Therapy of experimental cerebral nocardiosis with imipenem, amikacin, trimethoprim-sulfamethoxazole, and minocycline

Abstract

A mouse model of cerebral nocardiosis was used to determine relative antibiotic efficacy by reducing bacterial colony counts per gram of brain tissue. The antimicrobial agents employed were demonstrated in vitro to be inhibitory to most strains of Nocardia asteroides at very low concentrations. The agents used in this study were imipenem-cilastatin, amikacin, trimethoprim-sulfamethoxazole, and minocycline. Antibiotics were administered every 4 h for 72 h before animal sacrifice. Bacterial colony counts were assayed at various time points before the completion of therapy. Imipenem-cilastatin and amikacin were the most effective agents tested. Trimethoprim-sulfamethoxazole was less effective than imipenem and amikacin but more effective than minocycline. Minocycline did not eradicate intracerebral organisms and was similar to saline (control) in its effects.Nocardia asteroides is being increasingly recognized as a pathogen of normal and immunologically incompetent hosts (7,19). The most common sites of infection are the lungs, central nervous system, and skin (3). A central nervous system infection usually implies single or multiple brain abscesses, yet meningitis has been reported alone (14). Intracerebral nocardiosis, in contrast to other forms of nocardiosis in the immunologically incompetent patient, can be a rapidly progressive and fulminant infection and has been associated with mortality rates of up to 90% (15). Therapy for all forms of nocardiosis usually consists of a sulfonamide alone or in fixed combination with trimethoprim and these have been advocated by some authors as the drugs of choice (20,22). There are reports of cures with other antibiotics for those patients who have either failed on sulfonamides or experienced serious side effects which resulted in therapy being discontinued. These antibiotic regimens have included minocycline (23), amikacin, ampicillin (6), and erythromycin in combination with other agents (2). These alternative forms of therapy usually have been based on in vitro susceptibility testing of the specific strain of N. asteroides isolated from the patient and on previous anecdotal reports.Recent as this represents one of the more common forms of treatment and would provide a basis for comparison with other agents. MATERIALS AND METHODSAnimals. Female Swiss Webster mice weighing approximately 20 g were used in this study. The animals were received from Charles River Breeding Laboratories, Inc., Wilmington, Mass., at 6 weeks of age and were used several days thereafter. The mice were housed in standard cages and fed food and water ad libitum.Bacteria. A strain of N. asteroides isolated from a patient with cerebral nocardiosis at the Downstate Medical Center was used throughout this study. The isolate was maintained on Sabouraud agar slants and transfers to new agar slants were performed periodically. Inoculum preparation was performed by the method of Beaman and Maslan (5)

The medically important aerobic actinomycetes: epidemiology and microbiology

“…In addition, in other experimental studies that used antimicrobial combinations that have been shown to demonstrate synergy in vitro, imipenem-amikacin, imipenem-cefotaxime, and amikacin-cefotaxime were found to be efficacious (42,192,195). In a study of central nervous system nocardiosis, these combinations were also proven to be statistically superior to single-agent therapy (193 (23). Also, these authors were clearly able to distinguish the genus Actinomadura from N. dassonvillei by using numerical data.…”

“…Antimicrobial agents that may be of clinical benefit include broad-spectrum cephalosporins, fluoroquinolones (166,568), clindamycin, erythromycin, ampicillin, aminoglycosides (in particular, amikacin), tetracyclines (including minocycline), and imipenem (42,128). Broad-spectrum cephalosporins such as cefotaxime have also been shown to be very active in vitro and successful in the therapy of experimental infections (570 (193,194). In addition, in other experimental studies that used antimicrobial combinations that have been shown to demonstrate synergy in vitro, imipenem-amikacin, imipenem-cefotaxime, and amikacin-cefotaxime were found to be efficacious (42,192,195).…”

Clinical and Laboratory Features of theNocardiaspp. Based on Current Molecular Taxonomy

“…The investigators found that treatment with either amikacin or sulfonamides for 2 to 3 weeks increased the rate of resolution of infection (209). Later, Gombert and colleagues used a mouse model of cerebral nocardiosis to evaluate the relative efficacy of four antimicrobials, i.e., TMP-SMX, amikacin, imipenem, and minocycline (68,69). Of the four agents tested, amikacin and imipenem were found to be the most effective agents against a single strain of N. asteroides complex (which in neither this study nor the previously mentioned study was identified to species using modern taxonomic methods) (68,69).…”

Susceptibility of Nocardia asteroides to new quinolones and beta-lactams

“…There are also patients who develop side effects, necessitating the withdrawal of these compounds. Other antimicrobial agents, such as amikacin and imipenem, as well as several newer beta-lactams, have shown activity against N. asteroides in vitro, as well as in an experimental model of cerebral nocardiosis (6,7,9,10). There are also reports of successful therapy with agents other than the sulfa compounds (3).…”