Bacteria have been characterized as "borg” entities, meaning that they express group identity1 and a collective decision-making process. Bacterial virulence and metabolism are features controlled through quorum sensing, a population density based regulating system that integrates individual bacterial behaviors into a collective, coherent response, termed swarm intelligence.²

Shortly after the introduction of antibiotics in clinical practice, bacterial resistance has started to emerge and multiple studies have been dedicated to ascertaining the exact mechanisms whereby bacteria become resistant to available antimicrobials.

Multiple evolutionary pathways have led to the development and transfer of antimicrobial resistance, as bacteria exhibit different resistance mechanisms, which block antimicrobial drugs at various steps. For example, antibiotic entry into the bacterial cell can be limited or prevented altogether through mechanical impermeability of the bacterial wall,³modification of the drug’s binding target,³ or through porin inhibition.⁴

Before reaching or after penetrating the bacterial cell, antibiotics can be degraded through hydrolyzation by the direct action of enzymes synthesized by bacteria, namely penicillinases, beta-lactamases (accounting for resistance to penicillin and first generation cephalosporins – e.g., TEM-1, TEM-2 and SHV-1), extended spectrum beta-lactamases (ESBLs – more than 500 identified enzymes, e.g., SHV-2, TEM-type ESBLs, CTX-M, OXA, etc. responsible for resistance to monobactams and third generation cephalosporins), carbapenemases (e.g., Klebsiella pneumoniae carbapenemase (KPC), metallo-beta-lactamases, specific OXA subgroups). Beta-lactamases can be coded on chromosomes, conferring constitutive resistance, or on transposons/plasmids that can be readily transmitted to other bacteria, thus extending the range of antimicrobial resistance even further. These beta-lactamases can act in the intracellular space, inside the bacteria, or they can be expressed in the extracellular milieu, where they can hydrolyze the drug prior to its entry into the bacterial cell. When extracellular, the enzymes may become "common goods”,⁵ being protective for other surrounding bacteria, particularly in poly-microbial biofilms. Other types of enzymes are acetyltransferases, involved in covalent modification of aminoglycosides that renders them inactive.³

If the antibiotic does enter the bacterial cell and is not hydrolyzed by specific enzymes, efflux pumps come into play and eject the drug back into the extracellular space. Moreover, specific mutations in the drug’s target can also confer resistance to antimicrobials such as fluoroquinolones (the target enzymes being DNA gyrase and/or topoisomerase IV)⁶or rifamycins (RNA polymerase).³

Escherichia coli represents a group of Gram-negative bacilli harboring comprehensive virulence mechanisms that drive infections with variable localizations: gastrointestinal tract, urinary tract, bloodstream etc. The resistance of E. coli to currently available antimicrobials is worrisome, with different figures being reported in different parts of the world. This is a brief meta-analysis, summing up relevant studies published in field literature in order to better characterize E. coli resistance.

By using the search terms "E. coli” and "resistance” on PubMed and narrowing the search down to the publication timespan 2010-2016, 27 relevant articles have been extracted (Table 1), reporting studies performed in 15 different countries such as: Iran (n=7), India (n=4), China (n=2), Pakistan (n=2), USA (n=2), and France, Germany, Turkey, Kuwait, Lebanon, Libya, Mexico, Nepal, Nigeria, and Venezuela (n=1 each). Most of the studies presented resistance patterns of E. coli strains isolated from urinary tract infections (UTI, n=18), while others reported laboratory data valid for all E. coli strains, irrespective of sample type (n=4), 2 studies presented resistance rates in strains involved in bloodstream infections (BSI), and others reported data from pneumonia, neonatal meningitis, and diabetic foot ulcers (1 study each). The median number of strains was 200 per study, with a minimum of 16 and a maximum of 16,511, interquartile range: 120, 821.

