Treatment outcome and follow-up of multidrug-resistant tuberculosis patients, West Coast/Winelands, South Africa, 1992-2002.

SETTING: Brooklyn Chest Hospital, Western Cape, South Africa. OBJECTIVE: To evaluate the treatment outcome and 2- and 5-year follow-up of patients treated for multidrug-resistant tuberculosis (MDR-TB) with individualized regimens. DESIGN: Retrospective cohort study of all MDR-TB patients starting treatment during 1992-2002. Patients were evaluated every 6 months for 2 years after treatment and at 5 years when possible. RESULTS: Over 11 years, 491 (66%) of 747 MDR-TB patients received treatment with two or more second-line drugs; 239 (49%) were cured or completed treatment, 68 (14%) died, 144 (29%) defaulted from treatment, 27 (5%) failed, 10 (2%) transferred out and 3 (<1%) remained on treatment. Only 176 (36%) were tested for human immunodeficiency virus and 15 were positive. The proportion with a successful MDR-TB treatment outcome declined over time, while the proportion who defaulted remained stable. Among 410 patients who had not transferred out or died, 281 (69%) had 2-year data available: 185 (66%) were cured or completed treatment, 32 (11%) were retreated for TB and 64 (23%) died. CONCLUSIONS: Under program conditions in the West Coast/Winelands District, default rates were high and treatment success rates low. Outreach strategies for MDR-TB treatment should only be implemented if adequate resources are committed to the program.

Drug-resistant tuberculosis: worldwide trends, problems specific to Eastern Europe and other hotspots, and the threat to developing countries.

Although it had been appreciated that high levels of antituberculous drug resistance existed in some regions of the world, the full extent of the problem was not known. A combined initiative by the World Health Organization and the International Union Against Tuberculosis and Lung Disease was launched in 1994 to address this. A second report was issued in March 2000, in which surveillance of drug resistance had been extended to 72 countries and regions. A number of drug resistant "hotspots," where there are high levels of combined multidrug-resistant tuberculosis (> 3% prevalence), have been identified. Particular areas of concern are countries of the former Soviet Union, India, and China, because these countries have the highest burden of multidrug-resistant tuberculosis. For the first time, information on trends in global drug resistance is available.

A prospective, randomized, multicenter comparative study of clinafloxacin versus a ceftriaxone-based regimen in the treatment of hospitalized patients with community-acquired pneumonia.

In an open-label, phase 3, randomized, multicenter study, clinafloxacin (200 mg/d) was compared to ceftriaxone (2 g/d; with or without erythromycin) in 527 patients with acute community-acquired bacterial pneumonia (CAP). Primary efficacy parameters were clinical cure rate and microbiologic eradication rates (by pathogen and by patient) determined 5-9 d post-therapy (test of cure; TOC). Clinical cure rates at TOC for the 2 treatment groups were equivalent in the intention-to-treat (clinafloxacin 79.3, ceftriaxone 78.6%), clinically evaluable (clinafloxacin 88.1, ceftriaxone 85.0%), modified intention-to-treat (clinafloxacin 82.6, ceftriaxone 86.9%) and microbiologically evaluable populations (clinafloxacin 86.2, ceftriaxone 86.2%). Microbiologic eradication rates were similar in the 2 treatment groups. Both drugs were tolerated. Treatment of hospitalized CAP patients with clinafloxacin is a reasonable choice, especially when a resistant pathogen is anticipated.

Drug-resistant tuberculosis.

There is increasing concern in many countries about the problem of drug-resistant tuberculosis, particularly so because no new classes of drugs have been developed for the treatment of tuberculosis since the 1960s. Although drug resistance is thought to be fairly common in some countries and rare in others, the global extent of this condition is not precisely known. This problem is currently being investigated by a combined initiative of the World Health Organization and the International Union Against Tuberculosis and Lung Disease. Recently, there have been advances in the understanding of the genetic basis of drug-resistant tuberculosis. With the sequencing of the whole genome of Mycobacterium tuberculosis, the possibility of new targets for drug development has emerged. For the present, however, cure rates on average remain modest, and nonadherence with chemotherapy remains a major problem. Drug resistance is a man-made problem and efforts to prevent it through directly observed therapy, short course are essential.

