[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
3. MACROLIDES AND AZALIDES
There has been a keen interest in the macrolide antibiotics as a result of their broad range of antimicrobial activity. These drugs are called "macrolides" because they possess a macrocyclic lactone nucleus (9). The primary targets of the macrolides include many respiratory and intracellular pathogens (Table I). Macrolides are both bacteriocidal (for Streptococcus pyogenes and Streptoccus pneumoniae) and bacteriostatic (for staphylococci). Erythromycin, the prototype macrolide, remains an inexpensive, effective, and time-honored therapy for the treatment of many community-acquired respiratory infections, uncomplicated skin and soft-tissue infections, and for group A streptococcal pharyngitis in penicillin allergic individuals (10). Newer macrolide derivatives promise to be effective against an even greater number of pathogens than erythromycin.
Macrolides available in the United States and Europe include erythromycin,clarithromycin, azithromycin, roxithromycin, dirithromycin, spiramycin, and josamycin.
So far, only clarithromycin , dirithromycin and azithromycin are used in the United States. clarithromycin dirithromycin and roxithromycin are 14-membered ring compounds. Josamycin and spiramycin are 16 membered macrolides. Azithromycin is a fifteen membered ring azalide antibiotic (10).
Azithromycin and clarithromycin expand the spectrum of the macrolides to include Gram negative organisms such as H. influenzae (11,12). The excellent tissue levels of the new macrolides, less frequent dosing, and broad spectrum activity make them ideal agents in the treatment of community-acquired bacterial respiratory infections, uncomplicated soft tissue infections, and sexually transmitted diseases (11-17). In numerous clinical trials they have been found to be as effective as the currently available oral antibiotics. The most compelling indications for the use of the new macrolides in the community setting is in documented bacterial infections such as sinusitis and community-acquired pneumonia especially when Gram stains or cultures confirm the presence of a potentially beta-lactamase positive organism such as Haemophilus influenzae or when the concern for Mycoplasma, Legionella and Chlamydia is very great. Using azithromycin to treat sexually transmitted diseases in the office, the primary care physician can be visually certain that the entire therapy for gonorrhea and uncomplicated Chlamydia cervicitis can be administered without the concern for noncompliance.
Important new applications for the macrolides have been in the treatment of the disseminated Mycobacterium intracellulare and Mycobacterium. avium complex (MAC) infections (18-22). Both clarithromycin and azithromycin penetrate phagocytes and have been shown to effectively inhibit the replication of MAC in macrophage cell lines (21). Used alone, clarithromycin and azithromycin were initially very effective in treating disseminated MAC in AIDS (18,19,20). In AIDS patients treated with azithromycin or clarithromycin as monotherapy, there was a significant reduction in viable mycobacteria detected in blood cultures. Relapse with resistant strains was seen with both agents (18,19,20). Although the in vitro minimum inhibitory concentrations are not as low as with clarithromycin , the high degree of penetration of azithromycin into phagocytes makes this drug uniquely effective (21). In combination with other agents, clarithromycin and azithromycin have now assumed a central role in the treatment and prophylaxis of MAC (18).
A body of experience is emerging regarding the effectiveness of the macrolides (particularly clarithromycin ) in the treatment of other nontuberculous mycobacterial infections(23). In vitro, clarithromycin is the most effective macrolide against M. chelonae and M. fortitutum (22). As part of a multi-drug regimen the macrolides are recommended either as primary agents or as alternatives in the treatment of M. kansasii, M. chelonae (subspecies abscessus and chelonae), M. scrofulaceum, M. simiae, M. malmonese, M. szulgai, and M. fortuitum (22).
The macrolides azithromycin or spiramycin in combination with pyrimethamine have superior activity in vitro against several stages of Toxoplasma (24). A number of studies demonstrate that this combination shows promise in treating acute toxoplasmic encephalitis in AIDS (25,26). This alternative therapy is of major importance since the side effects of clindamycin and sulfadiazine in AIDS patients are substantial.
Protozoan infections such as cryptosporidiosis, giardiasis, and Entamoeba histolytica, and even Plasmodium falciparium have been successfully treated with the new macrolides (27,28,28a,28b). Azithromycin has been identified as particularly promising in the treatment of severe cryptospoidial diarrhea and may prove to be an effective alternative to paromomycin (29).
In the treatment of Lyme disease, azithromycin also was shown to be more effective than amoxicillin or doxycycline-as measured by the response time to resolution of erythema chronicum migrans (30-32).
An unappreciated quality of macrolide antibiotics is their tendency to augment host immune function and their ability to exert significant anti-inflammatory effects. Normal human serum has been shown to potentiate the antibacterial effect of azithromycin (33). Incubating polymorphonuclear leukocytes with erythromycin influences phagocytic activity. This has been shown with Gram negatives as well as streptococci (34,35). In vitro, clarithromycin has been shown to inhibit production of interleukin-1 (36). This immunomodulatory effect may have important implications in the modulation of cytokine activity and in the treatment of infections in immunocompromised hosts (37).
Gastrointestinal intolerance has been the primary disadvantage of erythromycin. This is due to the motilin-like effect of the antibiotic (38). Approximately 14-19% of patients taking erythromycin experience gastrointestinal side effects that lead to discontinuation of the drug while only 2-5% of patients taking the newer macrolides have significant gastrointestinal intolerance (10,39). This side effect has been exploited in treating patients with disorders of gastric emptying (39,40). All macrolides have the potential to increase levels of carbamazepine, digoxin, theophylline, terfenadine and astemizole and to decrease the effectiveness of oral contraceptives. These considerations should be kept in mind.
Although clarithromycin and azithromycin have superior bioavailability, pharmacokinetic properties, and are better tolerated, it is uncertain under what circumstances the increased cost is justified when compared to erythromycin in the treatment of many infections encountered in primary care. In cases of treatment of acute bronchitis in young patients, a disease which is predominantly viral in origin, antibacterial therapy has not been shown to improve the outcome of acute bronchitis in otherwise healthy individuals (6). When the patient remains symptomatic for more than 7-10 days and the suspicion for Mycoplasma or Chlamydia infection is present, treatment with erythromycin or doxycycline is appropriate. The efficacy of any antibiotics in the treatment of "bacterial bronchitis" is controversial at best and then only in a subset of patients with chronic pulmonary conditions and with the most severe symptoms. Despite the superior in vitro activity of the newer macrolides against beta-lactamase producing H. influenzae, there is no clinical evidence that this difference is significant in the treatment of acute or chronic bronchitis. In fact, traditional therapy with amoxicillin is still the clinical standard. Trimethoprim-sulfamethoxazole remains an inexpensive broad spectrum alternative for the treatment of upper respiratory infections due to community-acquired bacterial pathogens. Clinicians should not anticipate that the newer agents will be more potent than erythromycin to treat macrolide resistant Gram positive pathogens (41).