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)

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The in vitro activities of imipenem (formerly imipemide, N-formimidoyl thienamycin, or MK0787) and amikacin in combination with cefotaxime, trimethoprimsulfamethoxazole, and each other were tested against 26 Nocardia asteroides strains. The agar dilution method was used for all tests. Synergy was present in 80% of tests with imipenem-trimethoprim-sulfamethoxazole, in 92% of tests with imipenem-cefotaxime, and in 83% of tests with amikacin-trimethoprim-sulfamethoxazole. Indifference was found on rare occasions, and no antagonism was seen.Several antibiotics, including amikacin, cefotaxime, and imipenem (formerly imipemide, Nformimidoyl thienamycin, or MK0787), among others, have been shown to be efficacious against Nocardia asteroides (3). The antibiotic combination of trimethoprim-sulfamethoxazole (TMP-SMX) has less activity than the aforementioned agents on a weight basis in vitro but has proven efficacy in vivo and has been advocated as the agent of choice in the therapy of nocardial infections (6). There have been reports, however, of unsuccessful therapy when single agents have been used, and combination antimicrobial therapy has proven to be superior to single-agent therapy (2, 4).In this study, the minimal inhibitory concentrations (MICs) of imipenem, amikacin, cefotaxime, and TMP-SMX for 26 N. asteroides strains were determined by the agar dilution technique. In addition, synergy studies were performed with the following antibiotic combinations: imipenem-TMP-SMX, imipenem-cefotaxime, imipenem-amikacin, amikacin-cefotaxime, and amikacin-TMP-SMX.The antibiotics used in this study and their sources were as follows: imipenem, Merck & Co., Inc., Rahway, N.J.; amikacin, Bristol Laboratories, Syracuse, N.Y.; TMP-SMX, Burroughs-Wellcome Co., Research Triangle Park, N.C.; and cefotaxime, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, N.J.A total of 26 clinical isolates of N. asteroides were identified by standard criteria and have been previously described (3). All isolates were maintained on Sabouraud agar slants. A loopful of each isolate was placed in Mueller-Hinton broth containing sterile glass beads (1 mm in diameter). The tubes were incubated at 37°C in a shaker bath and vortexed frequently for 3 days, after which time 1 ml of homogeneous suspension was subcultured into 5 ml of MuellerHinton broth containing glass beads. These suspensions were incubated as described before for approximately 72 h (3).After this incubation period, colony counts were performed; each isolate was in the range of 106 to 107 CFU/ml. A Steers replicating apparatus was used which delivered 0.002 ml per inoculum spot on Mueller-Hinton agar. The final inoculum was 103 to 104 CFU/ml. The agar plates contained antibiotics in serial twofold dilutions with concentration ranges as follows:imipenem, 16 to 0.0075 ,ug/ml; TMP-SMX (1:20), 4-80 to 0.015-0.3 pug/ml; cefotaxime, 16 to 0.0075 ,ug/ml; and amikacin, 8 to 0.03 jig/ml. The MIC was defined as the lowest antibiotic concentration suppressing all growth at 48 h of incubation at 37°C.S...

We compared the bactericidal efficacies of various antimicrobial agents and combinations thereof in experimentally induced Nocardia asteroides pneumonia in immunocompromised mice. Cortisone acetate treatment, which produced impaired cell-mediated immune function, was followed by nasal inoculation of 5

The susceptibility of 31 strains of Nocardia asteroides to various quinolones and beta-lactams, as well as coumermycin, amikacin, and minocycline, was determined by the agar dilution technique. Ciprofloxacin was the most active fluoroquinolone tested on a weight basis, as it inhibited approximately 50% of the isolates at achievable drug levels in serum. Ceftriaxone and cefpirome were the most active cephalosporins in this system with MICs of 8 ,ug/ml for 80% of strains tested. Imipenem, amikacin, and minocycline were the most effective agents tested.Nocardia asteroides is a pathogen in the immunologically incompetent and immunologically normal host (4, 15). Depending upon the site infection and the immunological status of the patient, this disease can be associated with extremely high mortality rates (14).Sulfonamides are the preferred therapy for many forms of nocardiosis, yet there are reports of patients unsuccessfully treated with these agents (5). 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).A class of carboxyquinolones is being tested in a wide range of clinical settings, and these agents have been shown to have an extremely broad spectrum of activity against a variety of organisms, particularly the family Enterobacteriaceae (1,11,16). These agents are inhibitors of DNA gyrase and are not subject to alteration or degradation by plasmid-mediated mechanisms. The present study was designed to determine if members of the carboxyquinolones, as well as several other antimicrobial agents, have in vitro activity against N. asteroides.The in vitro susceptibility of 31 strains of N. asteroides to six quinolones, six cephalosporins, and other antimicrobial agents, was determined by the agar dilution technique. These strains were obtained from patients with a variety of forms of nocardial infections. All strains were identified by standard criteria.A loopful of each isolate was placed in 50 ml of brain heart infusion broth and incubated in a rotary incubator. After 48 h, 1 ml of a homogeneous solution of N. asteroides was subcultured into another 50 ml of brain heart infusion broth. The organisms were in a homogeneous suspension, and little visible or microscopic clumping was observed. These cultures were incubated for 72 h in a rotary incubator as described above. After this period of incubation, all flasks were turbid and the suspensions were homogeneous. Colony counts were assayed, and each culture contained between 107 and 109 CFU of N. asteroides per ml of broth. These suspensions were placed into the wells of a Steers replicator, * Corresponding author. which delivered 0.002 ml per inoculum spot onto agar plates. These agar plates contained serial ...