In general, bacteria resist to the inhibitory action of antibiotics through three primary mechanisms that often operate concurrently with each other. These are decreased uptake of the drug (1,2), target modification (3) and inactivation of the drug (4). Resistance develops among microorganisms by spontaneous mutations in existing genes or by the acquisition of extraneous genes. The survival and success of resistant mutants, on the other hand, is a matter of cost of fitness to the environment (5,6).
Decreased uptake of antibiotics
Bacteria may avoid accumulation of antibacterial molecules on their targets by reducing the absorption of these molecules or increasing the discharge of them, or by employing both mechanisms simultaneously.
In general, antibiotics must penetrate the outer membrane (OM) of bacteria to reach to their targets. The OM of Gram-negative bacteria consists of a lipid bilayer and porins (7). In theory, hydrophobic antibiotics, such as quinolones and macrolides, pass through the lipid bilayer while hydrophilic antibiotics, such as beta-lactams, pass through porins (7,8). However, the OM of bacteria is a highly complex structure, and the permeation pathways of antibiotics are not fully understood (9). In some way, the OM of bacteria may be modified via the substitution of even one or two amino acids and transform to a permeability barrier for antibiotics.
Upregulated efflux molecules may work concurrently with porin modifications which dramatically augment the discharge of antibiotics, thereby avoiding accumulation on target (2). Efflux-mediated resistance to tetracycline was first detected among Escherichia coli (E. coli) isolates during the 1970s (10,11). Since then, various structures operating as efflux pumps have been discovered. The substrate specificity of efflux pumps varies widely, and some of them have an extraordinarily broad spectrum (12). Efflux pumps are accepted as one of the primary mechanisms of multi-drug resistance (MDR) among bacteria, particularly among gram-negative bacteria (12,13).
Bacteria replace or modify target molecules to avoid the harmful effects of antibiotics (14). Methicillin resistance among Staphylococcus aureus (S. aureus) was first noticed in the 1960s which emerge through the replacement of the target molecule (15). Beta-lactam antibiotics inactivate PBPs, particularly PBP 2 of S. aureus, initiate dysregulation of peptidoglycan synthesis and trigger a chain of events that eventually lead to the death of the bacteria (16). Methicillin-resistant S. aureus produces PBP 2a, a homolog enzyme with a low affinity to beta-lactam antibiotics, which is fully active and able to restore the vital functions of inactivated PBPs. PBP 2a is encoded on the mec locus, a gene package that is extraneous, likely evolved and spread from another Staphylococcus species to S. aureus (17).
There are several modes of target modification. Resistance to linezolid occurs by the alteration of 50S subunit of rRNA (3). Another form of target modification occurs through the methylation of ribosomal genes. Methylation protects the target molecule from the inhibitory effect of antibiotics. Macrolide resistance is mostly caused by this type (18).
Plasmid-mediated quinolone resistance (PMDR) is a notable example of target protection. Some proteins are capable of protecting gyrase from the inhibition of quinolones (19). These unique proteins are encoded on naturally occurring alleles, which are now referred to as “qnr” and primarily spread on multi-resistance plasmids, mostly along with extended-spectrum beta-lactamases (ESBLs) (19,20).
Bacteria, specifically Acinetobacter spp., resist to polymyxin antibiotics by modifying the lipid A component of the OM through spontaneous mutations (21,22). It was, however, surprising to discover that plasmidic colistin resistance conferred by lipid A modifying enzymes are insidiously spreading around the members of Enterobacteriaceae (23,24).
Enzymatic inactivation of antibiotics
Resistance to aminoglycosides emerged among various species of bacteria, particularly among Gram-negatives, Gram-positives, and Mycobacterium, due to the dissemination of aminoglycoside-modifying enzymes (AMEs) on mobile genetic elements (25). AMEs mimics the rRNA targets of aminoglycosides, and so can pair with aminoglycosides in the replacement of the target molecule and inactivate them (26).
