Mice treated with imipenem had significantly fewer organisms than untreated mice (Fig. ). By day 28, imipenem-treated mice had 1.8 log10 CFU/g fewer organisms in splenic tissue (P < 0.001) and 1.2 log10 CFU/g fewer in lung tissue (P < 0.04) than untreated mice. Isoniazid was more effective than imipenem in eliminating organisms from both spleen and lung (P < 0.001 for each organ).
FIG. 1. Mean burdens of M. tuberculosis strain H37Rv as log10 CFU/g in spleen and lung tissues. The numbers of mice are as follows: for untreated mice (black diamonds), 14, 19, and 14 on days 0, 14, and 28, respectively; for imipenem-treated mice (open circles), (more ...)
Imipenem-treated mice also had improved survival compared to controls, with a 28-day mortality rate of 35% versus 70% (Fig. ) (P = 0.016 by log rank test). The survival benefit was delayed, however, with similar mortality rates for untreated and imipenem-treated mice during the first 2 weeks of treatment. Survival of INH-treated mice was 100% (P values of <0.001 versus imipenem).
Survival curves for untreated mice (black diamonds), imipenem-treated mice (open circles), and isoniazid-treated mice (black squares).
Ten patients, nine with smear-positive pulmonary infection and one with AIDS and gastrointestinal tuberculosis, received imipenem in combination with two or more other agents. The mean age (± standard deviation) was 45.3 ± 12.8 years (range of 26 to 61 years). Eight patients were foreign born (five Asians and three Mexican-Americans), and five were women. Eight had radiographic evidence of cavitary disease. The clinical isolates were resistant to 7 ± 2 antituberculous agents (range, 5 to 10) (Table ); four isolates were fluoroquinolone resistant. With the exceptions that it produced rash (two patients) and occasional diarrhea, the imipenem combination regimen was well tolerated.
Eight patients (95% confidence interval, 50 to 100%) initially responded with conversion of cultures to negative. Seven patients (95% confidence interval, 35 to 100%) remained culture negative off of therapy and were considered cured. Two patients died.
Six of the eight patients who responded had serial quantitative cultures performed. These showed a continuous and sustained reduction of mycobacterial burden in sputa averaging approximately 0.35 log10 CFU/ml/week (Fig. ). Patients 7 and 10 had only qualitative cultures performed. Patient 7, with 40 prestudy weeks of documented positive smears and cultures, became smear and culture negative after 3 months of imipenem plus other agents. Patient 10, with smear-positive and culture-positive tuberculosis, with ulcerations and perforation of the stomach and duodenum, had healing documented by follow-up endoscopy after 6 months of imipenem combination therapy. Smears and cultures of the duodenal biopsy specimen were negative for M. tuberculosis.
FIG. 3. Results of quantitative sputum cultures indicating M. tuberculosis burdens, expressed as log10 CFU/ml, over time in sputa of individual patients (numbers correspond to patient numbers in Table ) (A) and as a calculation of the overall (more ...)
Two patients, patients 4 and 9, each of whom had an isolate that was resistant to 10 drugs, were treatment failures. In both cases, there were transient reductions in the numbers of organisms in sputa, but these eventually returned to pretreatment levels (Fig. ). The 18-week clinical isolate from patient 4 had acquired secondary resistance to streptomycin during treatment. This isolate also had acquired resistance to imipenem, as it was able to grow slowly in the presence of imipenem at concentrations of 8 and 16 μg/ml; growth of the prestudy isolate was inhibited at these concentrations (Fig. ). Whether resistance was beta-lactamase mediated, was due to target alterations, or was a penetration defect was not determined.
FIG. 4. Means and standard errors for proportional growth indices (GI) (the ratio of counts per minute on each day to counts per minute for the strain at day 0) for three separate experiments performed with starting growth indices ranging between 100 and 300. (more ...)
Three patients, i.e., patients 7, 8, and 10, relapsed shortly after the discontinuation of imipenem and aminoglycoside or capreomycin in the regimen. In patient 7, 3 months after discontinuing imipenem and amikacin, given for 4 months, smears and cultures were again positive, and secondary resistance to ofloxacin was documented. Imipenem and amikacin were reinstituted, with smears and cultures converting to negative after 1 and 2 months, respectively. Imipenem, amikacin, and oral agents were administered for another 9 months; patient 7 remained culture negative for the 36-month follow-up period.
Patient 8, who had a single positive culture on week 18 of imipenem therapy, received an initial course of 9 months of imipenem and capreomycin in addition to oral agents. Three months after imipenem and capreomycin were discontinued, multiple sputum smears and a single culture were again positive. Smears and cultures again converted to negative during a second 5.5-month course of imipenem and capreomycin in addition to oral medications, which were given for a total of 18 months after the last positive culture. This patient had no evidence of active tuberculosis after 2 years of follow-up off of therapy.
Patient 10 relapsed 6 months after the discontinuation of imipenem, which was stopped because of severe rash, and died of disseminated tuberculosis. Patient 2 died of cor pulmonale and chronic respiratory insufficiency 6 months after completing therapy; there was no evidence of active tuberculosis.