Tuberculous tenosynovitis and carpal tunnel syndrome as a presentation of HIV disease.

We describe a patient who presented with carpal tunnel syndrome secondary to tuberculous tenosynovitis and who was subsequently shown to have HIV infection. Recognition of this atypical presentation of tuberculosis is important for early, effective treatment.

A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia.

A multinational, multicentre, open, randomised study in hospitalised patients with pneumonia compared levofloxacin 500 mg twice daily with ceftriaxone 4 g i.v. once daily. Levofloxacin patients started on i.v. treatment and switched to oral on d 3-5 of therapy if signs and symptoms had improved. The minimum treatment duration was 5 d, except for treatment failure, and the median 8 d. The primary efficacy analysis was based on the per-protocol assessment of the clinical cure rate determined 2-5 d after the end of treatment in the per-protocol (PP) population (levofloxacin 127, ceftriaxone 139). Of 625 patients enrolled and randomized, 6 received no treatment, giving an intention-to-treat (ITT) population of 619 (levofloxacin 314, ceftriaxone 305). At the clinical endpoint, 2-5 d after the end of treatment, the cure rates for levofloxacin and ceftriaxone were similar in both the ITT (76% and 75%, respectively) and PP (87% and 86%, respectively) populations. Both drugs were well tolerated. Twice-daily levofloxacin 500 mg, either i.v. or as sequential i.v./oral therapy, was as effective as i.v. once-daily ceftriaxone 4 g in the treatment of hospitalized patients with pneumonia and offers the advantage of sequential therapy.

Community-acquired Staphylococcus aureus bacteraemia in patients who do not abuse intravenous drugs.

Despite advances in antimicrobial therapy and intensive care support, Staphylococcus aureus continues to cause significant morbidity and mortality. We studied community-acquired S. aureus bacteraemia in a population where intravenous drug abuse is extremely uncommon, prospectively reviewing all such patients (n = 113) admitted to Groote Schuur Hospital from February 1986 to January 1991. Overall mortality was 35%. Factors associated with poor outcome were: confusion on presentation, failure to mount a febrile response, acute renal failure, adult respiratory distress syndrome, shock, endocarditis, disseminated intravascular coagulation and platelet count of < 100 x 10(9)/l. Only confusion, acute renal failure and shock were independently associated with death by stepwise regression analysis. Skin infections were the most commonly identified source of bacteraemia (22%), but in 58% of patients the source was not determined. Twenty-six percent of patients were diabetic. Almost all patients (90%) developed one or more complications. In those who survived, therapy was generally prolonged, with a median of 70 days and range of 7-393 days, depending on the associated complications. Community-acquired S. aureus bacteraemia is a serious condition associated with a high complication rate and mortality.

Pulmonary resection as an adjunct in the treatment of multiple drug-resistant tuberculosis.

BACKGROUND: Over the past decade the incidence of pulmonary disease due to drug-resistant strains of Mycobacterium tuberculosis has increased worldwide. We reviewed our local experience to clarify the benefits and risks of pulmonary resection in the management of drug-resistant strains of Mycobacterium tuberculosis. METHODS: A retrospective review was performed of 62 patients undergoing pulmonary resection for drug-resistant strains of Mycobacterium tuberculosis between January 1990 and November 1995. RESULTS: Fifty-three percent were men and 47% women with an average age of 34 years (range, 16 to 72 years). There was one postoperative death, for a perioperative (30-day) mortality of 1.6%. Sixteen complications occurred in 14 patients for an overall morbidity of 23%. Eighteen of 24 patients (75%) who were persistently sputum positive at the time of operation immediately converted to a negative sputum smear and culture. For all patients who were sputum negative after operation 80% remain relapse-free by actuarial analysis. CONCLUSIONS: We believe that operation plays an important ancillary role in the treatment of drug-resistant strains of Mycobacterium tuberculosis. The operation can be performed with acceptable morbidity and mortality and must be combined with appropriate and well-monitored pre- and postoperative antituberculous drug therapy.

