs. 13 days, P < 0.0001) than infections caused by susceptible strains (2). Physicians are faced daily with the absence of rapid and reliable diagnostic methods, broader therapeutic options, and effective infection control measures. The elucidation of mechanisms of antimicrobial resistance and their relationship with bacterial virulence and pathogenicity and the development of new therapeutic options against MDR pathogens are a dilemma constantly faced by the scientific community. Finally, the impact of antimicrobial resistance on the environment with the possible acquisition of MDR foodborne illness has led all of us to think about the risk of acquisition of community-acquired MDR infections.
Carbapenems are often used as antimicrobials of last resort for treatment of seriously ill patients with gram-negative infections (3). Pseudomonas aeruginosa, Acinetobacter species, and more recently Enterobacteriaceae isolates resistant to carbapenems are frequently isolated in the ICU setting and constitute a real clinical problem. The last decade was marked by the spread of carbapenem resistance determinants especially in Enterobacteriaceae species. In this review, using Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) as an example, we discuss the difficulties in dealing with MDR pathogens in the ICU setting and how they represent a challenge to the medical-scientific community and, ultimately, the whole society (Fig. 1).
KPC-Kp epidemiology and detection
Until the last decade, carbapenem resistance was reported only in a small number of Enterobacteriaceae isolates and mainly attributed to extended-spectrum β-lactamase (ESBL) and/or AmpC β-lactamase production coupled with a decrease in the outer membrane permeability (4, 5). However, in the last years, carbapenemase production, such as metallo-β-lactamases or class A carbapenemases, has become the most frequent mechanism of carbapenem resistance in Enterobacteriaceae species. Klebsiella pneumoniae carbapenemase is a class A carbapenemase enzyme that was first described in a clinical strain of K. pneumoniae isolated from North Carolina, United States, in 1996 (6).
Klebsiella pneumoniae carbapenemases are predominantly encountered in K. pneumoniae, but it has also been detected in many other Enterobacteriaceae species including Escherichia coli, Citrobacter freundii, Salmonella enterica, Enterobacter species, and Proteus mirabilis because the blaKPC gene is harbored by a transferable plasmid (7). Carbapenemase-producing K. pneumoniae has been responsible for outbreaks in the United States, Israel, Greece, China, and South America, as well as sporadic cases worldwide (8). A difficult laboratorial recognition of carbapenem-resistance phenotype among KPC-Kp has contributed to the rapid dissemination of KPC (9). Unfortunately, KPC-Kp isolates may show low imipenem and/or meropenem in vitro minimal inhibitory concentrations (MICs), being miscategorized as susceptible to carbapenems, especially by automated susceptibility testing (AST) systems because of inoculum effect (10, 11). Therefore, AST system results must be confirmed by an alternative method. The modified Hodge test was initially recommended by the Clinical and Laboratory Standard Institute (CLSI) as a confirmatory test, but recent studies have shown it has low specificity, especially in a higher ESBL prevalence setting (12, 13). To address this challenge, in June 2010 CLSI updated document modified the carbapenem breakpoints for Enterobacteriaceae species and recommended modified Hodge test only for epidemiological purposes (14). Nevertheless, even with the reduction of the carbapenem breakpoints for Enterobacteriaceae isolates, a few KPC-Kp isolates still remain categorized as susceptible to carbapenems (10). Therefore, there is not yet a consensus of which of them, the KPC production or carbapenem MIC, is the best predictor of clinical outcome.
The identification of blaKPC gene by molecular tests is the criterion-standard methodology for detection of KPC-producing isolates. Even though these methods are able to give more rapid results, they do not inform whether blaKPC gene is being expressed. Therefore, a phenotypic test will still be necessary. To date, 10 different KPC enzymes variants (KPC-2 to KPC-11, because KPC-1 is identical to KPC-2) have been reported; KPC-2 and KPC-3 are the most frequently detected (15). Although KPC variants are important from the epidemiological viewpoint, it has not been established if there are any differences regarding pathogen eradication or clinical response.
