The clinical use of fluoroquinolones for the treatment of mycobacterial diseases

Mycobacterial diseases often require prolonged therapy with multidrug regimens. Fluoroquinolones have excellent bactericidal activity against many mycobacteria; achieve effective serum, tissue, and intracellular levels following oral administration; and produce few adverse effects. These properties have led to the increasing use of fluoroquinolones for the treatment of mycobacterial infections. We reviewed clinical studies and reports involving the use of fluoroquinolones for mycobacterial diseases. Ofloxacin, ciprofloxacin, sparfloxacin, and pefloxacin exhibit clinical efficacy against mycobacterial diseases, especially tuberculosis and leprosy. Fluoroquinolones have generally been administered in regimens that include other agents. However, when a fluoroquinolone has been found to be the sole active agent in a multidrug regimen, the ready emergence of resistance to fluoroquinolones has been recognized, just as when they have been used as monotherapy. Therefore, to forestall the emergence of resistance to fluoroquinolones during the treatment of mycobacterial diseases, these drugs should always be used in combination with at least one other active agent, and they should be used only when effective alternative drugs are not available.     

Mapping of chromosomal gains and losses in primitive neuroectodermal tumors by comparative genomic hybridization

Pediatric fungal pulmonary infections are being seen with increasing frequency. The dimorphic fungi Histoplasma capsulatum. Blastomyces dermatitidis, Coccidioides immitis, and Cryptococcus neoformans frequently cause infections that are asymptomatic. However, patients may suffer pneumonia and disseminated disease. Diagnosis can be made definitively by isolation of the causative organism, but serology or skin testing is often necessary when this is not successful. Severe or life threatening infections are treated with amphotericin B. Recently, new oral azole antifungals are being used more frequently for mild to moderate disease with good success.     

Mycobacterium avium complex endocarditis: spurious diagnosis resulting from laboratory cross contamination

Contamination between specimens within clinical microbiology laboratories may be responsible for spurious outbreaks of mycobacterial infections. We report the case of a patient who had culture-negative endocarditis and whose cardiac tissue obtained at surgery yielded Mycobacterium avium complex (MAC). Epidemiologic investigation suggested cross contamination probably occurred during processing of the sputum specimens of a patient with pulmonary MAC disease and the cardiac samples from our patient; molecular strain typing showed the isolates from both patients to be identical. When mycobacterial infection rates increase or an unexpected case of mycobacterial infection occurs, the clinician should be alert to the possibility of cross contamination in the laboratory as a possible explanation.     

Protection by CD4 or CD8 T cells against pulmonary Mycobacterium bovis bacillus Calmette-Guérin infection

Mice deficient in CD8 T cells demonstrated levels of Th1 cytokines and granulomatous responses in the lungs very similar to those demonstrated by normal control mice and were fully capable of controlling pulmonary mycobacterial infection by Mycobacterium bovis BCG as assessed at day 37 postinfection. In comparison, mice deficient in CD4 T cells had similar levels of interleukin-12 (IL-12) and tumor necrosis factor alpha but lower levels of gamma interferon in the lungs and were still able to mount tissue granulomatous responses and control pulmonary mycobacterial infection. In contrast, IL-12(-/-) mice with impaired CD4 and CD8 T-cell responses had a markedly weakened control of infection, whereas SCID mice deficient in all T cells succumbed to such pulmonary mycobacterial infections.     

Approach to the diagnosis of pulmonary disease in patients infected with the human immunodeficiency virus

