Mycobacterium avium complex (MAC) disease emerged early in the epidemic of AIDS as one of the common opportunistic infections afflicting human immunodeficiency virus-infected patients. However, only over the past few years has a consensus developed about its significance to the morbidity and mortality of AIDS. M. avium was well known to mycobacteriologists decades before AIDS, and the MAC was known to cause disease, albeit uncommon, in humans and animals. The early interest in the MAC provided a basis for an explosion of studies over the past 10 years largely in response to the role of the MAC in AIDS opportunistic infection. Molecular techniques have been applied to the epidemiology of MAC disease as well as to a better understanding of the genetics of antimicrobial resistance. The interaction of the MAC with the immune system is complex, and putative MAC virulence factors appear to have a direct effect on the components of cellular immunity, including the regulation of cytokine expression and function. There now is compelling evidence that disseminated MAC disease in humans contributes to both a decrease in the quality of life and survival. Disseminated disease most commonly develops late in the course of AIDS as the CD4 cells are depleted below a critical threshold, but new therapies for prophylaxis and treatment offer considerable promise. These new therapeutic modalities are likely to be useful in the treatment of other forms of MAC disease in patients without AIDS. The laboratory diagnosis of MAC disease has focused on the detection of mycobacteria in the blood and tissues, and although the existing methods are largely adequate, there is need for improvement. Indeed, the successful treatment of MAC disease clearly will require an early and rapid detection of the MAC in clinical specimens long before the establishment of the characteristic overwhelming infection of bone marrow, liver, spleen, and other tissue. Also, a standard method of susceptibility testing is of increasing interest and importance as new effective antimicrobial agents are identified and evaluated. Antimicrobial resistance has already emerged as an important problem, and methods for circumventing resistance that use combination therapies are now being studied.

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Clarithromycin (CLM) and azithromycin (AZM) are important agents in the treatment of disseminated Mycobacterium avium complex disease; however, monotherapy with these macrolides often leads to clinically significant resistance. The underlying resistance mechanism was investigated by comparing 23S rRNA gene sequences in the domain V region of 10 CLM-susceptible M. avium strains and 8 CLM-resistant strains. Four of the CLM-resistant strains were derived from CLM-susceptible strains included in this study. The only differences in the domain V sequences associated with CLM resistance were at position 2274 of the complete M. avium 23S rRNA gene (GenBank accession no. X74494). All the CLM-susceptible strains had an A residue at this site, whereas seven of the eight CLM-resistant strains had either a C, G, or T. Four of these seven CLM-resistant strains emerged during monotherapy with CLM and two emerged during AZM monotherapy, showing that resistance selected by either macrolide was associated with mutation of the 23S rRNA gene. Thermodynamic analysis of secondary rRNA structure suggests that the observed mutations cause an alteration in free energy associated with rRNA folding, which may result in a localized conformation change in assembled ribosomes. Such a shift may be important in the resistance of ribosomes to the effects of macrolides. This study therefore establishes a link between mutations within the 23S rRNA gene and clinically significant macrolide resistance in M. avium and also identifies a possible molecular mechanism of resistance at the level of the ribosome. Macrolides such as clarithromycin (CLM), azithromycin (AZM), and roxithromycin are important agents for the treatment of a variety of mycobacterial infections, including disseminated Mycobacterium avium complex (MAC) infection (11).Initial clinical trials of CLM and AZM demonstrated that these agents were effective in reducing or eliminating the mycobacteremia commonly associated with disseminated MAC disease and that this microbiological response was reflected in a positive clinical response (3,5,10,30). However, when any one of these agents was used for monotherapy, macrolide resistance developed usually within 12 weeks of the start of therapy (5, 10). As a consequence, the recommendation was made that these agents be used to treat disseminated MAC disease only in combination with at least one additional agent, such as ethambutol (16). Nevertheless, at present it is unknown whether combination therapy actually prevents or delays the emergence of macrolide resistance.Macrolide resistance in other bacteria has been studied, and the predominant mechanism of clinically significant resistance appears to be posttranscription methylation of an adenine residue within the peptidyl transferase loop of 23S rRNA (28). Other bacterial mechanisms of macrolide resistance that have been described include macrolide-inactivating enzymes (4), changes in membrane permeability (8), active drug efflux (4), mutated ribosomal proteins (4), and mutations within the 23S...

Various methods were used to determine the in vitro susceptibility of Mycobacterium avium complex strains isolated from patients with acquired immunodeficiency syndrome. Our results confirm the noted resistance of the M. avium complex to conventional antituberculosis agents. The procedures used were both agar dilution and broth dilution, including a commercially available radiometric system (BACTEC; Johnston Laboratories, Towson, Md.). In general, all strains were more resistant by an agar dilution procedure than by a broth dilution procedure. Radiometric data were analyzed by defining a value, termed T100, which provides a discrete MIC. The broth (radiometric) procedure is reproducible and convenient for screening antimicrobial agents for in vitro activity and assessing potential therapeutic efficacy. Nevertheless, there is no standard procedure for determining the in vitro susceptibility of the M. avium complex, and appropriate clinical correlation studies are needed to accurately assess the clinical relevance of any in vitro result.Disseminated infections caused by the Mycobacterium avium complex commonly occur in patients with acquired immunodeficiency syndrome (AIDS) and are increasingly recognized as a cause of serious disease in other immunocompromised patients (7, 22; R. C. Good, Clin. Microbiol. Newsl., 1:1-4, 1979). Treatment of M. avium complex infections in patients with AIDS has been particularly frustrating. M. avium complex clinical isolates are commonly resistant to isoniazid (INH) and variably susceptible to rifamycins (RIF), ethambutol (EMB), and aminoglycosides (19; R. C. Good, V. A. Silcox, J. C. Kilburn, and B. D. Plikaytis, Clin. Microbiol. Newsl. 7:133-136, 1986). There is recent evidence that M. avium complex isolates from patients with AIDS may be more resistant to antimicrobial agents than are isolates from non-AIDS patients (10). Treatment regimens including four to six different antimycobacterial agents are often used, but there is little evidence that treatment can eradicate the infection and prolong life in these severely immunocompromised patients (2, 3). The situation is complicated not only by the lack of clearly effective therapeutic agents but by the lack of a standard method for determining the in vitro susceptibility of M. avium complex isolates to either conventional or entirely novel antimycobacterial agents. Interpretation of results determined by any in vitro method is mitigated by a lack of correlation with clinical efficacy. Our strategy was to identify a convenient and reproducible procedure for in vitro susceptibility testing of M. avium complex isolates. Such a procedure should provide a discrete MIC and a reasonably rapid result, be convenient for screening large numbers of agents, and correlate with in vivo studies of single drugs in animals and, eventually, with clinical efficacy in humans. Angeles, Los Angeles. In each case, the patient was diagnosed as having disseminated M. avium complex disease, and the sites of isolation included blood, bone marrow, lung, liv...