Emerging technologies for rapid identification of microorganisms and resistance determinants propose a shift from traditional biochemical algorithm methods toward automated molecular testing and mass spectrometry methodologies for the analysis of microbial proteins and genetic elements (16–20). Although these are promising methodologies, they are not readily available, and to date phenotypic methods are the tools available in the routine laboratory. Rapid and reliable diagnostic methods are highly desirable for detection of KPC-Kp, so adequate therapy and prevention control measures could be performed earlier.
Treatment of KPC-Kp
The optimal treatment of severe infections due to KPC-Kp has not been determined yet (21). The blaKPC is usually carried on genetic mobile elements that also harbor other resistant determinants, limiting the available therapeutic options (22). Hence, a restricted number of antibiotics retain a good in vitro activity against KPC-Kp isolates, including tigecycline, polymyxins, aminoglycosides, and, less frequently, carbapenems. Hirsch and Tam (7) reported higher success rates when KPC-Kp infections have been treated with aminoglycosides (75%), polymyxin combinations (73%), and tigecycline (71%). However, much lower success rates were documented for monotherapy with carbapenem (40%) or polymyxin (14%) (7).
Unfortunately, few studies have evaluated the clinical outcome of infections caused by KPC-producing bacteria treated with carbapenems in which MICs were within the susceptible category. To address this issue, Weisenberg and colleagues (23) performed a historical cohort evaluating the clinical outcome of infections with isolates initially reported as susceptible to imipenem or meropenem by an automated system. In their study, only 44% of patients had successful clinical and microbiological outcomes. Recently, the clinical efficacy of carbapenem monotherapy was evaluated in 44 patients and was clearly associated with in vitro MICs. Briefly, efficacy rates were 29% and 69% for isolates with MICs greater than 8 μg/mL and 4 μg/mL, respectively (24). In addition, Bulik and colleagues (25) reported that optimized doses of meropenem (2 g every 8 h administered as a 3-h infusion) could constitute a suitable therapeutic option because it reduced the bacterial densities of KPC-Kp. Similarly, Ho and colleagues (26) reported a clinical case where a meropenem-nonsusceptible (MICs <16 μg/mL) KPC-Kp bloodstream infection was successfully treated with high-dose (6 g/d), continuous infusion of meropenem. High-dose, prolonged-infusion doripenem has been also found to be a suitable therapy likely in combination with another agent, against KPC-Kp (27). Recently, double-carbapenem therapy using both ertapenem and doripenem has also been suggested based on the high affinity of KPC by ertapenem (28). The rationale is that the enzyme would hydrolyze ertapenem, leaving doripenem freely to act against KPC-Kp isolates.
In a retrospective analysis of bloodstream infections due to KPC-Kp, monotherapy showed significantly inferior clinical outcome than that of combined therapy (28). The most common combination regimens were carbapenem with either colistin/polymyxin B or tigecycline and a combination of the last two antimicrobials. Although there is an effort of researchers in providing PK/PD data for polymyxins, the pharmacodynamic target to predict the best clinical response has not yet been established. Recent studies have shown that low dosages and delay in initiating adequate therapy were associated with poor clinical response in the patients treated with polymyxins (29). In addition, polymyxin susceptibility testing has been problematic with overestimation of polymyxin MIC values by Etest (10). Moreover, Enterobacteriaceae breakpoints have not been established by CLSI yet. EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommends colistin breakpoints for Enterobacteriaceae species only by dilution methodologies (http://www.eucast.org/clinical_breakpoints/).
