[Frontiers in Bioscience 2, e63-71, August 15, 1997]
ORAL ANTIBIOTICS IN THE NINETIES: NEW DRUGS AND NEW CHALLENGES IN PRIMARY CARE
Robert A. Bonomo1, John Aucott2, and Robert A. Salata3
Division of Geriatrics1 and Division of Infectious Diseases3, University Hospitals of Cleveland, and Division of General Internal Medicine2 Veterans Affairs Medical Center, Cleveland, Ohio
Received 6/12/97 Accepted 8/10/97
6. BETA-LACTAM BETA-LACTAMASE INHIBITOR COMBINATIONS
Amoxicillin/clavulanic acid is the current oral beta-lactam beta-lactamase inhibitor combination antibiotic available for use. Clavulanate permanently inactivates the beta-lactamase so that the beta-lactam can reach its target, the penicillin binding proteins (PBPs). Amoxicillin/clavulanate is effective against methicillin-susceptible S. aureus, plasmid determined beta-lactamase producing Escherichia coli, Klebsiella spp., Neisseria spp., as well as anaerobic organisms such as Bacteroides spp. Specific indications for use of amoxicillin/clavulanate include upper respiratory infections, human and animal bites (especially due to cats) and skin and soft tissue infections involving anaerobic organisms such as complicated oral-pharyngeal infections, and beta-lactamase producing respiratory infections due to H. influenza.
Amoxicillin/clavulanic acid is effective in therapy of bacterial otitis media, sinusitis or bacterial lower respiratory infections where beta-lactamase producing organisms such as H. influenzae or M. cattarhalis may be involved (58). Amoxicillin/clavulanic acid is not appropriate as a single empiric therapy for community-acquired pneumonia where Legionella, Mycoplasma or Chlamydia are suspected. Although amoxicillin/clavulanic acid is an effective therapy for acute pyelonephritis, it has no obvious advantages over other agents (8). A promising application for amoxicillin/clavulanate has been entertained in the treatment of M. tuberculosis and M. fortuitum infection. Both species possess beta-lactamase enzymes that are constitutively expressed. Inhibition of this mycobacterial beta-lactamase may prove to be therapeutically useful (59,60). Unfortunately, beta-lactams do not penetrate phagocytes well.
There is a reported high incidence of diarrhea in patients administered amoxicillin/clavulanic acid perhaps reflects the depletion of normal bowel flora caused by this broad spectrum antibiotic. Surprisingly only 1-3% of patients discontinue the drug due to diarrhea (38). The new twice-a-day oral formulation of amoxicillin/ clavulanate has gained widespread acceptance in the community, especially for the treatment of refractory otitis media in children. It may also reduce the incidence of diarrhea.
Resistance to beta-lactam beta-lactamase inhibitor combinations can arise by a variety of ways (hyperproduction of beta-lactamase, presence of a chromosomal beta-lactamase, alterations in the genes encoding beta-lactamases that are normally inhibitor sensitive making them inhibitor resistant, change in outer membrane proteins) potentially making this combination also ineffective. There are reports of clinical isolates bearing plasmid mediated beta-lactamases that are resistant to inactivation by mechanism based inhibitors (61,62).