A prospective randomised study in limited disease small cell carcinoma--doxorubicin and vincristine plus either cyclophosphamide or etoposide.

A prospective randomised study was undertaken in patients with limited disease small cell carcinoma of the lung (SCCL), which compared doxorubicin, 50 mg/m2, and vincristine, 2 mg i.v. (intravenously) on day 1, with either cyclophosphamide, 800 mg/m2 on day 1 (CAV) or etoposide, 60 mg/m2 i.v. on day 1 and 120 mg/m2 orally on days 2-5 (AVE). Responding patients were to receive six cycles of chemotherapy at 3 weekly intervals followed after 2 weeks by mediastinal irradiation. Response rates and toxicity were evaluated by the chi square or Fisher's exact test and survival by the logrank test. 81 patients were entered into the study, 38 of whom received CAV and 43 received AVE. In the patients treated with CAV and AVE, the overall response rate was 61% (confidence limit (CL), 45-71%) and 74% (CL, 61-87%) respectively, the complete response rate was 32% (CL, 17-47%) and 51% (CL, 36-66%), respectively (P = 0.07) and the median survival was 12 and 14.5 months, respectively (P = 0.15). In the patients treated with CAV and AVE, the incidence of grade 3 and 4 leucopenia was 29% (CL, 15-43%) and 9% (CL, 0-18%), respectively (P = 0.025). No patient developed doxorubicin cardiomyopathy. These findings support the role of etoposide in first line chemotherapy for SCCL. AVE is among the more efficacious regimens for SCCL and also has a relatively low toxicity.

The effect of irradiation on lung function and perfusion in patients with lung cancer.

PURPOSE: To prospectively study the changes in lung function in patients with lung carcinoma treated with relatively high doses of irradiation. METHODS AND MATERIALS: Lung function was assessed prior to and at 6 and 12 months following radiation therapy by a clinical dyspnea score, formal pulmonary function tests (lung volume spirometry and diffusion capacity) as well as an ipsilateral hemithorax lung perfusion scan. Changes in dyspnea score were evaluated by the chi-square and the Fishers exact test. Changes in formal lung function tests were compared with the t-test for dependent data and correlations with the t-test for independent data. Fifty-one patients were entered into the study. There were 42 evaluable patients at 6 months after irradiation and 22 evaluable patients at 12 months after irradiation. RESULTS: A worsening of dyspnea score from 1 to 2, which is clinically acceptable, occurred in 50% or more of patients. However, a dyspnea score of 3, which is a serious complication, developed in only 5% of patients. The diffusion capacity (DLCO) decreased by 14% at 6 months and 12% at 12 months) (p < 0.0001). The forced vital capacity and total lung capacity decreased between 6% and 8% at 6 months and 12 months, which was statistically significant. The forced expiratory volume in 1 s decreased between 2 and 3% at 6 month and 12 months, which was not statistically significant. The ipsilateral hemithorax perfusion decreased by 17 and 20% at 6 and 12 months (p < 0.0001). There was no correlation between the initial hemithorax perfusion, or its decrease at follow up and the decrease in DLCO. CONCLUSION: Lung irradiation results in some loss of lung function in patients with lung cancer with a projected survival of 6 months or more. The pretreatment DLCO assessment should be useful in predicting clinical tolerance to irradiation.

Mycobacterial infection in renal transplant recipients.