Tigecycline has been approved by the US Food and Drug Administration only for treating complicated skin and soft-tissue, complicated intra-abdominal infections or community-acquired pneumonia (30). Low concentrations of tigecycline found in urine and blood have limited its use on treatment of carbapenem-resistant K. pneumoniae infections affecting these body sites. However, clinical success has been reported when high doses of tigecycline (off-label) were prescribed (31). In addition, recently, Food and Drug Administration has issued a warning communication about the increased risk of death with intravenous use of tigecycline, compared with other antibiotics (http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm). Moreover, the quality of Mueller-Hinton agar has been reported to affect susceptibility testing of tigecycline. Furthermore, tigecycline clinical breakpoints for Enterobacteriaceae isolates have not been established by CLSI. EUCAST recommends tigecycline breakpoints for Enterobacteriaceae only by dilution methodologies, except for urinary E. coli (http://www.eucast.org/clinical_breakpoints/), where disk diffusion breakpoints are available. To make the scenario even worse, monotherapies with both polymyxins and tigecycline have been associated with emergence of resistant isolates during therapy (32, 33). In addition, KPC-Kp isolates resistant to all antimicrobials clinically available have also been reported (34). The lack of therapeutic options has been recognized by medical community, and recently many international organizations have launched the “10 × ′20” initiative, which consists a call for a global commitment to develop 10 new systemic antibiotics to treat infections caused by the so-called “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, K. pneumoniae, Acinetobacter baumannii, P. aeruginosa, and Enterobacter species) by 2020 (35).
Related mortality, control, and prevention of KPC-Kp infections
The remarkable transmissibility coupled with few therapeutic options among the KPC-producing isolates reduces drastically the eradication of this pathogen in the nosocomial setting.
Over the past decade, outbreaks of infection due to KPC-Kp increased drastically worldwide especially in the United States, Israel, and Greece and reached endemic levels in several countries (36–38). Initially, outbreaks took place in New York City and were characterized by high mortality rates (47%–67%) strongly associated with prescription of inadequate antimicrobial therapy. Most of these patients received imipenem therapy because KPC-Kp isolates were misdetected as ESBL-producing isolates (11, 39). Rapid identification and notification of emerging KPC-Kp strains are of crucial importance for implementing control measures. In Puerto Rico, Gregory and colleagues (40) reported an outbreak of KPC-Kp that was efficiently controlled after introducing an active surveillance program for detection of KPC-Kp colonization and implementing barrier measures. Intensification of hand and environmental hygiene measures and rapid public health interventions, such as moving patients to isolation wards or emptying and deep-cleaning contaminated wards, are recommended to prevent the uncontrolled spread of MDR pathogens (41, 42). Although antibiotic exposure is likely to increase the patient’s colonization and infection by antimicrobial-resistant bacteria, controlling carbapenem usage may not be an effective measure to prevent and control KPC-Kp spread. The phenomenon of coresistance impairs drastically the efficacy of this measure because other resistance determinants are carried along with the blaKPC gene on the same plasmid, a mobile genetic element (43). Hence, even with the decrease in the consumption of a specific antibiotic, the selective pressure would be exerted by another group of antibiotics that was not selected for restricted use.
In 2007, a national outbreak of carbapenem-resistant K. pneumoniae affected 1,275 patients in 27 Israeli hospitals (44). The dominant clone responsible for this outbreak harbored the KPC-3 variant and was the same clone isolated from multiple outbreaks in the United States (38). It exemplifies the high efficiency of KPC-Kp cross-transmission. The outbreak was successfully controlled with central coordinated infection-control interventions, issuance of mandatory guidelines, physical separation of carriers from noncarriers, and the health care personnel’s dedication to adopt the infection control measures. Although the prevalence of MDR pathogens varies according to the geographic areas, global travel and medical tourism contribute to worldwide spread of almost any MDR bacteria and not only as exemplified by KPC-Kp (21, 30). The medical challenges including detection, treatment, and infection control measures related to KPC-Kp are summarized in Figure 2.
