Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Mycobacterium llatzerense lung infection in a liver transplant recipient: case report and review of the literature.

Nontuberculous mycobacteria are increasingly encountered pathogens in organ transplant recipients. We report the first case of human disease attributed to Mycobacterium llatzerense that occurred in a liver transplant recipient in the midwestern United States who developed pneumonia and describe the treatment of this patient.

Disseminated infection with Mycobacterium avium-intracellulare. A report of 13 cases and a review of the literature.

Thirteen cases of disseminated infection with Mycobacterium avium-intracellulare (MAI) seen at the National Jewish Hospital and Research Center and 24 cases from the literature were analyzed to define clinical and therapeutic features of the disease. Disseminated MAI infection was a disease of immunocompromised and apparently normal hosts. It was acquired from the environment by unknown mechanisms, usually entering the body through the lungs and spreading to include the reticuloendothelial system, bones, and less commonly, the skin. Diagnosis was often delayed and required culture of tissue or secretions. Medical personnel must maintain a high index of suspicion for MAI disease, especially in immunocompromised hosts. These patients should be monitored carefully for evidence of MAI with frequent cultures of blood and bone marrow. Blood culture systems able to recover MAI promptly and reliably should be employed (52, 64). New diagnostic aids, such as the standardized preparation of PPD-B currently being prepared or tests for antibody to MAI, will help in differentiating MAI from other processes. If MAI is recovered, broad-spectrum therapy should be instituted. Response to combination antimicrobial chemotherapy in the patients surveyed in this report was gratifying. Over two-thirds of treated patients responded to therapy. New antimycobacterial agents such as ansamycin and thienamycin have been shown to have activity against MAI in vitro (40, 81, 92) and may further improve therapeutic efficacy. Studies of in vitro synergy, currently in progress in our laboratory, will also help define the optimal therapeutic regimen for each individual patient. While the patients presented in this report had a reassuring response to therapy, those who had many bacilli in the tissues had a poorer outcome. Patients with AIDS often have this lepromatous histology (37) and thus may respond more poorly than the patients in this report even when optimal therapy is employed. Careful monitoring of AIDS patients for MAI infection may permit earlier institution of therapy and improve the chances for control of the infection. Studies to assess the relationship of in vitro sensitivity to therapeutic response in these patients are currently underway in our laboratory. It is hoped that early institution of therapy and optimization of regimens according to in vitro sensitivity data will lead to decreased morbidity and mortality in all patients with MAI infection.

Syndrome and pancreatic disease, subcutaneous fat necrosis and polyserositis. Case report and review of literature.

Immunologic evaluation of a patient with pancreatitis, subcutaneous fat necrosis, pleuritis, pericarditis and synovitis is presented. The previously recognized syndrome of pancreatic disease, subcutaneous fat necrosis and arthritis is reviewed. Based on analysis of all the cases described in the English language literature it is suggested that this syndrome be expanded to include polyserositis rather than arthritis alone. Although experimental and clinical evidence tends to implicate physiocochemical tissue injury by pancreatic lipase as the primary pathogenic mechanism in this syndrome, studies in our patient suggest the possible contribution of immune-mediated injury. Supporting data include eosinophilia, biopsy demonstration of vasculitis antedating the subcutaneous fat necrosis, immunofluorescent identification of immunoglobulin G (IgG) and C3 in the pleura, and reduced levels of total hemolytic complement in the serum, and pleural and pericardial effusions.

Drug-resistant tuberculosis: what do we do now?

Drug-resistant tuberculosis (TB) represents a threat to TB control programmes. Erratic and inappropriate use of currently available medications, HIV-TB co-infection, and concern about transmission of drug-resistant strains in the general population all contribute to a worrying picture. What do we do now? In the last few years, there has been considerable progress in the understanding of mechanisms of action and resistance to antituberculosis agents, and in establishing the value of directly observed therapy in preventing treatment failure. However, a limited effort has been devoted to the development of new active compounds or of rapid diagnostic tests, and their relevance to global tuberculosis control has been questioned.

