Mycobacterium avium strains resistant to clarithromycin and azithromycin

Heifets, Leonid; Mor, N; Vanderkolk, J.

doi:10.1128/aac.37.11.2364

Cited by 102 publications

(57 citation statements)

References 17 publications

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“…This trend is also apparent from data from other studies (9,17). Moreover, the mechanism of clinically significant acquired resistance is the same (i.e., 23S rRNA mutation) with either macrolide.…”

Section: Discussionsupporting

confidence: 71%

“…The sequence evidence is compelling support for the hypothesis that resistance to CLM and AZM can occur by mutation during monotherapy. Furthermore, we speculate that this may be the major mechanism of clinically significant resistance (at least when patients receive monotherapy) rather than the emergence of a preexisting (extant) resistant subpopulation (9). Interestingly, the domain V genotypes of the M. tuberculosis strains, H37Ra and H37Rv, suggest that the ribosomes of these strains should be susceptible to macrolides; however, the macrolides perform poorly in animal models of tuberculosis (14).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic basis of macrolide resistance in Mycobacterium avium isolated from patients with disseminated disease

Nash

Inderlied

1995

Antimicrob Agents Chemother

119

101

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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...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Genetic basis of macrolide resistance in Mycobacterium avium isolated from patients with disseminated disease

Nash

Inderlied

1995

Antimicrob Agents Chemother

119

101

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“…In general, MAC isolates from patients never treated with a macrolide are susceptible to the macrolides. After exposure to a macrolide, MAC may acquire a one-step point mutation in the adenine at position 2058 or 2059 in the 23S rDNA, resulting in clinical resistance and MICs in the resistant range (11,18). MAC isolates with intermediate susceptibility to macrolides are very infrequently encountered and, therefore, were not included in this evaluation.…”

Section: Discussionmentioning

confidence: 99%

Multisite Reproducibility of Results Obtained by Two Broth Dilution Methods for Susceptibility Testing of Mycobacterium avium Complex

et al. 2003

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A multicenter study was conducted to assess the interlaboratory reproducibility of susceptibility testing of Mycobacterium avium complex (MAC) by broth microdilution using two different media (cation-adjusted Mueller-Hinton broth with 5% oleic acid-albumin-dextrose-catalase and 7H9 broth with casein) and by macrodilution using the BACTEC 460TB and 12B media at pH 6.8 and 7.3 to 7.4. Ten well-characterized strains of MAC (four macrolide susceptible, six macrolide resistant) were tested against clarithromycin and azithromycin (the latter only by BACTEC 460TB, pH 6.8). At each site, strains were tested against clarithromycin three times on each of three separate days (nine testing events per isolate) by using a common lot of microdilution trays and BACTEC 12B medium, pH 6.8; strains were tested once on three separate days against clarithromycin in 12B medium at pH 7.3 to 7.4 and against azithromycin. Agreement among MICs (i.e., mode ؎ 1 twofold dilution) was 100% for all strains and both drugs when BACTEC 460TB was used, regardless of the pH of the medium, but varied when microdilution with either medium was used, particularly with susceptible strains. Agreement based on interpretive category, with NCCLS-recommended breakpoints, was 100% for all strains with the BACTEC 460TB method (both drugs and both pH values) and with microdilution using 7H9 broth. With microdilution and Mueller-Hinton broth, agreement by interpretive category was 100% for eight isolates and >90% for two; errors occurred only in laboratories where personnel had minimal experience with this technique. MAC susceptibility testing may be performed by broth macrodilution or microdilution at either pH, with NCCLS-recommended interpretive breakpoints. However, because visual interpretation of broth microdilution end points is subjective, it is more prone to reader error; therefore, this method requires greater expertise than the BACTEC 460TB. Both techniques require appropriate validation and continued documentation of proficiency.