Biological cost of antimicrobial resistance
Biological fitness cost is the energy necessary to maintain the microorganism’s metabolism, virulence, and resistance determinants that confer survival advantages. Antimicrobial resistance, whether encoded by chromosomal mutations or by genes carried on mobile elements, can be associated with a biological fitness cost. Generally, an increase in the antimicrobial resistance is often associated with reduced bacterial fitness. Reduction of bacterial fitness is expressed as reduced bacterial growth, virulence, or transmission (45). Although antimicrobial resistance can lead to an advantage under antibiotic exposure, when it is discontinued, wild-type bacteria will prevail over resistant bacteria. However, available data demonstrated that fitness cost can be overcome by additional mutations. Thus, compensatory evolution stabilizes antibiotic-resistant bacteria and renders them as fit as the susceptible one (46, 47). Resistance factors, such as porins and efflux systems, may act as virulence factors during bacterial infection caused by K. pneumoniae. In addition, virulence factors could be sufficient to enhance the dissemination potency of this pathogen in a nosocomial setting, especially when associated with the production of an ESBL (48, 49). Therefore, linkage between virulence and resistance determinants seems to give bacterial strains an advantage to survive and persist in awkward environments. These phenomena may have contributed to the survival and spread KPC-Kp in the hospital environment.
Very few studies have evaluated the presence of virulence factors, as well as the biological cost in KPC-Kp isolates. Recently, Bachman and colleagues (50) conducted a unique and interesting study demonstrating that the iron-scavenging siderophore Ybt is a prevalent virulence factor in KPC-Kp isolates. This siderophore promotes respiratory tract infections, despite the host’s innate immune response.
Cyclic exchange of antimicrobial resistance
The use of antimicrobials in medical health, veterinary, and agriculture contributes for emergence and promotes the dissemination of bacterial resistance genes. Continuous contact between farm animals and the soil increases the possibility of genetic exchange between commensal and environmental bacteria (51, 52). To establish its ecological niche in the environment, bacteria must produce natural substances including antibiotics. Therefore, environmental bacteria may serve as source of searching for new antibiotic compounds and, at the same time, constitute a reservoir of resistance genes. For instance, quinolone resistance gene (qnr), which is naturally present in environmental bacteria, was acquired by bacterial pathogens (53).
A study conducted by Picão and colleagues (54) evaluated the role of hospital sewage in spreading blaKPC from nosocomial pathogens to Aeromonas species and Kluyvera species, both environmental bacteria. This study illustrated how dynamic are the mobilization and transmission of resistance genes. Therefore, as discussed above, because these genetic mobile elements carry other resistance determinants, other antimicrobial agents used on agriculture and/or as growth factors to animals farms may exert pressure on selection of MDR isolates.
The consequences of water and soil contamination by MDR isolates to community are still unknown, but it may lead to food contamination. In 2011, an outbreak initiated in Germany that affected 15 other countries was caused by a strain of Shiga toxin–producing E. coli of serotype O104:H4. This strain also harbored a plasmid characteristic of enteroaggregative E. coli and another plasmid encoding an ESBL. The outbreak was characterized by bloody diarrhea and hemolytic uremic syndrome with high mortality rates. The source of the outbreak was associated with contaminated sprouts and had been connected to a seed shipment from Egypt that arrived in Germany 2 years earlier. This is an example that virulence and resistance factors can coexist in a community-acquired strain, and their medical effects can be unpredictable (55).
The time of untreatable infections has arrived. Seriously ill patients infected by KPC-Kp have died without receiving any effective antimicrobial therapy because these bacterial isolates have become resistant to polymyxins and tigecycline, the last available therapeutic options. Although these cases remained restricted to ICUs from few geographic areas and affecting patients with severe underlying diseases, no much attention has been given to them. Despite shy campaigns as that developed by the World Health Organization (http://www.who.int/world-health-day/2011) or the Infectious Diseases Society of America, no strong actions engaging the whole society have been initiated. It requires much courage to really discuss antimicrobial resistance with all sectors of the society. It is easier to blame antimicrobial overuse and misuse by physicians than discuss the impact of using antimicrobials for food production as this situation has direct impact on economy. However, in our opinion, all sectors must talk and discuss measures that could minimize the risk of antimicrobial resistance.