Patients infected with the human immunodeficiency virus are predisposed to develop a variety of common and uncommon infectious and neoplastic pulmonary diseases. Clinical information that can stratify the risk of occurrence of these pulmonary conditions includes: 1) CD4 cell count-the most important determinant; 2) concurrent antimicrobial therapy; 3) prior travel history; 4) known latent infections that may reactivate: and 5) underlying respiratory disease. Specific pulmonary diseases are discussed including: bacterial pneumonia, bronchitis, mycobacterial and fungal infections, pneumocystis carinii pneumonia, toxoplasmosis, cytomegalovirus, Kaposi sarcoma, lymphoma, and lung cancer. A differential diagnosis can be generated based on the chest radiographic pattern. Focal or multifocal areas of consolidation usually represent conventional bacterial pneumonia or, less commonly, tuberculosis. In severely immunocompromised patients, unusual diseases causing consolidation should be considered including: Rhodococcus infection, nocardiosis, cryptococcosis, aspergillosis, and lymphoma. Nodules can be present in tuberculosis, histoplasmosis, cryptococcosis, and Kaposi sarcoma. Interstitial opacities are common in pneumocystis carinii pneumonia, histoplasmosis, and cytomegalovirus pneumonia. Cavitation and cysts are features of pneumocystis carinii pneumonia, tuberculosis, aspergillosis, and lung cancer. Disease of the airways is increasingly recognized in those with acquired immunodeficiency syndrome. Lymphadenopathy is most common in mycobacterial infection, but can be a feature of fungal infection, lymphoma, Kaposi sarcoma, and lung cancer. The combined use of clinical information, knowledge of typical conditions associated with the human immunodeficiency syndrome, and radiographic patterns offers a useful approach to the diagnosis of pulmonary disease in the patient with the human immunodeficiency virus.     

Phenotypic and molecular characterization of three clinical isolates of Mycobacterium interjectum

Introduction of molecular biology-based technology into an Australian mycobacterial reference laboratory has resulted in the identification of three isolates of Mycobacterium interjectum in the past 12 months. Conventional phenotypic methods failed to identify the species of these isolates, and high-performance liquid chromatography found that only one of the three isolates had a mycolic acid pattern similar to that of the type strain. In contrast, all three isolates were rapidly identified as M. interjectum by 16S rRNA gene sequence analysis. Two isolates were recovered from the lymph nodes of children with cervical lymphadenitis, confirming the pathogenicity of this organism. However, the third isolate was obtained from the sputum of an elderly male with chronic lung disease without evidence of clinical or radiological progression, suggesting that isolation of M. interjectum should not imply disease. With the increasing use of molecular biology-based technology in mycobacterial laboratories, M. interjectum may be recognized more frequently as a pathogen or commensal organism.     

Genetic determination of the meso-diaminopimelate biosynthetic pathway of mycobacteria

The increasing incidence of multiple-drug-resistant mycobacterial infections indicates that the development of new methods for treatment of mycobacterial diseases should be a high priority. meso-Diaminopimelic acid (DAP), a key component of a highly immunogenic subunit of the mycobacterial peptidoglycan layer, has been implicated as a potential virulence factor. The mycobacterial DAP biosynthetic pathway could serve as a target for design of new antimycobacterial agents as well as the construction of in vivo selection systems. We have isolated the asd, dapA, dapB, dapD, and dapE genes involved in the DAP biosynthetic pathway of Mycobacterium bovis BCG. These genes were isolated by complementation of Escherichia coli mutations with an expression library of BCG DNA. Our analysis of these genes suggests that BCG may use more than one pathway for biosynthesis of DAP. The nucleotide sequence of the BCG dapB gene was determined. The activity of the product of this gene in Escherichia coli provided evidence that the gene may encode a novel bifunctional dihydrodipicolinate reductase and DAP dehydrogenase.     

Ureaplasma urealyticum infections in the perinatal period

Good evidence indicates the widespread carriage of U. urealyticum among sexually active females. Colonization of the upper genital tract appears to be a risk factor for adverse pregnancy outcomes, though this is not the case for lower-genital-tract colonization. Based on studies in which amniotic fluid obtained from amniocenteses was already positive for U. urealyticum, and its high prevalence in very-LBW neonates, it is likely that the infection is acquired during early pregnancy. A number of observational studies have linked this organism to pulmonary infections, meningeal infections, and bacteremias, particularly in LBW neonates. It is difficult, however, to separate the morbidity that is directly attributable to infection with the organism from morbidity owing to extreme prematurity. Problems in measuring the burden of illness resulting from this organism are compounded by difficulties in its diagnosis. The organism's fastidious nature prevents many laboratories from isolating it from specimens. Rapid and practical methods for identifying the organism are urgently needed. These need to be followed by RCTs to determine if outcomes of pregnant women and babies with various conditions, from whom the organism has been isolated, can be improved through treatment with antimicrobial agents.     

Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency

In humans, interferon gamma (IFN-gamma) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells. Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12-independent IFN-gamma secretion.     

Atypical mycobacterial pulmonary disease and bronchial obstruction in HIV-negative children

Atypical mycobacterial infection in HIV-negative children usually presents with cervical lymphadenopathy. We report on 10 children who are HIV-negative and who presented with pulmonary disease, in whom either culture-proven atypical mycobacterium infection (four), positive avian Mantoux test (five), or lack of response to human tuberculosis treatment (one) had been observed. One case was subsequently diagnosed as chronic granulomatous disease and illustrates that children with atypical mycobacterial pulmonary infection should have their immune status fully investigated. Bronchial obstruction was observed in eight cases, and of these, endobronchial disease was found in six children. The diagnosis of atypical mycobacterial disease is difficult, and a negative avian Mantoux test does not exclude the diagnosis. The availability of clarithromycin and rifabutin has offered new therapeutic options in treating atypical mycobacterial pulmonary infection, but management of these cases can be prolonged and difficult.     

Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review

Suppurative thyroiditis is rare, and the major pathogens are Staphylococcus and Streptococcus species. We present a case caused by Acinetobacter baumanii, which has never before been reported. We review another 191 cases from the English-language literature (1980 to April 1997) and make a comparison with a review of 224 cases (1900-1980). As the numbers of immunocompromised patients increase, cases of suppurative thyroiditis are increasing. Pneumocystis carinii has become an important pathogen. Most patients (83.1%) with bacterial infections were euthyroid, whereas those with fungal or mycobacterial infections tended to be hypothyroid (62.5%) and hyperthyroid (50%), respectively.     

The value of in vitro drug activity and pharmacokinetics in predicting the effectiveness of antimycobacterial therapy: a critical review

Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.     

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.     

Indications for influenza vaccination in children with lung disorders. Dutch Association for Pediatric Medicine

The Dutch Association for Paediatric Medicine has formulated guidelines regarding influenza vaccination of children with pulmonary disease. Influenza virus is the most frequent cause of airway infections in humans over two years of age. It may lead to serious morbidity in children with pulmonary disease: exacerbations, (transient) disturbances in pulmonary function, and symptoms lasting weeks, but mortality is probably very low. The effects of influenza vaccination of children with pulmonary disease are similar to those in normal healthy children. A positive long-term effect on the asthma has never been demonstrated. It is advised that children with moderate to severe asthma who require treatment to be vaccinated against influenza every year. If the first vaccination ever occurs before the age of six years, it should be followed by a booster vaccination after four weeks. In both instances, a full vaccination dose should be administered.     

Tuberculosis in respiratory system--tracheo-bronchial tuberculosis, pulmonary tuberculosis, tuberculous pleurisy and thoracic empyema

Tuberculosis in respiratory system is most common in mycobacterial infections. Eighty percent of the patients with pulmonary tuberculosis visit hospital because of the respiratory symptoms, and only 10% of them were discovered by chest X-ray mass screening. In order to confirm respiratory tuberculosis, various methods to obtain specimens for mycobacterial examination have been carried out; hypertonic saline nebulizing for sputum expectoration, trans-bronchoscopic biopsy, percutaneous needle aspiration, and so on. The recent development of imaging modalities including CT, MRI, and ultrasonogram have been much contributed to the improvement of diagnosis of pleural tuberculosis. Basically, the main treatment for respiratory tuberculosis is chemotherapy except chronic tuberculous thoracic empyema. The initial chemotherapy regimen should be chosen among the three arms; [INH + RFP + PZA + EB (or SM)] x 2-->[INH + RFP] x 6, [INH + RFP + EB (or SM)] x 6-->[INH + RFP] x 3-6, and [INH + RFP] x 6-9. The sputum positive patient is recommended to have the chemotherapy regimen including PZA. In the patients with tracheo-bronchial tuberculosis an attention should be paid for the airway narrowing or obstruction during and after the scheduled chemotherapy. For a part of patients with tuberculous pleurisy and thoracic empyema, a surgical treatment must be indicated.     