Chronic tuberculous empyema with bronchopleural fistula resulting in treatment failure and progressive drug resistance.

We treated five patients with a past history of tuberculous pleural infection that led to chronic, quiescent, loculated empyema. Reactivation of TB was associated with formation of BPF and recovery of drug-susceptible Mycobacterium tuberculosis from sputum. All patients had recurrence of positive sputum cultures that yielded tubercle bacilli resistant to drugs they were receiving. The lungs demonstrated gross thickening with calcification of both visceral and parietal pleura. Two patients underwent retreatment chemotherapy followed by decortication-empyemectomy and lung resection surgery; both are now culture-negative for TB. One patient received retreatment chemotherapy but refused surgery; he remains clinically stable with negative sputum cultures. Two other patients' organisms became drug-resistant and they remain sputum-culture positive. We believe that thick, calcified pleural walls limit penetration of drugs into the infected empyema space, resulting in suboptimal drug concentrations and drug resistance. Intensified chemotherapy and surgical intervention should be considered in these cases.

Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens.

A 48-year-old woman with profound, rapidly progressive dyspnea requested a second opinion regarding the diagnosis and management of an undiagnosed interstitial process. One year prior to this evaluation, she had been placed on therapy with exogenous estrogens for the treatment of osteoporosis. During this therapy, she had a marked deterioration of her pulmonary status. Review of her open lung biopsy, which was obtained five years previously, revealed lymphangioleiomyomatosis. Discontinuation of estrogen therapy and treatment with tamoxifen were successful in stopping the progressive course. This patient's clinical course suggested an association between estrogen therapy and clinical deterioration during the menopause.

Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections.

Between August 1983 and October 1990, 42 patients with resistant Mycobacterium tuberculosis underwent 44 pulmonary resections. During the same time, 38 patients with mycobacterial infections other than tuberculosis had 41 pulmonary resections. All patients either were poor candidates for medical therapy alone or had existing complications requiring surgical intervention. There was one operative death in each group, both from adult respiratory distress syndrome (postpneumonectomy pulmonary edema). Complications were high, with bronchopleural fistula most commonly occurring after right pneumonectomy in patients infected with Mycobacterium avium with superimposed infection with nonmycobacterial pathogens. In patients undergoing pneumonectomy for resistant Mycobacterium tuberculosis, the left lung was most often resected. It is recommended that if localized disease is present and medical treatment is likely to fail, pulmonary resection should be performed for resistant Mycobacterium tuberculosis infection after 3 months of drug-specific therapy. Muscle flaps were used frequently to avoid residual space and bronchial stump problems. Earlier resection in patients with indolent nontuberculous mycobacterial pulmonary infections is advocated before extensive polymicrobial contamination and right lung destruction.

Resection of the right middle lobe and lingula for mycobacterial infection.

BACKGROUND: In a series of 229 patients infected with mycobacterial organisms, we noted a specific female phenotype that involves isolated infections of the middle lobe and lingula. METHODS: Thirteen patients were found to have infections of the middle lobe, lingula, or both. All of them were infected with Mycobacterium other then Mycobacterium tuberculosis, all were women, 12 of the 13 were slender, and most had variable combinations of skeletal abnormalities. All underwent resection of the middle lobe, lingula, or both. RESULTS: There were no operative deaths. Only 2 patients have had reactivation requiring additional antibiotic therapy. All patients have had a decreased number of pulmonary infections in the postoperative period. Anatomic findings at operation included a complete major fissure and at least a partially complete minor fissure with middle lobe resections or an elongated lingula. CONCLUSIONS: Mycobacterial infection of the middle lobe and lingula is primarily a disease of asthenic women and is often associated with skeletal abnormalities and complete fissures or an elongated lingula. We recommend that surgical intervention be performed early once the condition is identified.

