Treatment and developmental therapeutics of Mycobacterium tuberculosis infections

Tuberculosis still remains a serious health problem in many regions of the world, especially in developing nations. With the spread of AIDS and the increase in the number of immunocompromised patients, the problem of tuberculosis has been greatly exacerbated because of the susceptibility of such patients to mycobacteria. Currently, chemotherapy using multiple drug regimens with isoniazid, rifampin, streptomycin, pyrazinamide, and ethambutol is the recommended treatment for tuberculosis. The presence of drug resistance is still a major concern and new generations of more effective antimycobacterial agents (antibiotics, fluoroquinolone derivatives) are the subject of active investigation. The search for novel strategies to cure tuberculosis led to studies exploring the role of cytokines in host defenses and the application of adoptive immunotherapy. New and improved methodology for in vitro and in vivo screening of antimycobacterial activity has also been reported.     

Opportunistic infections: Treatment and developmental therapeutics of cryptosporidiosis and isosporiasis

Cryptosporidium sp. and Isospora sp. are coccidian protozoans taxonomically related to Toxoplasma gondii and Plasmodium sp. Although associated with many animal species, these pathogens are also the causative agents of cryptosporidiosis and isosporiasis, 2 invasive opportunistic infections in humans. In immunocompetent hosts, the infections are usually self-limited, flu-like gastrointestinal disorders which resolve spontaneously. In immunocompromised patients, however, cryptosporidiosis is a severe, debilitating, and prolonged illness, with high morbidity and no known therapy effective against it. Spiramycin has been proven largely ineffective. In recent years, however, the use of immunotherapy is being actively pursued as one potentially useful approach for the treatment of cryptosoporidiosis. Azithromycin, a new macrolide antibiotic, has also shown promise in preclinical studies. In the case of isosporiasis, the combination of trimethoprim and sulphamethoxazole has been found to be effective, although AIDS patients have shown a high rate of relapse and, therefore, the need for suppressive maintenance therapy. © Wiley-Liss, Inc.     

Treatment and developmental therapeutics of Mycobacterium avium complex (MAC) infections

Opportunistic infections associated with AIDS pose very serious problems because of their exceedingly high morbidity and mortality. For their part, Mycobacterium avium and M. intracellulare, two organisms belonging to M. avium complex (MAC), are the most often isolated bacteria from AIDS patients. Although in recent years, some progress has been made, by and large, there is no viable drug and /or combinations of drugs effective against MAC, especially in AIDS patients. Conventional therapies with multiple drug combinations involving isoniazid, rifampin, ethambutol, streptomycin, ethionamide, and cycloserine are still widely used, as well as prophylactic treatment with rifabutin. The use of clofazimine and ciprofloxacin has also been reported. Studies on new quinolones (sparfloxacin, difloxacin, WIN 57273), macrolides, folate antagonists and antimcobacterial anitbiotics are being actively pursued along with novel strategies involving drugs inhibiting mycobacterial cell wall biosynthesis. The role of various cytokines in enhancing host immune defenses against MAC infections is also discussed.     

Treatment of picornavirus infections.

The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infections of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens-the enteroviruses (including polioviruses, coxsackieviruses, and echoviruses), the rhinoviruses, and the hepatoviruses (including hepatitis A). Recently, the parechoviruses (formerly, echoviruses 22 and 23) have been classified as a fourth genus of human picornaviruses. This article will focus on the enteroviruses and rhinoviruses agents, for which substantial effort has been expended and recent successes reported towards the development of safe and effective antiviral therapy.     