Mycobacteria of the intracellulare-scrofulaceum group in soils from the Adelaide area

Soil samples from the Adelaide area--where organisms belonging to the Mycobacterium intracellulare-scrofulaceum (MIS) group are rarely encountered in sputum of persons under investigation of pulmonary mycobacterial disease--were examined for the MIS group. Thirty-one per cent were positive for MIS organisms and 17% were positive for MIS serotypes known to be disease-associated. Comparison with an earlier study of soils from the Brisbane area--where this group of organisms is frequently isolated from sputum of persons under investigation for pulmonary mycobacterial disease--suggests that the disease-associated MIS serotypes are significantly more common in the environment of the Brisbane area. This implies a positive correlation, and consolidates existing evidence that the environment is the reservoir of, and a source of infection with, organisms of the MIS group.     

Visceral fungal infections due to Petriellidium boydii (allescheria boydii). In vitro drug sensitivity studies

Four patients with visceral infections due to the fungus Petriellidium boydii, who were recently hospitalized in our institutions, are described. Three of the patients were compromised hosts; in the fourth patient, infection occurred after trauma. All had received prior steroid and antibiotic therapy. Studies of patients with mycetoma or secondary infection of a pulmonary cavity due to this organism and of patients with visceral infections are reviewed. Because of histologic similarities to Aspergillus species, infections due to P. boydii may have been misdiagnosed in the past if the infecting fungus was not isolated in culture. The fungus has been shown to be resistant in vitro to currently available antifungal agents. Resistance to amphotericin and 5-fluorocytosine is demonstrated in our studies. There are few reports of successful chemotherapy of any manifestation of this infection, and no such reports of visceral disease. We demonstrate in vitro sensitivity of isolates in our cases and in others to micronazole, a new antimicrobial agent; this drug may be indicated for treatment of disease due to P. boydii.     

Breast cancer five-year survival, by New South Wales regions, 1980 to 1991

Mycobacterium xenopi is one of the most frequently isolated nontuberculous mycobacteria in Ontario, Canada. We reviewed the records of 28 human immunodeficiency virus (HIV)-infected patients from whom M. xenopi was isolated between 1982 and 1995. M. xenopi was recovered from respiratory specimens from 24 patients, most of whom had clinical and radiographic evidence of pulmonary disease. However, coexistent pulmonary infection due to other pathogens was found in 17 patients: Pneumocystis carinii (9 patients), cytomegalovirus (5), Haemophilus influenzae (2), Mycobacterium avium complex (2), Streptococcus pneumoniae (1), Staphylococcus aureus (1), Aspergillus species (1), and Histoplasma capsulatum (1). Three patients had bacteremia with M. xenopi, including two patients with pulmonary infection. Two of the bacteremic patients had chronic fever and a wasting syndrome. Twenty-one (75%) of the 28 patients were thought to be colonized, and seven patients (25%; of whom four had CD4 cell counts of < or = 50/mm3) were thought to have significant infection due to M. xenopi. Sixteen patients died, but in no case was death attributable to M. xenopi infection. In a region where M. xenopi is a relatively common mycobacterial isolate, the organism frequently colonizes HIV-infected patients. Significant disease occurs in those patients with more advanced HIV infection.     

An evaluation of intravenous ethanol in hospitalized patients

A series of arabinofuranosyl oligosaccharides found as constituent parts of the polysaccharide portion of the cell wall of Mycobacterium tuberculosis have been chemically synthesized. Screening of these oligosaccharides as substrates for arabinosyltransferases present in mycobacterial membrane preparations suggests that modified oligosaccharide analogs as small as disaccharides may be inhibitors of glycan biosynthesis. Such inhibitors would be of potential utility as lead compounds in the identification of new drugs for the treatment of mycobacterial infections.