Drug-resistant tuberculosis.

Multiply resistant tuberculosis is on the rise throughout the world. It poses the risk that an increasing percentage of patients will have disease that cannot be cured in economically limited nations and, thus, resistant tubercle bacilli will be spread in an exponential manner. For such patients in the United States, aggressive chemotherapy, coupled with surgery in cases of localized disease, is the best hope for cure.

Pharmacokinetic evaluation of thiacetazone.

STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of thiacetazone (TB-1), which is active in vitro against Mycobacterium avium complex (MAC). DESIGN: Open-label phase I study. SETTING: Specialized referral hospital. PATIENTS: Twelve healthy men and women. INTERVENTIONS: Oral TB-1 150 mg/day was administered for 7 days, followed by blood and urine collection over 48 hours. MEASUREMENTS AND MAIN RESULTS: The serum concentration versus time curves of TB-1 showed sustained concentrations, with maximum values of 1.59 +/- 0.47 micrograms/ml, time to maximum 3.30 +/- 1.18 hours, and serum half-life of 15-16 hours. Less than 25% of TB-1 was recovered unchanged in the urine over 48 hours. Rashes occurred in two subjects at the end of the 7-day dosing period and resolved without progression or sequelae. CONCLUSIONS: Based on these data, we initiated a phase II study of TB-I in patients with pulmonary MAC infection who do not have the acquired immunodeficiency syndrome.

Pharmacokinetic evaluation of aconiazide, a potentially less toxic isoniazid prodrug.

STUDY OBJECTIVE: To determine the bioavailability and renal elimination of isoniazid, acetylisoniazid, monoacetylhydrazine, diacetylhydrazine, aconiazide, and 2-formylphenoxyacetic acid. STUDY DESIGN: Randomized, double-blind, two-period, crossover phase I study. SETTING: Pharmacokinetics unit at a referral hospital that specializes in the treatment of mycobacterial infections. SUBJECTS: Twelve healthy volunteers selected from the hospital staff. INTERVENTIONS: Subjects received aconiazide tablets 650 mg (containing isoniazid 300 mg) and isoniazid tablets 300 mg. Blood and urine samples were collected over 24 hours after the dose. MEASUREMENTS AND MAIN RESULTS: Intact aconiazide and 2-formylphenoxyacetic acid were not detected in the serum. Compared with isoniazid tablets, aconiazide's relative bioavailability (based on the area under the serum concentration-time curve) was 50.7%; its relative maximum serum concentration was 13.4%. CONCLUSIONS: Isoniazid is less bioavailable after aconiazide tablets than after isoniazid tablets. The optimum dose of aconiazide remains to be determined.

Determination of MICs of conventional and experimental drugs in liquid medium by the radiometric method against Mycobacterium avium complex.

The aim of this study was to search for new drugs active against the Mycobacterium avium complex and to re-examine the activity of some conventional antituberculosis drugs against these species. This progress report describes the protocol and phases of in vitro experiments in a search which included 57 different compounds tested against numerous strains of M. avium clinical isolates. The preliminary screening and MIC determination of these drugs were conducted in 7H12 broth by the radiometric method (BACTEC system). Of the total of 57 drugs, 23 were discarded after preliminary screening and 17 after MIC determination. The remaining 17 drugs were considered sufficiently promising for more detailed in vitro studies. These, now in progress, include MIC determination by two additional methods (in broth by sampling and plating and in 7H11 agar plates), MBC determination and drug combination studies. The following drugs are currently undergoing these detailed studies: isoniazid, rifampin, rifabutine (ansamycin LM427), amikacin, streptomycin, ethambutol, ethionamide, cycloserine, clofazimine (CF), CF derivative B746, CF derivative B1865, ofloxacin, ciprofloxacin, cephalosporin BMY 28142, trimethoprim-sulfamethoxazole, spectinomycin derivative U6633F(B), and dihydromycoplanecin.