Introduction

Pseudomonas aeruginosa is discussed separately.

Gram-negative organisms conferring antibiotic resistance are a growing problem.  Enterobacteriaceae with resistance to a wide range of beta-lactams were first observed in Europe in 1982 and have since spread worldwide.  These organisms were found to produce beta-lactamase enzymes, which are able to hydrolyse beta-lactam based antibiotics such as penicillins, cephalosporins and carbapenems.

Extended-spectrum beta-lactamase (ESBL) producing organisms are typically:

• Resistant to many other classes of antibiotics, including aminoglycosides and fluoroquinolones, as a consequence of genes for other antibiotic resistance mechanisms residing on the same plasmids as the ESBL genes
• Difficult to detect and treat
Associated with increased mortality.

• Production of a large amount of beta-lactamases (either constitutively or by induction)
• Rapid turnover of the substrate
• High affinity to the substrate
• Impermeability of the organism due to a major lack of porins.

The commonest ESBL-producing strains are:

• Klebsiella spp. particularly Klebsiella pneumoniae and Klebsiella oxytoca (ESBLs found in 25% of Klebsiellae isolates)
• Escherichia coli.

In Europe, the prevalence of ESBL-producing Klebsiella spp. has not changed significantly between 1994 and 1998.  However, over the same time period, the proportion of ESBL-producers resistant to the beta-lactam/beta-lactamase inhibitor combination (piperacillin/tazobactam) rose from 31% to 63%.  Prevalence of ESBL-producing Klebsiella spp. is low in the UK (9% in 1998) compared to the rest of Europe (eg. 32% in France in 1998).

Beta-lactamase producing organisms frequently colonise the lower gastrointestinal tract, where the genes encoding the resistance enzymes may be easily transferred and maintained in the host flora without causing an infection.  ESBL-producing organisms may also transfer their plasmid-encoded genes to nosocomial pathogens such as Citrobacter diversus and Morganella morganii.

Emergence of extended-spectrum beta-lactam resistance

The widespread use of extended-spectrum third-generation cephalosporins, introduced in the 1980s to treat antibiotic-resistant bacteria, is believed to be a major contributor to the emergence of extended-spectrum beta-lactamase (ESBL) producing organisms. 

Classical beta-lactamase enzymes have minimal activity against the newer cephalosporins other than cefamandole and cefoperazone, whereas ESBL-producing organisms are able to attack newer cephems and monobactams as well as narrow-spectrum cephalosporins and anti-Gram-negative penicillins.

Enterobacteriaceae may also carry genes for AmpC beta-lactamases, which confer intrinsic resistance to cephalosporins.

The genes encoding the beta-lactamases may be chromosomal or plasmid-borne.  The enzymes are usually distinct but there is some overlap, for example a chromosomal beta-lactamase of Klebsiella pneumoniae is encoded by a plasmid in other Enterobacteriaceae.

Factors affecting susceptibility to infection

• Prolonged hospitalisation or residence in a nursing home.
• Prior antimicrobial therapy.
• Treatment in an ICU, haematology or burns ward where antibiotic use is high.

Patient evaluation

Laboratory

Resistance to ceftazidime or cefpodoxime implies ESBL-production in Escherichia coli and Klebsiella spp., especially if susceptibility to cefoxitin is retained.

A commercially available double disk test (Combination Test, Oxoid), validated by the BSAC, is able to distinguish between ESBL-producers and AmpC-producers. 

Management of infection

ESBL-producing organisms are frequently resistant to many classes of antimicrobials including aminoglycosides, fluoroquinolones, tetracyclines, chloramphenicol and trimethoprim/sulfamethoxazole, making treatment of these multi-drug resistant organisms difficult.

Principles of treatment

Life-threatening infections:

• Fluoroquinolones, carbapenems and cephamycins are particularly effective and reliable antimicrobial agents against ESBL-producing organisms.  Monotherapy with carbapenems should be avoided to prevent future emergence of resistance.

Non life-threatening infections:

• Beta-lactamase inhibitor combinations may be used as empirical treatment.  Piperacillin/tazobactam is particularly effective.