Beta-lactamase-mediated resistance accounts for the most significant negative impact on human health care. Beta-lactam antibiotics attack PBPs and interfere with cell wall synthesis. Three-dimensional configuration of beta-lactamases imitates PBPs. Therefore, beta-lactamases can bind to and inactivate beta-lactam antibiotics as a substitute of PBPs (27).
Beta-lactam antibiotics are natural products of some microorganisms. Therefore, in nature, even before the human history, microorganisms produced beta-lactamases and survived against antibiotic producers (28). These enzymes remained rare before the mass-production and consumption of beta-lactam antibiotics. Extensive selective pressure caused by the widespread use of antibiotics enabled the evolution and dissemination of beta-lactamases, especially among gram-negative microorganisms. This scenario repeated after the introduction of every new beta-lactam antibiotic to the market, irrespective of how expanded the spectrum of the new antibiotic was. Now, gram-negative microorganisms produce various beta-lactamases simultaneously and confer resistance to multiple classes of beta-lactam antibiotics.
Ambler classified beta-lactamases under four molecular classes, Class A through Class D (29). Enzymes from molecular Class A, Class C and Class D are typically serine beta-lactamases, while enzymes from Class B are metalloenzymes (MBLs) those require zinc ion for activation.
The distinctive feature of Class A beta-lactamases is that these enzymes are highly susceptible to inhibitor beta-lactams clavulanate, sulbactam, and tazobactam (30). Most Class A enzymes exhibit extended-spectrum activity towards third-generation cephalosporins. These enzymes are also referred to as ESBLs and evolved from a TEM, SHV or CTX-M narrow-spectrum precursor by one or more amino-acid substitutions. TEM and CTX-M type Class A ESBLs are primarily encoded on a mobile element and have a tendency to spread among the members of Enterobacteriaceae, whereas VEB and PER type Class A ESBLs have a tendency to spread among Acinetobacter and Pseudomonas (31,32). KPC type enzymes are Class A carbapenemases, classically found among Klebsiella species (33).
AmpC enzyme of Enterobacter cloacae is the most studied chromosomally-encoded Class C enzyme (34). Typically, this is an ESBL, encoded on the chromosome downstream to some regulatory genes and, hence, inducible. Clinical significance of being inducible is that exposure to a substrate, such as cefotaxime and ceftazidime, causes overexpression of the enzyme which increases the MICs and leads to treatment failures.
Class D enzymes (oxacillinases) are weak-to-moderate substrates of beta-lactamase inhibitors (30). Genes encoding oxacillinases are mostly joined to an insertion sequence or located in an integron as a gene cassette (35). OXA-carbapenemases have variable substrate specificity. However, they are usually weak carbapenemases and confer high-level resistance to carbapenems with the simultaneous involvement of other resistance mechanisms (35,36).
MBLs, belonging to Ambler Class B, have high hydrolytic capability over carbapenem antibiotics and spread on virulent or resistant plasmids. The dissemination of MBLs herald the emergence of pan-resistant bugs and an approaching health-care crises worldwide (37).
Evolution of resistance and mobile genetic elements
Spontaneous mutation is one of the key mechanism bacteria use to survive stress conditions. Mutation frequencies of bacterial species are limited but may change in stress conditions (38). Environmental stress factors, such as antibiotic pressure, may select bacterial subsets with deficient DNA mismatch repair mechanisms. These bacterial subsets with less DNA replication fidelity are termed as mutators. A mutator may have 100 to 1,000 times the mutation rate of the wild-type bacteria. Therefore, mutators readily accumulate compound mutations to develop complex resistance mechanisms and gain a short term fitness advantage (39).
Mobile genetic elements, jumping genes (40), are the principal means of the spread and accumulation of resistance genes. From the simplest to most complex; insertion sequence, integron, transposon, and plasmid are currently explored mobile elements.