STUDY OBJECTIVE: To determine the prevalence and presentation of mycobacterial infection as well as the influence on outcome in graft function and patient survival in renal transplant recipients at our institution. DESIGN: A retrospective review of case records of all renal transplant recipients from 1980 to 1992. SETTING: Groote Schuur Hospital, a large teaching hospital and regional tertiary referral center in Cape Town, South Africa. PATIENTS: During the period reviewed, 857 transplants were performed. The records of 487 patients who had remained in Cape Town were examined. RESULTS: There were 22 cases of mycobacterial infection (21 confirmed or presumed Mycobacterium tuberculosis and 1 unidentified Mycobacterium other than tuberculosis). In seven cases, immunosuppression had been intensified within 3 months of diagnosis. The median time from transplantation to diagnosis was 14 months (range, 2 to 74). Chest radiograph findings included consolidation (14), miliary pattern (4), pleural effusion (3), tuberculoma (2), cavitation (2), and hilar lymphadenopathy (1). Diagnosis of tuberculosis was made on sputum smears (eight), pleural biopsy specimen (two), fine-needle aspiration (one), and fiberoptic bronchoscopy in ten cases (brushings, eight; transbronchial biopsy specimen, three). Extrapulmonary tuberculosis (in addition to pulmonary tuberculosis) occurred in five patients (tuberculous meningitis, one; renal tuberculosis, one; and dissemminated infection, four). Five of the seven patients in whom immunosuppression had been intensified had concurrent infections; two of these died and the remainder returned to dialysis within 6 months. All but one patient received three antituberculosis drugs, including rifampin and isoniazid, for between 6 and 18 months. At the end of the period of review, 12 (59 percent) patients were alive, 10 with functioning grafts and 2 receiving dialysis. Four patients died while receiving antituberculosis treatment, but death was only directly related to tuberculosis in one case. CONCLUSIONS: Tuberculosis is an important infection in renal transplant recipients in Cape Town, but disseminated disease is less common than reported elsewhere.

Changes in lung function and perfusion after irradiation in patients with lung cancer.

The changes in lung function were prospectively studied for patients with lung carcinoma who were treated with relatively high doses of irradiation. Their dyspnoea score, lung volume spirometry, diffusion capacity and ipsilateral hemithorax perfusion were measured at presentation, again between 5 and 6 months after irradiation (Group 1, 36 evaluable patients), and once more between 11 and 12 months (Group 2, 16 evaluable patients). There was a worsening of the dyspnoea score from 1 to 2, in a large percentage of patients, but only 6% developed a dyspnoea score of 3. The largest change in lung function tests was a decrease in the diffusion capacity (DLCO) to 14% at 6 months and 12% at 12 months (statistically significant, P < 0.0001 paired t-test). The forced vital capacity (FVC) and the total lung capacity (TLC) showed a lesser decrease at 6 and 12 months, and the smallest decrease, which was not statistically significant, was in the forced expiratory volume in 1 s (FEV1). There was also a statistically significant decrease in the ipsilateral hemithorax lung perfusion of 16% at 6 months and 20% at 12 months. There was a weak correlation between the decrease in the DLCO and the FEV1 at follow-up. There was no statistically significant correlation between initial perfusion or decreased perfusion and the decrease in lung function. Lung irradiation should be regarded as an ablative form of therapy, analogous to surgery, in patients with a projected survival of 6 months or more. The DLCO is the most sensitive indicator of clinical damage and its pretreatment assessment should be useful in predicting clinical tolerance to irradiation.

The spectrum of endocrine dysfunction in active pulmonary tuberculosis.