Current concepts in clinical therapeutics: intra-abdominal infections

The etiology, pathophysiology, clinical presentation, and treatment of the two major types of intra-abdominal infections--peritonitis and abscesses--are described. Peritonitis of infectious origin is the acute response of the peritoneum to microorganisms; it is classified as primary (when the source of bacteria is not apparent) or secondary (usually involving perforation of a hollow structure of the GI tract with subsequent release of microbes). Peritonitis results in mortality because of fluid shifts and endotoxins that may cause hypovolemia and shock. Abscesses, purulent collections of fluid physically separated from the surrounding tissues, are the result of chronic inflammation following failure of the body to eradicate a pathogen completely. Secondary intra-abdominal infections are often polymicrobial because of the diversity of organisms in the GI tract. The size of bacterial inocula and the number and types of species present substantially affect patient outcome. The patient with peritonitis usually presents in acute distress, with generalized abdominal pain and faint bowel sounds. The presentation of the patient with intra-abdominal abscess is more variable and less dramatic; pain and fever may be present. The treatment of these infections requires the coordinated use of prompt surgical intervention, support of vital functions, and appropriate antimicrobial therapy. Surgical procedures are used to stop continuing bacterial contamination of the peritoneum, remove foreign material from the abdomen, and drain purulent collections; it is the foundation of treating most types of intra-abdominal infections. Aggressive fluid therapy is required to assure adequate intravascular volumes in most patients. Generally, antimicrobial coverage for both aerobes and anaerobes must be started before culture results are available. Antimicrobial therapy for specific types of infections is given in the article. Surgical procedures are the foundation of treatment of most intra-abdominal infections; antimicrobial agents active against aerobic gram-negative bacilli and anaerobes are important adjuncts.     

Parasitic skin infections in the elderly: recognition and drug treatment

There are many parasitic infections of medical importance, which can produce both systemic disease as well as skin lesions. For the most part, treatment of these infections in the elderly does not differ very much from that of younger patients. However, one must be aware that the geriatric population can present with certain challenges with regard to diagnosis of these diseases because history taking may be more difficult and patients often already have a set of other medical problems, which may overshadow the skin lesions. In addition, the clinical manifestations of these infections may not appear classical and may be altered. Dosages of drugs used to treat these infections, even topical agents, may require adjustments in this population. The recognition of scabies in elderly people living together is important and early treatment with topical scabiecides, including oral ivermectin, will help to control the spread of the infestation. Pediculosis may be a cause of pruritus in the elderly and can be treated with malathione, lindane or permethrin. Less common parasitic infections in the elderly, including cutaneous larva migrans and cutaneous leishmaniasis, present with a characteristic clinical picture and can be effectively treated with oral thiabendazole and intravenous antimonials.     

Potential antiviral therapeutics for smallpox,monkeypox and other orthopoxvirus infections

We assessed the activities of 24 different antiviral compounds against smallpox (two strains of variola major and one of variola minor), monkeypox, vaccinia and cowpox viruses by a neutral red uptake assay. To establish assay parameters, we examined viral replication and its inhibition at various times postinfection and at several multiplicities of infection. Drugs were selected to target a range of functions involved in viral replication. Eight compounds (cidofovir, cyclic HPMPC (cHPMPC), HPMPA, ribavirin, tiazofurin, carbocyclic 3-deazaadenosine, 3-deazaneplanocin A and DFBA (1-(2,4-difluorobenzyloxy)adenosine perchlorate)-a derivative of adenosine N1-oxide) inhibited the replication of all three variola strains and the other orthopoxviruses at drug concentrations within a pharmacologically achievable range. Two others (methisazone and bis-POM-PMEA) showed a lesser degree of antiviral effect, while the remainder were inactive. To examine possible naturally occurring drug resistance among a large number of variola isolates obtained from different geographical regions and at different times, we examined the sensitivity of 35 different strains of variola as well as other orthopoxviruses to a subset of three of the most active compounds: cidofovir, cHPMPC, and ribavirin. Preliminary data indicate that nearly all isolates appear to have similar drug sensitivities. These findings are currently being verified and expanded.     

The TRPV1 receptor: target of toxicants and therapeutics.

Understanding the structural and functional complexities of the transient receptor potential vanilloid receptor (TRPV1) is essential to the therapeutic modulation of inflammation and pain. Because of its central role in initiating inflammatory processes and integrating painful stimuli, there is an understandable interest in its pharmacological manipulation (sensitization/desensitization). The present Highlight entitled "TRPV1 antagonists elevate cell surface populations of receptor protein and exacerbate TRPV1 mediated toxicities in human lung epithelial cells" describes how exposure to various antagonists produces TRPV1 sensitization and proposes a possible mechanistic explanation to that sensitization.     

Treatment of bacterial infections in pregnancy.

Treatment of bacterial infections in pregnancy requires an understanding of the unique problems related to the administration of antibacterial agents to pregnant women. The clinician must be aware not only of the antibiotic-associated untoward effects which may develop in the mother, but also of the possibility that adverse reactions may occur in the fetus. Precise knowledge of the microbial aetiology of those infections which occur during pregnancy and an understanding of the intricacies of antibiotic administration to pregnant women will assure the greatest likelihood that bacterial infections in pregnancy will be effectively, and safely, treated.