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Carbapenem and colistin resistance in Enterobacteriaceae

worldwide spread and future perspectives

Ghasemian, Abdolmajida,b; Shafiei, Morvaridd; Hasanvand, Fatemehc; Shokouhi Mostafavi, Seyyed K.c

Reviews in Medical Microbiology: October 2018 - Volume 29 - Issue 4 - p 173–176
doi: 10.1097/MRM.0000000000000142

Carbapenems and colistin antibiotics are the major weapons against multidrug-resistant (MDR) and extensively drug-resistant Gram-negative bacteria. Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacea, Klebsiella oxytoca, Proteus mirabilis, Citrobacter freundii, Citrobacter koseri, Serratia spp., Morganella morganii and Salmonella spp. have been reported as carbapenemase-producing Enterobacteriaceae members. Carbapenem resistance mostly occurs by means of some enzymes such as classes A, B and D carbapenemases. New Delhi metallo-β-lactamases, K. pneumoniae carbapenemase, imipenemase metallo-β-lactamase, Verona integron-encoded metallo-β-lactamase and OXA-48-like subtypes have been reported worldwide with some epidemiological differences. Plasmid-mediated transmission has facilitated their spread. In addition, colistin resistance by means of either chromosomal mutation in one of the three genes involved in the biosynthesis of LipA, LpxA, LpxC and LpxD cell wall components or via extrachromosomal elements (plasmid-mediated mcr genes) has recently reported in some species worldwide. MDR and extensively drug-resistant strains have become nonsusceptible to last-line antibiotics, thus consideration of effective ways such as the implementation of appropriate infection control strategies, separation of patients infected with MDR strains from others, public education, containment of antibiotic consumption in livestock industry, accurate antibiotic susceptibility testing and prescription and the proper implementation of antibiotic surveillance in hospitals are necessary. In addition, the use of last-line antibiotics in livestock and food animals must be restricted or banned.

aDepartment of Bacteriology, Faculty of Medicine, Aja University of Medical Sciences

bDepartment of Microbiology, Fasa University of Medical Sciences, Fasa

cDepartment of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University

dDepartment of Microbiology, Pasteur Institute of Iran, Tehran, Iran.

Correspondence to Abdolmajid Ghasemian, PhD, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran. E-mail:

Received 18 April, 2018

Revised 6 June, 2018

Accepted 8 June, 2018

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Enterobacteriaceae family members are among the most important bacterial pathogens in healthcare and community settings. Escherichia coli, Klebsiella pneumoniae, Proteus spp. and Enterobacter spp. are the most common species isolated from clinical specimens, especially in the ICU settings with the emergence of multiple antibiotic resistance. Antibiotic resistance is now recognized as one of the most serious global threats to human health in the 21st century. Enterobacter cloacea, Klebsiella oxytoca, Proteus mirabilis, Citrobacter freundii, Citrobacter koseri, Serratia spp., Morganella morganii and Salmonella spp. have been reported as other carbapenemase-producing species. Carbapenems and colistin are last-line antibiotics against which carbapenemase producing Enterobacteriaceae (CPE) and colistin-resistant Enterobacteriaceae (col-RE) have been developed [1,2]. The spread of these strains occurs as a result of various reasons. Tracking of risk factors associated with CPE col-RE acquisition among patients has important implications for empiric antibiotic therapy and also infection control management. The advent/emergence of col-RE and CPE Enterobacteriaceae among populations highlights a serious health threat against proper therapy and infection eradication, requiring the implementation of control strategies and surveillance in healthcare and community settings. Carbapenems and colistin need to be prescribed and consumed cautiously.