1. de Kraker ME, Wolkewitz M, Davey PG, Koller W, Berger J, Nagler J, Icket C, Kalenic S, Horvatic J, Seifert H, et al.: Burden of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay associated with bloodstream infections due to Escherichia coli
resistant to third-generation cephalosporins. J Antimicrob Chemother
66 (2): 398–407, 2011.
2. Evans HL, Lefrak SN, Lyman J, Smith RL, Chong TW, McElearney ST, Schulman AR, Hughes MG, Raymond DP, Pruett TL, et al.: Cost of gram-negative resistance. Crit Care Med
35 (1): 89–95, 2007.
3. Bradley JS, Garau J, Lode H, Rolston KV, Wilson SE, Quinn JP: Carbapenems in clinical practice: a guide to their use in serious infection. Int J Antimicrob Agents
11 (2): 93–100, 1999.
4. Bradford PA, Urban C, Mariano N, Projan SJ, Rahal JJ, Bush K: Imipenem resistance in Klebsiella pneumoniae
is associated with the combination of ACT-1, a plasmid-mediated AmpC β-lactamase, and the loss of an outer membrane protein. Antimicrob Agents Chemother
41 (3): 563–569, 1997.
5. Martinez-Martinez L, Pascual A, Hernandez-Alles S, Alvarez-Díaz D, Suárez AI, Tran J, Benedí VJ, Jacoby GA: Roles of β-lactamases and porins in activities of carbapenems and cephalosporins against Klebsiella pneumoniae
. Antimicrob Agents Chemother
43 (7): 1669–1673, 1999.
6. Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD, Alberti S, Bush K, Tenover FC: Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae
. Antimicrob Agents Chemother
45 (4): 1151–1161, 2001.
7. Hirsch EB, Tam VH: Detection and treatment options for Klebsiella pneumoniae
carbapenemases (KPCs): an emerging cause of multidrug-resistant infection. J Antimicrob Chemother
65 (6): 1119–1125, 2010.
8. Nordmann P, Cuzon G, Naas T: The real threat of Klebsiella pneumoniae
carbapenemase-producing bacteria. Lancet Infect Dis
9 (4): 228–236, 2009.
9. Smith Moland E, Hanson ND, Herrera VL, Black JA, Lockhart TJ, Hossain A, Johnson JA, Goering RV, Thomson KS: Plasmid-mediated, carbapenem-hydrolysing beta-lactamase, KPC-2, in Klebsiella pneumoniae
isolates. J Antimicrob Chemother
51 (3): 711–714, 2003.
10. Lat A, Clock SA, Wu F, Whittier S, Della-Latta P, Fauntleroy K, Jenkins SG, Saiman L, Kubin CJ: Comparison of polymyxin B, tigecycline, cefepime, and meropenem MICs for KPC-producing Klebsiella pneumoniae
by broth microdilution, Vitek 2, and Etest. J Clin Microbiol
49 (5): 1795–1798, 2011.
11. Bratu S, Mooty M, Nichani S, Landman D, Gullans C, Pettinato B, Karumudi U, Tolaney P, Quale J: Emergence of KPC-possessing Klebsiella pneumoniae
in Brooklyn, New York: epidemiology and recommendations for detection. Antimicrob Agents Chemother
49 (7): 3018–3020, 2005.
12. Carvalhaes CG, Picão RC, Nicoletti AG, Xavier DE, Gales AC: Cloverleaf test (modified Hodge test) for detecting carbapenemase production in Klebsiella pneumoniae
: be aware of false positive results. J Antimicrob Chemother
65 (2): 249–251, 2010.
