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 bla KPC 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 bla KPC 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 bla KPC 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 bla KPC 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 bla KPC 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 bla KPC 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.
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