Trends in Microbiology
Volume 14, Issue 9, September 2006, Pages 413-420
Journal home page for Trends in Microbiology

Review
The β-lactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter

https://doi.org/10.1016/j.tim.2006.07.008Get rights and content

Over the past 60 years, the use of successive generations of β-lactam antibiotics has selected successive generations of β-lactamase enzymes, each more potent than the last. Currently, rising problems include CTX-M extended-spectrum β-lactamases (ESBLs), plasmid-mediated AmpC β-lactamases and KPC carbapenemases in Enterobacteriaceae, while OXA- and metallo- carbapenemases are of growing importance in Acinetobacter spp. and (less so) in other non-fermenters. Escherichia coli isolates with CTX-M ESBLs are spreading multiresistance in the community and in hospitals, while carbapenemase-producing Acinetobacter spp., mostly from intensive care, are among the most multiresistant nosocomial bacteria known and are often susceptible only to polymyxins and, potentially, tigecycline. This review discusses the epidemiology and microbiology of these resistance problems, along with possible solutions.

Section snippets

Cycles of development and resistance

β-Lactams – penicillins, cephalosporins, carbapenems and monobactams – represent 60% of all antimicrobial use by weight. They are preferred because of their efficacy and safety and because their activity can be extended or restored by chemical manipulation. No other antibiotic class has such chemical malleability and versatility. Inevitably, however, their heavy usage has selected strongly for resistance. Among Gram-positive bacteria, resistance largely arises by penicillin-binding protein

Cephalosporin resistance in Enterobacteriaceae

Enterobacteriaceae are important opportunist pathogens and account for ∼35–40% of all bacteraemia isolates in the UK [Health Protection Agency (HPA); http://www.hpa.org.uk] and for the majority of urinary tract infections. When oxyimino-cephalosporins were introduced, virtually all Enterobacteriaceae were susceptible, but resistance has accumulated through the selection of strains with hyperproduced AmpC enzymes, acquired AmpC enzymes and, most importantly, extended-spectrum β-lactamases

Extended-spectrum β-lactamases

ESBLs were first described in the mid-1980s. Most early examples were mutants of the TEM and SHV plasmid-mediated penicillinases with one or more amino acid substitutions. The mutations enlarge the active site, which enables deflection of the oxyimino group and attack on the β-lactam ring. Such mutants – there are now >200 known (http://www.lahey.org/studies) – attack all oxyimino-cephalosporins but not α-methoxy-cephalosporins (cephamycins) or carbapenems. They are most prevalent in Klebsiella

Carbapenem resistance in Enterobacteriaceae

Growing cephalosporin resistance is causing increased reliance on carbapenems, which have good stability to both AmpC and ESBL enzymes. This reliance is increased by the fact that many ESBL producers (less so the AmpC hyperproducers) are also multiresistant to aminoglycosides, trimethoprim, tetracycline and, especially, fluoroquinolones.

Resistance in Pseudomonas aeruginosa

Like Enterobacter, P. aeruginosa has a chromosomal AmpC β-lactamase. It also has a recently discovered chromosomal class D enzyme OXA-50, although this seems of little significance in resistance [43]. AmpC might become derepressed by mutation and confer resistance to oxyimino-cephalosporins as in Enterobacter spp; however, derepression is rarer than in Enterobacter spp. and is often only partial [44]. Upregulated MexAB–OprM-mediated efflux is a more common mode of resistance and affects

Resistance in Acinetobacter spp.

Acinetobacter spp. – principally A. baumannii – are opportunistic pathogens of greatest concern in nosocomial pneumonias, especially in intensive care and as invaders of burn wounds. A. baumannii is notoriously associated with outbreaks, facilitated by resistance to disinfectants and desiccation. Until the 1970s, most isolates were susceptible to a wide range of antibiotics [54]; subsequently, A. baumannii has shown a remarkable propensity to develop resistance to virtually every antibiotic

Concluding remarks and future perspectives

From the 1940s to the 1980s there was a succession of β-lactam generations that each overcame resistance to earlier generations. The most important trend that now affects β-lactam utility is the spread of CTX-M ESBLs in Enterobacteriaceae. This shift, along with rapidly increasing quinolone resistance, will drive earlier and wider use of carbapenems, previously the ‘last reserve’ β-lactams. Carbapenem resistance remains rare in Enterobacteriaceae, although outbreaks of Klebsiella spp. with KPC

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