13. Endimiani A, Perez F, Bajaksouzian S, Windau AR, Good CE, Choudhary Y, Hujer AM, Bethel CR, Bonomo RA, Jacobs MR: Evaluation of updated interpretative criteria for categorizing Klebsiella pneumoniae
with reduced carbapenem susceptibility. J Clin Microbiol
48 (12): 4417–4425, 2010.
14. Clinical and Laboratory Standard Institute: Performance Standards for Antimicrobial Susceptibility Testing Twentieth Informational Supplement (June 2010 Update)
. M100S20U, 2010.
15. Chen L, Mediavilla JR, Endimiani A, Rosenthal ME, Zhao Y, Bonomo RA, Kreiswirth BN: Multiplex real-time PCR assay for detection and classification of Klebsiella pneumoniae
carbapenemase gene (blaKPC
) variants. J Clin Microbiol
49 (2): 579–585, 2011.
16. Endimiani A, Hujer KM, Hujer AM, Kurz S, Jacobs MR, Perlin DS, Bonomo RA: Are we ready for novel detection methods to treat respiratory pathogens in hospital-acquired pneumonia? Clin Infect Dis
52 (Suppl 4): S373–S383, 2011.
17. Burckhardt I, Zimmermann S: Using matrix-assisted laser desorption ionization-time of flight mass spectrometry to detect carbapenem resistance within 1 to 2.5 hours. J Clin Microbiol
49 (9): 3321–3324, 2011.
18. Hrabák J, Walková R, Studentová V, Chudácková E, Bergerová T: Carbapenemase activity detection by matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol
49 (9): 3222–3227, 2011.
19. Ecker DJ, Sampath R, Massire C, Blyn LB, Hall TA, Eshoo MW, Hofstadler SA: Ibis T5000: a universal biosensor approach for microbiology. Nat Rev Microbiol
6 (7): 553–558, 2008.
20. Endimiani A, Hujer AM, Hujer KM, Gatta JA, Schriver AC, Jacobs MR, Rice LB, Bonomo RA: Evaluation of a commercial microarray system for detection of SHV-, TEM-, CTX-M-, and KPC-type beta-lactamase genes in gram-negative isolates. J Clin Microbiol
48 (7): 2618–2622, 2010.
21. Bradford PA, Bratu S, Urban C, Visalli M, Mariano N, Landman D, Rahal JJ, Brooks S, Cebular S, Quale J: Emergence of carbapenem-resistant Klebsiella
species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor-resistant TEM-30 beta-lactamases in New York City. Clin Infect Dis
39 (1): 55–60, 2004.
22. Nordmann P, Naas T, Poirel L: Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis
17 (10): 1791–1798, 2011.
23. Weisenberg SA, Morgan DJ, Espinal-Witter R, Larone DH: Clinical outcomes of patients with Klebsiella pneumoniae
carbapenemase-producing K. pneumoniae
after treatment with imipenem or meropenem. Diagn Microbiol Infect Dis
64 (2): 233–235, 2009.
24. Daikos GL, Markogiannakis A: Carbapenemase-producing Klebsiella pneumoniae
: (when) might we still consider treating with carbapenems? Clin Microbiol Infect
17 (8): 1135–1141, 2011.
25. Bulik CC, Christensen H, Li P, Sutherland CS, Nicolau DP, Kuti JL: Comparison of the activity of a human simulated, high-dose, prolonged infusion of meropenem against Klebsiella pneumoniae
producing the KPC carbapenemase versus that against Pseudomonas aeruginosa
in an in vitro
pharmacodynamic model. Antimicrob Agents Chemother
54 (2): 804–810, 2010.
26. Ho VP, Jenkins SG, Afaneh CI, Turbendian HK, Nicolau DP, Barie PS: Use of meropenem by continuous infusion to treat a patient with a Bla(kpc-2)–positive Klebsiella pneumoniae
blood stream infection. Surg Infect (Larchmt)
12 (4): 325–327, 2011.