OBJECTIVE: Substantial variation in the prevalence (0-55%) of hypoadrenalism in tuberculosis (TB) has been reported. The aim of this study was to prospectively evaluate adrenal, thyroid and gonadal function in patients presenting with active pulmonary TB. DESIGN: A prospective study of 50 patients admitted to a single hospital. PATIENTS: Fifty hospitalized adults with newly diagnosed sputum positive pulmonary TB (mean age 38 years, mean body mass index 18 kg/m2, mean albumin 28 g/l) were studied. MEASUREMENTS: Adrenal reserve was assessed by intravenous tetracosactrin administration with measurement of basal and stimulated cortisol concentrations. Basal ACTH, thyroid and gonadal hormones were also measured. RESULTS: The mean basal serum cortisol was 625 nmol/l (range 394-1185). Basal plasma ACTH was undetectable (< 4.4 pmol/l) in 32, normal in 17 (mean 11.45, range 4.4-24.9 pmol/l) and elevated in one (54.2 pmol/l) subjects and did not correlate with cortisol. The mean increment in cortisol following tetracosactrin was 256 nmol/l (range 0-650) and was unrelated to basal cortisol or ACTH. All 50 patients had a stimulated plasma cortisol exceeding 550 nmol/l, indicating intact adrenal reserve. Ninety-two per cent of patients had the sick euthyroid syndrome, 72% of males had hypogonadotrophic hypogonadism and 4% of patients tested positive for the human immunodeficiency virus. CONCLUSIONS: Hypoadrenalism is uncommon in active pulmonary TB despite frequent dysfunction of the thyroid and gonadal axes.

Fiberoptic bronchoscopy in the intensive care unit--a prospective study of 147 procedures in 107 patients.

OBJECTIVE: To determine the value and safety of fiberoptic bronchoscopy in an intensive care unit (ICU). DESIGN: Prospective survey. SETTING: ICUs at a tertiary care hospital (except for seven procedures that were performed at a peripheral hospital ICU). PATIENTS: A total of 107 patients with a mean age of 43.9 yrs (range 15 to 84). INTERVENTIONS: One hundred forty-seven fiberoptic bronchoscopy procedures (116 performed on patients who were undergoing mechanical ventilation) were performed on 107 patients. Ninety-four procedures were for diagnostic reasons (upper and lower airway inspection, focal and diffuse pulmonary infiltrates), 37 for therapeutic reasons (bronchial toilet, pulmonary hemorrhage, endotracheal intubation), and 16 for both reasons. Topical anaesthesia was used for fiberoptic bronchoscopy; sedation was rarely needed. Appropriate diagnostic and therapeutic procedures were performed. MEASUREMENTS AND MAIN RESULTS: Oxygen saturation, electrocardiogram, and blood pressure were monitored. Transbronchial biopsies (all on mechanical ventilation) for diffuse pulmonary infiltrates were diagnostic in five of seven cases, and were suggestive of the diagnosis in a further case. Endobronchial biopsies were not diagnostic in any of three cases. Bronchial brushings for microbiology were positive in nine of 50 procedures and for cytology in one of nine procedures. Protected specimen brushes for pulmonary infiltrates gave positive microbiology findings in five of 23 procedures. In pulmonary hemorrhage, focal bleeding was found in five cases, diffuse bleeding in four, and no bleeding source in three. In lobar atelectasis, bronchial toilet led to full reexpansion (n = 20 procedures), partial reexpansion (n = 5), and no change (n = 3). Intubation with fiberoptic bronchoscopy was successful in four of five patients. Hypoxemia (oxygen saturation < 90%) occurred in 29 procedures; it caused no problems. Complications included hemorrhage (n = 2), supraventricular tachycardia (n = 1), pneumothorax (n = 1), pneumatocele (n = 1), and bronchospasm (n = 1). No deaths were attributable to fiberoptic bronchoscopy. CONCLUSIONS: Fiberoptic bronchoscopy in the ICU is safe, contributes valuable diagnostic information, and is useful for therapeutic purposes.

Community-acquired bacteremia in the elderly: a prospective study of 121 cases.