An insertion sequence (IS) is a short transposable DNA element composed of one or two genes encoding a transposase, a protein with recombinase activity, along with flanking inverted repeat sequences of various lengths on both sites (41). Based on a site-specific recognition, ISs wrap and carry a resistance gene, for example, a beta-lactamase gene, and its promoter sequence during transposition (42). A site-specific recombination means that ISs and associated resistant genes spread selectively among bacteria. A transposon is a more composite form of IS, bracketed by inverted ISs on both extremes and therefore capable of carrying more than one genetic determinant. Transposons may cause complex DNA rearrangements and may accumulate various resistance genes to confer an MDR phenotype (43). Integron is another mobile structure, composed of an integrase gene and a promoter sequence for its cargo. Gene cassette is a gene associated with a 59-base element which enables the gene to integrate to an integron. Integrons may carry multiple resistance determinants simultaneously (44,45).
The structures as mentioned earlier may unintentionally accumulate over a plasmid during the evolution, thereby conferring resistance to virtually all antibiotics (43). These plasmids with MDR islands spread among compatible microorganisms.
Leading microorganisms and major resistance mechanisms: a global perspective
Studies reporting gram-positive bacteria as the predominant etiology of sepsis and septic shock are rare (46). Most studies found gram-negative bacteria as the leading cause (47-49). Predominant pathogens identified in severe sepsis and septic shock, however, may vary among studies depending on the setting, study time and the country in which the study conducted. A prospective observational study carried out in multiple ICUs in China found pneumonia as the most common underlying disease associated with sepsis and septic shock (86.6%). In this study, Acinetobacter was the predominant microorganism (14.1%), followed by Pseudomonas spp. and Klebsiella spp. (48). A study conducted in 12 ICUs in France between 1996 and 2009, reported S. pneumoniae as the most common etiology of community-acquired sepsis followed by E. coli, whereas non-fermenters such as Acinetobacter, Pseudomonas, and Stenotrophomonas were the most common etiologies among nosocomial sepsis cases (50).
Briefly, S. pneumonia, E. coli, Klebsiella, Acinetobacter, and Pseudomonas are the predominant pathogens of sepsis and septic shock. Except S. pneumoniae, the MDR phenotype is common among these pathogens.
Therefore, main resistance mechanisms contributing to the MDR phenotype among these species worth mentioning.
E. coli & Klebsiella
Resistance is almost always plasmidic among E. coli and Klebsiella; the contribution of porin and efflux-mediated mechanisms are negligible. The hallmark of the MDR phenotype among E. coli and Klebsiella is the co-transfer of genes encoding an AME, a quinolone resistance determinant, and an ESBL on the same resistance plasmid (51,52).
ESBLs belonging to the CTX-M family are widespread among E. coli and Klebsiella (53-55). The recent spread of Class B carbapenemases among the members of Enterobacteriaceae is the herald of pan-resistant pathogens. VIM, IMP, and NDM-type Class B carbapenemases are increasingly more reported among E. coli and Klebsiella (43,51,56-59). The OXA-48 family is the primary OXA-type carbapenemase found among Enterobacteriaceae. The OXA-48 family enzymes were first reported from Turkey. These enzymes are weak carbapenemases. However, mutants of OXA-48 with various hydrolytic capabilities have also been identified (60). The OXA-48 family enzymes are mostly susceptible to expanded-spectrum cephalosporins like ceftazidime and cefepime (61).
It is noteworthy to mention that KPC-type Class A carbapenemases is the most prevalent carbapenemase among Klebsiella (62).
Porin/efflux-mediated resistance is not a major determinant among E. coli and Klebsiella.
Acinetobacter & pseudomonas
Porin/efflux-mediated resistance is mostly a major component of the MDR phenotype among Acinetobacter and P. aeruginosa (63). Since porin/efflux mechanisms are activated by spontaneous mutations, emergence of resistance during treatment is a significant concern for Acinetobacter and P. aeruginosa infections.
PER, VEB & GES type enzymes are the most common Class A ESBLs among Acinetobacter (64). PER-1 is the first ESBL identified in P. aeruginosa (65). It was later found to be widespread among Acinetobacter and P. aeruginosa in Turkey (32).
OXA-type carbapenemase, such as OXA-23, OXA-51, and others are suggested to occur naturally in Acinetobacter (66). Also, multiple OXA-type carbapenemases may co-exist in Acinetobacter and contribute to high-level carbapenem resistance (67).