27. Bulik CC, Nicolau DP: In vivo
efficacy of simulated human dosing regimens of prolonged-infusion doripenem against carbapenemase-producing Klebsiella pneumoniae
. Antimicrob Agents Chemother
54 (10): 4112–4115, 2010.
28. Bulik CC, Nicolau DP: Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae
. Antimicrob Agents Chemother
55 (6): 3002–3004, 2011.
29. Zavascki AP, Carvalhaes CG, Picão RC, Gales AC. Multidrug-resistant Pseudomonas aeruginosa
and Acinetobacter baumannii
: resistance mechanisms and implications for therapy. Expert Rev Anti Infect Ther
8 (1): 71–93, 2010.
30. Schafer JJ, Goff DA: Establishing the role of tigecycline in an era of antimicrobial resistance. Expert Rev Anti Infect Ther
6 (5): 557–567, 2008.
31. Cunha BA: Pharmacokinetic considerations regarding tigecycline for multidrug-resistant (MDR) Klebsiella pneumoniae
or MDR Acinetobacter baumannii
urosepsis. J Clin Microbiol
47 (5): 1613, 2009.
32. Zarkotou O, Pournaras S, Voulgari E, Chrysos G, Prekates A, Voutsinas D, Themeli-Digalaki K, Tsakris A: Risk factors and outcomes associated with acquisition of colistin-resistant KPC-producing Klebsiella pneumoniae
: a matched case-control study. J Clin Microbiol
48: 2271, 2010.
33. Neuner EA, Yeh JY, Hall GS, Sekeres J, Endimiani A, Bonomo RA, Shrestha NK, Fraser TG, van Duin D: Treatment and outcomes in carbapenem-resistant Klebsiella pneumoniae
bloodstream infections. Diagn Microbiol Infect Dis
69 (4): 357–362, 2011.
34. 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
49 (2): 271–274, 2009.
35. Infectious Diseases Society of America: The 10 × ′20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis
50 (8): 1081–1083, 2010.
36. Kitchel B, Rasheed JK, Patel JB, Srinivasan A, Navon-Venezia S, Carmeli Y, Brolund A, Giske CG: Molecular epidemiology of KPC-producing Klebsiella pneumoniae
isolates in the United States: clonal expansion of multilocus sequence type 258. Antimicrob Agents Chemother
53 (8): 3365–3370, 2009.
37. Giakkoupi P, Papagiannitsis CC, Miriagou V, Pappa O, Polemis M, Tryfinopoulou K, Tzouvelekis LS, Vatopoulos AC: An update of the evolving epidemic of blaKPC-2
-carrying Klebsiella pneumoniae
in Greece (2009–10). J Antimicrob Chemother
66 (7): 1510–1513, 2011.
38. Navon-Venezia S, Leavitt A, Schwaber MJ, Rasheed JK, Srinivasan A, Patel JB, Carmeli YIsraeli KPC Kpn Study Group: First report on a hyperepidemic clone of KPC-3-producing Klebsiella pneumoniae
in Israel genetically related to a strain causing outbreaks in the United States. Antimicrob Agents Chemother
53 (2): 818–820, 2009.
39. Woodford N, Tierno PM Jr, Young K, Tysall L, Palepou MF, Ward E, Painter RE, Suber DF, Shungu D, Silver LL, et al.: Outbreak of Klebsiella pneumoniae
producing a new carbapenem-hydrolyzing class A beta-lactamase, KPC-3, in a New York Medical Center. Antimicrob Agents Chemother
48 (12): 4793–4799, 2004.
40. Gregory CJ, Llata E, Stine N, Gould C, Santiago LM, Vazquez GJ, Robledo IE, Srinivasan A, Goering RV, Tomashek KM: Outbreak of carbapenem-resistant Klebsiella pneumoniae
in Puerto Rico associated with a novel carbapenemase variant. Infect Control Hosp Epidemiol
31 (5): 476–484, 2010.