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Carbapenem resistance

The concern is critical regarding CPE which produce K. pneumoniae carbapenemase-2 (KPC-2), New Delhi metallo-β-lactamase-1 (NDM-1), imipenemase metallo-β-lactamase (IMP), Verona integron-encoded metallo-β-lactamase (VIM) and OXA-48-like subtypes resulting in resistance to many classes of antibiotics including broad-spectrum penicillins, third-generation cephalosporins, aminoglycosides, fluoroquinolones and carbapenems [3–5]. Some carbapenemases are located on several plasmid types (IncA/C, IncF, IncL/M or untypeable) such as KPC, imipenem-hydrolysing-2 and guiana extended spectrum and can be transmitted more rapidly among Enterobacteriaceae family [3]. Plasmid-mediated drug resistance to carbapenems and colistin has spread rapidly among the Enterobacteriaceae members in hospital and community settings. Carbapenems are drug of choice for eradication of extended-spectrum beta-lactamase (ESBL)-producing species. ESBLs cause bacterial resistance to third and fourth generation cephalosporins. If the carbapenem resistance occurs, colistin would be a therapeutic choice. Carbapenems and colistin are last-line antibiotics for the eradication of infections caused by Gram-negative bacteria. However, these infections have been reported worldwide [4]. According to recent US data, CPE increased from 2.1% in 2001 to 4.2% in 2011 [6]. In Indian subcontinent [metallo-batalactamase (MBL)-producing CPE], the United States (mostly KPC-producing CPE), some countries in Europe, including Romania, Denmark, Spain and Hungary (MBL-producing CPE) and Turkey and surrounding countries (OXA-48-like-producing CPE) carbapenemase genes have been detected [1]. KPC family carbapenemases are most common enzymes in Enterobacteriaceae around the world. Nonetheless, their spread have scarce in the US hospitals, they are widespread in central and south America. In the Europe, countries of Mediterranean region; especially, Italy and Greece have the highest rate of this family. The highest increase was observed from 1/6 to 10.4% for Klebsiella species at equal intervals [7]. This family has also distributed in Asia, but is less common in Africa [8]. In addition, MBL-producing CPE are common in Asia such as NDM-1 and IMP families, but are less common in North America. NDM and VIM families have been reported from South America and some African countries, but studies are scarce in Africa. OXA-48 type family is endemic in Turkey neighboring countries and is epidemic in some European countries including France, Belgium, Spain and Romania [9]. This family is scarce in the United States, but has been detected in other areas worldwide. Considering the fact that this family is not detected in routine laboratory tests because of low level of carbapenem resistance, their existence is underestimated [8]. The antibiotic treatment choices against infections due to CPE strains are limited. Tetracycline, approved in 2005 by the Food and Drug Administration, colistin, phosphomycin and aminoglycosides have remained as few options to combat against infections caused by multidrug-resistant (MDR) strains [10,11].

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Colistin resistance

One of the effective therapeutic agents against infections caused by CPE is colistin. Colistin, also called polymyxin E, is placed in class of lipid antibiotics. This antibiotic is a cationic polypeptide composed of a circular decapeptide, coupled to a fatty acyl with alpha-amide bond. This antibiotic confers its antimicrobial activity via two mechanisms including the initial binding and permeability of the outer membrane layer, which is followed by the re-establishment of the cytoplasmic membrane. Although the precise mechanism for bacterial killing has not been yet clearly defined, the first critical point in the polymyxin function is the electrostatic reaction between positive peptides and negative lipid A receptors [the endotoxin component of lipopolysaccharides (LPS)] [12,13]. Colistin has a huge antimicrobial spectrum on many Gram-negative bacteria and is often used as one of the latest antibiotics against MDR Enterobacteriaceae. But in recent years, colistin-resistant clinical isolates have been emerged. Colistin resistance occurs by two mechanisms including plasmid-mediated hydrolysis and via chromosomal mutations. Furthermore, recent studies have provided a unique mechanism for the resistance of the bacteria to colistin by the presence of the mcr-1-mcr-4 genes, which was introduced as a member of the phosphor-ethanolamine transferase family and catalyzes the transfer of lipid A into bacterial LPS. Recently, MCR-1 gene has been detected in at least five Enterobacteriaceae species: E. coli, Enterobacter spp., Salmonella spp., K. pneumoniae and K. oxytoca [14–16]. Most of the NDM-1-producing bacteria are susceptible to colistin and are resistant to most antibiotics. Proteus, Morganella and Providencia species are inherently resistant to colistin. Some strains of NDM-1-producing bacterial strains are resistant to nearly all antibiotics, including colistin, and there is currently no therapy choice for its treatment [17–19].

Colistin resistance can also occur due to mutations in one of the three genes involved in the synthesis of LipA, LpxA, LpxC and LpxD, or due to the transfer of the ISAbaII insertion sequence, which can lead to the inactivation of the genes involved in the lipid A biosynthesis, resulting in the incomplete formation of bacterial LPS and leading to high-level resistance to colistin [16,20]. As colistin is used as the last-line antibiotic for the Gram-negative infections chemotherapy, the increased resistance is an alarm for health systems. Therefore, it is necessary to use new therapeutic regimes, its detection with more sensitivity and control of hospital infections.