OBJECTIVE: To describe community-acquired bacteremia in the elderly and correlate clinical and laboratory findings with outcome. DESIGN: Prospective study of consecutive cases. SETTING: Large community-based teaching hospital. PATIENTS: One hundred and twenty-one elderly patients aged 65 to 89 years, seen between February 1, 1986 and January 31, 1988. MAIN OUTCOME MEASURES: Bacteriological cultures, symptoms and signs, laboratory findings, and mortality. RESULTS: Gram-negative organisms accounted for 65 (54%) cases and Gram-positive organisms for 47 (39%) cases, while nine (7%) cases were polymicrobial. E. coli (39%), Klebsiella sp. (8%), S. pneumoniae (14%), and S. aureus (12%) were the most commonly isolated organisms. The overall mortality was 38%. A poor prognosis was associated with confusion as a presenting symptom (P < 0.0003), hypotension (P < 0.0003), and inappropriate or delayed treatment (P < 0.02). A good prognosis was associated with E. coli as the pathogen (P < 0.0003) and prompt, appropriate antibiotic therapy. CONCLUSION: Community-acquired bacteremia in the elderly has a high mortality rate. Early recognition and prompt, appropriate treatment are critical in reducing the mortality.

Primary biphasic lymphoplasmacytic lymphoma of the lung. A mucosa-associated lymphoid tissue lymphoma with compartmentalization of plasma cells in the lung and lymph nodes.

A primary mucosa-associated lymphoid tissue lymphoma of the lung in a 27-year-old man was found. The tumor was composed mainly of centrocyte-like cells and plasma cells. These two components were demarcated sharply from each other, resulting in a zoning or biphasic pattern. This characteristic pattern also was present in the involved regional lymph nodes. Monoclonality of tumor cells was shown immunohistochemically and by in situ hybridization techniques. This article also highlights the use of in situ hybridization in detecting light chain mRNA in paraffin sections.

Concurrent radiation and weekly cisplatin for non-small-cell lung cancer--a phase I/II study.

A total of 20 patients with loco-regional non-small-cell lung carcinoma were entered into a study of irradiation (3.0 Gy x 15 doses to a total dose of 45 Gy given in 4 fractions per week on days 1, 2, 4 and 5 of each week) and cisplatin given at a dose of 40 mg/m2 on day 3 of each week for a total of three infusions. One patient who had stage 1 disease showed a complete response to therapy and is alive and clear of disease at 35 months. In 19 patients with stage 3 disease, the complete response rate was 16% and the partial response rate was 42%. The rate of 1-year survival was 42% and the rate of 2-year survival was 11%; the median survival of these patients was 11 months. Relapse occurred, mostly at metastatic sites, in 10 of the 11 patients who responded to therapy. Acute toxicity was modest and tolerable by our patients. No severe late toxicity was encountered, and none of the patients developed grade 3 dyspnoea (an inability to walk 100 yards because of breathlessness) while clear of recurrent disease. Changes in lung function observed at follow-up examinations were similar to those seen after irradiation alone. Weekly administration of cisplatin is therefore feasible in patients receiving a continuous course of irradiation. The high relapse rate observed in responding patients indicates the need for evaluation of the efficacy of combination chemotherapy in the adjuvant or neo-adjuvant setting.

Management of invasive thymoma at Groote Schuur Hospital, Cape Town.

Fifteen patients (median age 55 years; range 23-69 years) with macroscopic invasive thymoma or thymic carcinoma were treated at Groote Schuur Hospital between 1969 and 1988. Stage 3 (macroscopically invasive) disease was present in 12 patients (80%) and stage 4 (metastatic disease) in 3 (20%). Ten of the patients with stage 3 disease were treated by combined surgery and full-dose mediastinal irradiation; in 2 resection was not possible and they were treated with irradiation alone. One of the patients with stage 3 disease developed progressive thymoma (median follow-up 74 months). This patient and 2 others died; 1 from mediastinitis after surgery for thymic carcinoma and 1 of unrelated disease. Both patients treated by irradiation alone were free of disease at follow-up. In the patients with stage 3 disease, the relapse rate was 8% (crude) and the 5-year disease-free survival rate 86% (life table). The patients with stage 4 disease received cisplatin-based combination chemotherapy, which was combined with further irradiation and debulking surgery in 2 of the 3 cases. These patients died of malignant disease at between 5 and 42 months, although 1 had a temporary response to chemotherapy. Tumour extent is the most important prognostic factor in these patients. A multidisciplinary approach to therapy is required.