The epidemiology of antibiotic resistance
S. aureus is a leading cause of bloodstream infections (BSIs), and is also the main reason regarding BSIs-associated death, especially MRSA. In Europe, according to the latest report from ECDC in 2013, Romania has the highest rates of MRSA (>50%) isolated from cerebrospinal fluid (CSF) or blood. In another five regions (Cyprus, Greece, Hungary, Italy and Spain), the isolate rate of MRSA ranged from 25% to 50% (68). In the USA, 50% of S. aureus associated the central line-associated bloodstream infections (CLABSIs) was MRSA, data from the CDC’s National Healthcare Safety Network (NHSN) (69). In mainland China, data from the Ministry of Health National Antimicrobial Resistance Investigation Net (Mohnarin) showed the rate of MRSA BSIs was 51.3% in 2011 (70). Over the last decade, the rates of nosocomial MRSA bacteremia remained stable or decreased in many geographic regions of the world (71).
VRE was first identified in the late 1980s in Europe, and then in the United States, caused epidemiological controversy (72,73). In the USA, VRE was a much bigger problem than elsewhere, according to the data from NHSN, the proportion of VRE isolated from CLABSIs remained stable from 2011 to 2014, the approximate rates of resistant isolates were 82% in E. faecium and 10% for E. faecalis (69). In Europe, Ireland has the highest rate of vancomycin-resistant E. faecium isolated from blood of nosocomial patients, which increased from 33% in 2007 to 45% in 2012 (74). In China, the incidences of vancomycin-resistant E. faecalis and E. faecium were 1.8% and 6.9% in 2011, respectively, according to Mohnarin (70).
Production of ESBLs was the main mechanism conferring antibiotic resistance in gram-negative pathogens. E. coli was one of the most frequently isolated pathogens in BSIs. CTX-M-15 ESBL producing-E. coli has spread worldwide (75). In the USA, the rates of ESBL-producing E. coli isolates were varied between 8.1% to 13.7% (76,77). According to Chinese antimicrobial resistance surveillance of nosocomial infections (CARES), ESBL producing in E. coli caused BSIs was 63.4% (78).
K. pneumonia was the most common Enterobacteriaceae specie exhibiting carbapenem resistance. In the USA, data from NHSN in 2014 showed that the all CRE rate in CLABSI was 7.1%, carbapenem-resistant K. pneumonia or K. oxytoca was 10.9%, carbapenem-resistant Enterobacter spp. was 6.6% and carbapenem-resistant E. coli was 1.9 (69). Few studied have known their CRE epidemiology in children, a recently study reported that the frequency of CRE increased from 0.0% in 1999–2000 to 5.2%, 4.5%, and 3.2%, respectively, in 2011–2012, among children in the USA (79). In Europe, the top three regions with highest rates of carbapenem resistant K. pneumonia were Greece (59.4%), Italy (34.3%) and Romania (20.5%) (68). There was rare report about carbapenem resistant E. coli and the highest prevalence were found in Bulgaria and Turkey, with 2.6% and 4.0% of frequency, respectively (68,80). A comprehensive study from China reported the overall prevalence of carbapenem-resistant E. coli and K. pneumoniae was 1.0% and 5.5%, respectively (81).
Non-fermenting Gram-negative bacteria
The most common non-fermenting Gram-negative bacteria caused BSIs are Acinetobacter spp. and P. aeruginosa, always exhibiting multidrug-resistant (called MDR-A and MDR-PA). The prevalence of MDR-A and MDR-PA isolated from CLABSIs were 43.7% and 17.9%, which decreased than 2011 (60.9% and 21.7%) (69). One study from China, the overall prevalence of extensively drug-resistant strains of Pseudomonas aeruginosa (XDRPA) and Acinetobacter baumannii (XDRAB) isolated from BSIs were 13.7% and 4.2%, respectively (81).
Conflicts of Interest: The authors have no conflicts of interest to declare.
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