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Combination therapies

The efficiency of monotherapy or combined therapy is an important question that remains unresponsive to physicians. A study on patients admitted to the ICU showed that treatment failure in patients receiving combination therapy was 16.7%, whereas treatment failure in patients receiving monotherapy was 40% [21]. In another study, the rate of failure in patients receiving concomitant colistin–tigecycline therapy was 42.9% and patients receiving the colistin–tigecycline–gentamicin regimen were 0% [22]. In general, in most studies, there has been no statistically significant difference between mortality and failure of treatment among patients prescribed with combined therapeutic regimens and monotherapy. However, studies also highlight the benefits of combination therapies compared with monotherapy for successful treatment and lower mortality rates due to these infections [23–25].

In addition, combinations of tigecycline and colistin, carbapenems and colistin, ceftazidime/avibactam and tigecycline with gentamicin regimens, used in MDR Enterobacteriaceae, have reduced the deaths rate than that for other antibiotics. In a study, the mortality rate of patients treated with colistin–tigecycline was reduced significantly when the morphine was added to this compound [24]. Other studies have suggested the combination of colistin–tigecycline and carbapenem even among patients infected with isolates with resistance to carbapenems, possibly due to the potential correlation between colistin and carbapenems [23,26]. Tigecycline with colistin, colistin with carbapenem, phosphomycin with carbapenem, phosphomycin with an aminoglycoside and an aminoglycoside with carbapenem have been effective antibiotic compounds for the treatment of patients infected with CPE [27]. In addition, the clinical evidence has demonstrated that the combination of tigecycline–colistin in the onset of colistin resistance is more effective in carbapenem-resistant K. pneumoniae than colitis monotherapy [28]. There should be care in the administration of colistin in combination with aminoglycoside, as both agents can lead to the occurrence of constant antibiotic resistance and nephrotoxicity [7,24,29]. The efficacy of colistin monotherapy was challenged due to low plasma concentrations of drug injections, especially in patients with impaired renal function. On the other hand, increase in the dose of colistin is not possible due to its nephrotoxic effects [30].

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Reasons for drug resistance spread

Antibiotic resistance occurs as a natural selection. Rapid evolution of bacterial resistance is possibly result of a complex interaction of several factors such as treatment uncertainty, higher burden of infectious diseases, ICU residence, inadequate access to standard laboratory facilities, lack of treatment guidelines, government support to pharmaceutical industries, self-medication, prescription based on availability of market centers, fragmented public health system, antibiotics prescribed by unqualified health professionals, less strict law enforcement, insufficient adherence to universal hygiene and infection control or surveillance, antibiotic consumption in livestock and food animals, crowding situations, poor population-wide insurance coverage and low population-wide education level. Some important reservoirs of these strains are colonized patients, biofilms, sink, standard toilets, drainage system, stuff computers and mobiles, endoscopes and hospital foodstuff. It is notable that some species such as Klebsiella spp. can survive in dry conditions. Pediatric population is important regarding acquisition of CPE due to their vulnerability, unawareness of children about the issue and thus low adherence with the hygiene and more contact among them than adults [31–34].

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Control strategies and future perspectives

Investigations for novel compounds in the era of antibiotic resistance seem essential and investments will be helpful. Few agents are present such as avibactam (inhibitor) and plazomicin (novel aminoglycoside). Combination treatment possibly offer an advantage over monotherapy for severely ill patients; however, it may be followed by more severe side effects. For decolonization, chlorhexidine gluconate and sodium hypochlorite have demonstrated the strongest effects [34]. Furthermore, the use of antiseptics, probiotics and bacteriophages are currently under survey. It is crucial to clear sources for resistance evolution and reservoirs for MDR strains in the environment due to high economical costs in future and mortality rate. In addition, obligatory antibiotic stewardship programs should be considered in all therapeutic fields, and there should be attempts for sustained risk evaluation and risk management performances [35]. Furthermore, waste materials should be safely disposed. In addition, the use of last-line antibiotics in livestock and food animals must be restricted or banned [34].

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Considering the high prevalence of MDR and extensively drug-resistant strains in the Enterobacteriaceae family, the need for more attention to effective measures such as the implementation of more accurate infection control methods, the isolation of patients with MDR bacterial infection from other patients and the proper implementation of antibiotic surveillance in hospitals are necessary. In addition, the use of last-line antibiotics in livestock and food animals must be restricted or banned.

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Conflicts of interest

There are no conflicts of interest.

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carbapenemases; colistin; drug resistance; Enterobacteriaceae

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