E. coli strains displayed polymorphous resistance patterns (Table 2), with percentages varying slightly based on sample type and geographical distribution. The mean resistance to third generation cephalosporins ranged from 29.5% (ceftazidime) to 41.3% (cefotaxime), while resistance to fourth generation cephalosporins, namely cefepime, averaged around 31.9%, with a minimum value reported at 3.8% in CSF samples from neonates with bacterial meningitis in the USA⁷ and a maximum reported at 77% in bloodstream infections in India.⁸

Resistance to last-resort antimicrobials was fairly low, with median values of 0.8% for imipenem, 0.5% for meropenem, 0.9% for tigecycline and 0% for colistin. Of 18 studies reporting susceptibility results to imipenem, 10 placed E. coli resistance below 1% (6 of them reporting 0% resistance), 5 studies reported resistance values between 1% and 6.5% and a small number of other studies reported higher resistance rates, namely 13.8% in a study from Iran which included 29 strains isolated from patients with nosocomial infection after open heart surgery,⁹38.6% in another study from Iran with 57 strains isolated from UTIs,¹⁰and 50% in a study from Pakistan which included 16 strains isolated from diabetic foot ulcers.¹¹

 Table 1. Characteristics of the studies included in the analysis

 

 Table 2. Antimicrobial resistance of E. colicomputed based on 27 relevant studies published in field literature

 

Data on meropenem susceptibility was only available in 11 studies, 5 of which reported 5% resistance, another 5 reported resistance percentages ranging from 0.5% to 5%, and the same study from Pakistan on diabetic foot ulcers placed resistance as high as 25%.¹¹ Even fewer studies (n=3) presented data for tigecycline, reporting 0% resistance in strains (n=135) responsible for pneumonia in Germany during 2004-2014,¹⁶ 1% in bloodstream infections (n=1918) in India³³ and 1.8% in all (n=16,511) E. coli strains isolated in Lebanon during 2014.¹⁹ Of these papers, two also reported data on colistin, placing resistance at 0% in bloodstream infections³³ and pneumonia,¹⁶confirming that it may still represent a good option for treatment of otherwise resistant Gram-negative bacilli, as previously reported.³⁴

The lowest percentage of resistance to most antimicrobials was reported in a study from the USA, which included 51 E. coli strains responsible for neonatal meningitis; in this study

Wijetunge et al. described 0% resistance to ciprofloxacin, gentamicin, and piperacillin-tazobactam, 3.8% resistance to cefazolin, 9.4% to cefotaxime, 3.8% to cefepime, 10% to tetracycline, and 18.9% to co-trimoxazole.⁷ Resistance to cefuroxime was lowest in a study of 135 strains isolated from patients with pneumonia in Germany,¹⁶ and the rest of the lowest values were recorded in samples from UTIs. When comparing strains isolated from UTIs and from other sources of infection, the differences in terms of resistance were not statistically significant.

The highest percentage of resistance to most antimicrobials was reported in samples from UTIs, with the exception of resistance to gentamicin 51.5% (in 550 strains from various samples in China)¹⁷ cefazolin 71.7% (in 16,511 strains from various samples in China),¹⁸ ceftriaxone 80.6% and cefepime 77% (in 108 samples from bloodstream infections in India)⁸and to carbapenems in diabetic foot ulcers, as described above.¹¹Extremely high rates of resistance to carbapenems were reported in a study from India, in E. coli samples isolated from burn wound infections, with 66.6% resistance to imipenem and meropenem.³⁵However, this study was not included in the analysis, as the number of isolates (n=3) was too small to be considered representative.

Not surprisingly, the resistance of E. coli to currently available beta-lactam drugs is highest among aminopenicillins, somewhat lower but still worryingly high in cephalosporins (around 40% resistance to third generation cephalosporins and around 30% to fourth generation cephalosporins), while remaining consistently below 1% in carbapenems, with the exception of a few studies that reported higher resistance rates. Nitrofurantoin and fosfomycin appear to remain active agents, with resistance rates generally below 5%, and could be considered in the first intention treatment of uncomplicated UTI.

In conclusion, antimicrobial resistance rates in E. coli are diverse, with wide variations between different studies and therefore empiric treatment decisions should be based on educated choices taking into account, when available, local resistance patterns.

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