Antimicrobial synergism against Mycobacterium avium complex strains isolated from patients with acquired immune deficiency syndrome

Abstract

Pairs of 11 antimicrobial agents were tested in vitro for their ability to act synergistically against three strains of Mycobacterium avium complex isolated from patients with acquired immune deficiency syndrome. From the combinations tested, four drugs (ethambutol, rifampin, ciprofloxacin, and erythromycin) were selected for more extensive study against 20 strains of M. avium complex. The inhibitory and killing synergism obtained with combinations of two, three, or four drugs was assessed by determining the fractional inhibitory concentration index and fractional bactericidal concentration index. Inhibitory synergism occurred against 90 to 100% of the strains for all drug combinations in which ethambutol was included. Killing synergism occurred against 85 to 95% of the strains when ethambutol was used in combinations which included either rifampin or ciprofloxacin. However, killing synergism occurred against only 45% of the strains when drugs were tested at concentrations that can be obtained in patient serum. In other experiments, rifabutin (Ansamycin) gave results that were comparable to those obtained with rifampin. Clofazimine did not show synergistic killing activity at a concentration that is achievable in serum for any of the drugs tested. Our results indicate that there is considerable variability in the antimicrobial susceptibility of M. avium isolates obtained from patients with acquired immune deficiency syndrome. This variability could have significant impact on the clinical response to various therapies.

A bone marrow-derived murine macrophage model for evaluating efficacy of antimycobacterial drugs under relevant physiological conditions

“…Finally, in addition to the above information, the macrophage model should also be applicable to testing combinations of drugs; for example, we have observed (37a) a predicted synergism between rifabutin and ethambutol in the macrophage model, as was seen previously in cell-free assays (16,42,44). Moreover, the model can be adapted to different physiological conditions that reflect the emergence of immunity in the infected host; for example, such macrophages are highly responsive to cytokine activation by tumor necrosis factor alpha or gamma interferon (1), and it will interesting to see if such macrophage activation (reflecting the influence of acquired immunity or, alternatively, immunotherapy in the immunocompromised and infected host) might enhance or interfere with the capacity of given drugs to inhibit mycobacterial survival.…”

Epidemiology of Infection by Nontuberculous Mycobacteria

“…Certain antibiotic combinations have synergistic activities against M. avium complex isolates in vitro (223,224,227,280,406,407,408,553) and in macrophages (407,409,554). A postantibiotic effect of antimycobacterial drugs against M. avium complex isolates has also been reported (40).…”

In vitro susceptibility of Mycobacterium avium complex to the new fluoroquinolone sparfloxacin (CI-978; AT-4140) and comparison with ciprofloxacin

“…Ciprofloxacin and WIN 57273 are among the most active compounds in this group of agents (2,4), with ciprofloxacin showing inhibitory activity against approximately 30o of MAC strains (11). Sparfloxacin (CI-978; AT-4140) is a new agent in the fluoroquinolone class of antimicrobial agents (7,8,10).…”

“…To examine the in vitro activity of this new agent against MAC, we tested sparfloxacin against 30 strains of MAC isolated at San Francisco General Hospital from patients with acquired immune deficiency syndrome (AIDS) and compared this activity with that of ciprofloxacin. In addition, since ciprofloxacin has been shown to act synergistically with ethambutol and rifampin (11), synergism experiments were performed using sparfloxacin in combination with ethambutol and/or rifampin against 10 of the MAC strains.…”

“…The FIC index is the sum of the FIC for each drug in combination, and the FBC index is the sum of the FBC of each drug in combination (3). Synergism was defined as an FIC or FBC index of c0.5 for combinations involving two drugs (3,11), and an FIC or FBC index of 0.75 for combinations of three drugs (11), based on the definition of Berenbaum (1). FIC and FBC indices of sparfloxacin in combination with ethambutol or rifampin or both are shown in Table 2.…”