41. Tenover FC, Kalsi RK, Williams PP, Carey RB, Stocker S, Lonsway D, Rasheed JK, Biddle JW, McGowan JE Jr, Hanna B: Carbapenem resistance in Klebsiella pneumoniae
not detected by automated susceptibility testing. Emerg Infect Dis
12 (8): 1209–1213, 2006.
42. Moquet O, Bouchiat C, Kinana A, Seck A, Arouna O, Bercion R, Breurec S, Garin B: Class D OXA-48 carbapenemase in multidrug-resistant enterobacteria, Senegal. Emerg Infect Dis
17 (1): 143–144, 2011.
43. Cantón R, Ruiz-Garbajosa P: Co-resistance: an opportunity for the bacteria and resistance genes. Curr Opin Pharmacol
11 (5): 477–485, 2011.
44. Schwaber MJ, Lev B, Israeli A, Solter E, Smollan G, Rubinovitch B, Shalit I, Carmeli YIsrael Carbapenem-Resistant Enterobacteriaceae Working Group: Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae
in Israeli hospitals via a nationally implemented intervention. Clin Infect Dis
52 (7): 848–855, 2011.
45. Andersson DI: The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol
9 (5): 461–465, 2006.
46. Besier S, Ludwig A, Brade V, Wichelhaus TA: Compensatory adaptation to the loss of biological fitness associated with acquisition of fusidic acid resistance in Staphylococcus aureus
. Antimicrob Agents Chemother
49 (4): 1426–1431, 2005.
47. Kugelberg E, Lofmark S, Wretlind B, Andersson DI: Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa
. J Antimicrob Chemother
55 (1): 22–30, 2005.
48. Tsai YK, Fung CP, Lin JC, Chen JH, Chang FY, Chen TL, Siu LK: Klebsiella pneumoniae
outer membrane porins OmpK35 and OmpK36 play roles in both antimicrobial resistance and virulence. Antimicrob Agents Chemother
55 (4): 1485–1493, 2011.
49. Bialek S, Lavigne JP, Chevalier J, Marcon E, Leflon-Guibout V, Davin A, Moreau R, Pagès JM, Nicolas-Chanoine MH: Membrane efflux and influx modulate both multidrug resistance and virulence of Klebsiella pneumoniae
in a Caenorhabditis elegans
model. Antimicrob Agents Chemother
54 (10): 4373–4378, 2010.
50. Bachman MA, Oyler JE, Burns SH, Caza M, Lépine F, Dozois CM, Weiser JN: Klebsiella pneumoniae
yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2. Infect Immun
79 (8): 3309–3316, 2011.
51. Monier JM, Demanèche S, Delmont TO, Mathieu A, Vogel TM, Simonet P: Metagenomic exploration of antibiotic resistance in soil. Curr Opin Microbiol
14 (3): 229–235, 2011.
52. Jousset A: Ecological and evolutive implications of bacterial defences against predators. Environ Microbiol
14 (8): 1830–1843, 2012.
53. Nordmann P, Poirel L: Emergence of plasmid-mediated resistance to quinolones in Enterobacteriaceae. J Antimicrob Chemother
56 (3): 463–469, 2005.
54. Picão RC, Cardoso JP, Campana EH, Petrolini FVB, Assis DM, Neto LJ, Gales AC: Does the nosocomial sewage represent a threat for the environmental spread of blaKPC
? Presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011; Chicago, Illinois.
55. Grad YH, Lipsitch M, Feldgarden M, Arachchi HM, Cerqueira GC, Fitzgerald M, Godfrey P, Haas BJ, Murphy CI, Russ C, et al.: Genomic epidemiology of the Escherichia coli
O104:H4 outbreaks in Europe. Proc Natl Acad Sci U S A
109 (8): 3065–3070, 2011.