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Over the past twenty years, the rapid emergence and increased prevalence of opportunistic Gram-negative bacilli demonstrating resistance to the β-lactam class of antibiotics has become a major health care crisis.

The production of β-lactamases, the innate capabilities of these organisms to genetically adapt structural and regulatory genes and the ease with which resistance genes are transferred via plasmids, transposons and integrons between different species, have broadened the ability of Gram-negative bacteria to inactivate the β-lactam antibiotics. This diminishes the clinical utility of these key anti-microbial agents making them resistant.

Extended spectrum β-lactamases (ESβLs) hydrolyse the penicillins, first-, second- and third-generation cephalosporins, especially cefotaxime, ceftriaxone, ceftazidime and cefpodoxime, and the oxyimino-monobactam, aztreonam.

ESβLs are inhibited by β-lactamase inhibitors, such as clavulanic acid, and are susceptible to the carbapenems (imipenem, meropenem and ertapenem) and the cephamycins (cefoxitin and cefotetan), though there have been a number of reports stating that ESβL-producing organisms can become resistant to the cephamycins due to the loss of an outer membrane porin protein (Martinéz-Martinéz et al 1996).

Since their discovery following the clinical introduction of the third-generation oxyimino-cephalosporins in 1981, there are now approximately 160 Temoneira (TEM), 100 sulfhydryl-variable (SHV), 64 cefotaxime-hydrolysing (CTX-M) and 102 oxacillinase (OXA) variant enzymes, along with a number of minor ESβL variants (Jacoby and Bush 2007).

Extensive laboratory and clinical experience exists regarding the detection and treatment of ESβL-producing Gram-negative bacilli. This suggest that the knowledge of their existence via means of antibiotic selective pressure, adaption and dissemination, may have an impact on therapeutic choices and the health and well-being of patients via targeted pragmatic antimicrobial selection and infection control practices.

It is unclear; however, if ESβL-producing organisms are being accurately detected 100% of the time. Furthermore, with the recent emergence of metallo β-lactamase-producing Gram-negative bacilli, it is also unclear whether the same mandate exists for the accurate detection, treatment and control of metallo β-lactamases. Metallo β-lactamases (MβLs) are a therapeutic disaster.

These enzymes hydrolyse all β-lactam antibiotics (except the monobactams), including the “drugs of last resort” the carbapenems (imipenem and meropenem), thus requiring the use of alternative, potentially more toxic classes of antibiotics to circumvent the hydrolytic actions of these β-lactamases.

Metallo β-lactamases, which are found in organisms such as Pseudomonas aeruginosa, Acinetobacter specie and members of the Enterobactericeae group such as salmonella and especially Escherichia coli and Klebsiella pneumoniae. They all utilise metal ions (usually zinc) to coordinate water molecules that serve as nucleophiles and hydrolyse the amide bond of the β-lactam ring, rendering the β-lactam antibiotic inactive.

These enzymes are divided into four genetically mobile variants: the older imipenem-hydrolysing (IMP) and Verona integron-encoded metallo β-lactamase (VIM) enzymes; and the more recently described Sao Paolo metallo β-lactamase (SPM) and GIM types (Poirel et al 2004).

Gram-negative bacteria that produce extended-spectrum and metallo β-lactamases are being discovered and isolated at a significant rate worldwide, while the development of new synthetic and natural antimicrobial agents to combat and elude the hydrolytic actions of these β-lactamases has significantly decreased in recent years (Valenzuela et al 2004).

Clinicians prescribing antibiotics need to know, understand and appreciate the short and long term outcomes of the inappropriate use of antibiotics for their patients, which, if not controlled and decreased, will inevitably reduce or eliminate the therapeutic options available in the future.

References

Franklin, C., Liolios, L., Peleg, A.Y. (2006). Phenotypic detection of carbapenem-susceptible metallo β-lactamase-producing Gram-negative bacilli in the clinical laboratory. Journal of Clinical Microbiology, 44: 3139-3144.

Martinéz-Martinéz, L., Hernández-Allés, S., Albertí, S., Tomás, J., Benedi, V., Jacoby,G.A. (1996). In vivo selection of porin-deficient mutants of Klebsiella pneumoniae with increased resistance to cefoxitin and expanded-spectrum cephalosporins. Antimicrobial Agents and Chemotherapy, 40, pp. 342-348.

Poirel, L., Heritier, C., Spicq, C., Nordmann, P. (2004). In vivo acquisition of high-level resistance to imipenem in Escherichia coli. Journal of Clinical Microbiology, 42 (8), pp. 3831-3833.

Valenzuela, J., Thomas, L., Iredell, J. for Australian Society of Microbiology (ASM). (2004). Beta-lactam resistance in Gram-negative bacteria. Antimicrobial Susceptibility Testing: Methods and Practices with an Australian Perspective, 5, pp. 127-157.