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“…Clarithromycin concentrates within macrophages and tissues (2), and it has also been shown to be active in experimental animals (12,24) and AIDS patients with MAC infection, as shown in clinical trials (7, 9-11). The development of MAC resistance to clarithromycin has been observed in patients taking the antibiotic (18). For instance, in a recent compassionate-use study, resistance following clarithromycin therapy developed in 33% of patients (9).…”

mentioning

confidence: 99%

Clarithromycin, dapsone, and a combination of both used to treat or prevent disseminated Mycobacterium avium infection in beige mice

Bermudez

Inderlied

Kolonoski

et al. 1994

Antimicrob Agents Chemother

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Bacteremic infection caused by organisms of the Mycobacterium avium complex (MAC) is common in patients with AIDS. We evaluated both clarithromycin and dapsone alone and in combination for the treatment and prevention of disseminated MAC disease in beige mice. In the therapeutic model, C57BL/6 beige mice were infected intravenously with strain 101 of MAC (serovar 1). After 1 week postinfection, mice were given clarithromycin (200 mg/kg of body weight per day) and dapsone (15 mg/kg of body weight per day) alone or in combination by gavage. Treatment with clarithromycin resulted in a significant reduction in bacteremia and the numbers of CFU of MAC in the liver and spleen. Treatment with dapsone had no effect on the mycobacterial counts in blood, liver, or spleen, and the combination of dapsone with clarithromycin was no better than clarithromycin as a single agent. Clarithromycin and dapsone were used to prevent systemic disease in beige mice infected orally with MAC 101. Clarithromycin prophylaxis was associated with a significant reduction in the numbers of bacteria in the liver, spleen, and appendix compared with those in controls. Prophylaxis with dapsone resulted in a mild reduction in the numbers of MAC in the spleen but not in the other tissues. Clarithromycin both treats and prevents MAC disease in beige mice. Dapsone has no therapeutic effect, but it does have a slight prophylactic eflect, and in combination with clarithromycin it does not abrogate the effect of clarithromycin.Organisms of the Mycobacterium avium complex (MAC) are the most common cause of bacterial infection in patients with AIDS. Autopsy studies in AIDS patients have shown a large number of acid-fast bacilli in the liver, spleen, bone marrow, and intestines (17,20,28). Current observations suggest that most of the cases of MAC infection in AIDS patients are acquired by the gastrointestinal tract, and colonization of the gut appears to precede the onset of bacteremia (5,8).MAC is resistant to many of the standard antituberculosis antimicrobial agents, but some strains may be susceptible in vitro and in vivo to agents such as ethambutol, amikacin, rifabutin, macrolides, and azalides (clarithromycin, roxithromycin, and azithromycin), clofazimine, and certain fluoroquinolones (9, 10, 12-14, 22, 23). Clarithromycin, a new macrolide that is structurally related to erythromycin, is active in vitro (19,(25)(26)(27), inhibiting 90% of MAC strains (MICs, 1 to 8 ,ug/ml). Clarithromycin concentrates within macrophages and tissues (2), and it has also been shown to be active in experimental animals (12, 24) and AIDS patients with MAC infection, as shown in clinical trials (7, 9-11). The development of MAC resistance to clarithromycin has been observed in patients taking the antibiotic (18). For instance, in a recent compassionate-use study, resistance following clarithromycin therapy developed in 33% of patients (9).Dapsone is a synthetic antifolate that has activity against Mycobacterium leprae (15) vitro activity against MAC (16). We now report o...

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Mycobacterium avium strains resistant to clarithromycin and azithromycin

Cited by 102 publications

References 17 publications

Genetic basis of macrolide resistance in Mycobacterium avium isolated from patients with disseminated disease

Genetic basis of macrolide resistance in Mycobacterium avium isolated from patients with disseminated disease

Multisite Reproducibility of Results Obtained by Two Broth Dilution Methods for Susceptibility Testing of Mycobacterium avium Complex

Clarithromycin, dapsone, and a combination of both used to treat or prevent disseminated Mycobacterium avium infection in beige mice

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