Antimycobacterial therapy.

Tuberculosis is a major cause of illness and death worldwide. The epidemic of the acquired immunodeficiency syndrome and the increased number of other immunocompromised hosts have led to a remarkable increase in Mycobacterium avium-intracellulare complex infections. Adequate diagnostic, prevention, and treatment measures are available; however, resources for implementing these measures are limited. Processes for using these limited resources are not always well organized. This review of prevention and treatment of tuberculosis, including the six major recommendations from the Centers for Disease Control and Prevention, treatment of certain other mycobacterial infections, and information on some antimycobacterial agents, such as isoniazid, rifampin, rifabutine, pyrazinamide, and ethambutol, was written mainly for primary-care providers.

Isolated antral narrowing associated with gastrointestinal cryptosporidiosis in acquired immunodeficiency syndrome.

A 33-year-old man with human immunodeficiency virus infection had severe protracted diarrhea. Radiologic assessment disclosed narrowing of the gastric antrum. Biopsy specimens revealed diffuse Cryptosporidium infection of the antral mucosa. Isolated antral narrowing due to Cryptosporidium gastritis should be added to the list of gastrointestinal complications associated with acquired immunodeficiency syndrome (AIDS).

Prophylactic use of antimicrobial agents in adult patients.

The prophylactic use of antimicrobial agents is recommended for prevention of numerous infections, including tuberculosis, endocarditis, rheumatic fever, recurrent cellulitis and lymphangitis in patients with lymphedema, meningococcal meningitis, and bite wounds. In addition, the prophylactic use of antimicrobial agents has proved effective in certain surgical procedures such as various abdominal operations, hysterectomy, and major operations that involve the head and neck. Except for oral bowel preparations, antimicrobial prophylaxis should be limited, in general, to the operative period. Prolonged perioperative prophylaxis has not been shown to enhance effectiveness and may result in increased toxicity, resistant superinfections, and inflated costs. The investigation of antimicrobial prophylaxis necessitates adequate evaluation of the potential advantages and disadvantages in a prospective, double-blind fashion.

Antituberculous agents.

Antituberculous agents have radically improved the prognosis of patients with active tuberculosis. Generally, 6-month and 9-month antituberculous regimens have been successful, and surgical therapy is rarely needed. Extrapulmonary tuberculosis should be managed with the same drug regimens as pulmonary tuberculosis. The major cause of therapeutic failure is poor compliance of the patient in taking the prescribed medication regularly. A second cause of failure of treatment is resistance of tubercule bacilli to antimicrobial agents used. When failure of treatment is apparent, careful reassessment by physicians experienced in the treatment of tuberculosis is indicated. A single drug should never be added to a failing regimen. Isoniazid administered prophylactically for 6 to 12 months is effective in most cases.

The penicillins.

The penicillin family of antibiotics remains an important part of our antimicrobial armamentarium. In general, these agents have bactericidal activity, excellent distribution throughout the body, low toxicity, and efficacy against infections caused by susceptible bacteria. The initial introduction of aqueous penicillin G for treatment of streptococcal and staphylococcal infections was an important pharmacologic landmark. The emergence of penicillinase-producing Staphylococcus aureus prompted the development of the penicillinase-resistant penicillins (for example, methicillin, oxacillin, and nafcillin), in which an acyl side chain prevented disruption of the beta-lactam [corrected] ring. Subsequently, the aminopenicillins (such as ampicillin and amoxicillin) were developed because of the need for gram-negative antimicrobial activity. Their spectrum included Escherichia coli, Proteus mirabilis, Shigella Salmonella, Listeria, Haemophilus, and Neisseria. The search for a penicillin with additional antimicrobial activity against the Enterobacteriaceae and Pseudomonas aeruginosa led to the development of the carboxypenicillins (carbenicillin, ticarcillin, and temocillin) and the ureidopenicillins (mezlocillin, azlocillin, piperacillin, and apalcillin). Finally, the combination of a beta-lactamase inhibitor (clavulanic acid or sulbactam) and an aminopenicillin or ticarcillin has further extended their antibacterial spectra. The development of an ideal penicillin that is rapidly bactericidal, nonsensitizing, nontoxic, bioavailable, resistant to beta-lactamase, and without inoculum effect and that has a high affinity for penicillin-binding proteins remains the goal.

General principles of antimicrobial therapy.

Treatment with antimicrobial agents must be tailored to the individual patient, the site of infection, and the etiologic organism involved. Effectiveness, toxicity, and cost are the basic considerations in choosing a drug. Because initiation of therapy often cannot be delayed until microbiologic studies have been performed, empiric treatment should be sufficiently broad to cover the most likely pathogens, based on the site of infection and the type of host. Definitive therapy may differ from initial therapy and should be instituted as soon as specific laboratory and clinical data are available. Information about allergic reactions to drugs should be elicited; because of the numerous families of antimicrobial agents currently available, most infections in patients with drug allergies can be treated with adequate substitutes. Cautious conservatism is advocated in the use of new antimicrobial agents. The effects of new agents on the microbial ecology and the hospital environment should be considered.

Efficacy of ganciclovir in liver and kidney transplant recipients with severe cytomegalovirus infection.

Twelve liver and 5 kidney transplant recipients with severe cytomegalovirus infection were treated with Ganciclovir (7.5 mg/kg/day, intravenously). Ten were evaluable (compatible clinical picture, organ involvement shown histopathologically or by culture, viremia, and absence of concomitant infection). All 17 patients were studied for adverse drug side effects. A total of 9 evaluable patients survived the infection; 1 died during treatment due to infection or drug toxicity. A death 19 days after completion of treatment was due to unrelated causes. Patients became afebrile after 2-9 days (mean, 5.3 days) of treatment. Liver function improved, pulmonary infiltrates cleared, and hypoxemia reversed during therapy. Viremia ceased during therapy in 9 patients; asymptomatic viruria persisted or recurred in 6 of 7 patients studied. No relapses occurred during follow-up (7-17 months; mean, 13 months). Transient neutropenia and thrombocytopenia occurred in 3 and 1 patients, respectively. Ganciclovir appears promising for treatment of severe CMV infection in patients with kidney or liver transplants.

Antituberculous agents.

Antituberculous agents have radically improved the prognosis of patients with active tuberculosis. Generally, 6-month and 9-month regimens have been successful, and surgical therapy is rarely necessary. Extrapulmonary tuberculosis should be managed with the drug regimens outlined for pulmonary tuberculosis. The major cause of therapeutic failure is poor compliance of the patient in taking the medication regularly. The second major cause of treatment failure is resistance of tubercle bacilli to the antimicrobial agents used. When treatment failure is apparent, careful reassessment by physicians experienced in the treatment of tuberculosis is indicated. A single drug should never be added to a failing regimen. For prophylaxis, isoniazid, given for 6 to 12 months, is effective in most cases.

Prophylactic use of antimicrobial agents in adult patients.

Prophylactic antimicrobial agents are recommended for prevention of a variety of conditions, including tuberculosis, endocarditis, rheumatic fever, recurrent cellulitis and lymphangitis in patients with lymphedema, meningococcal meningitis, bite wounds, and herpes virus infections. In addition, prophylactic antimicrobial agents have proved effective in certain surgical procedures such as a variety of abdominal operations, hysterectomy, and head and neck operations for cancer. Except for oral bowel preparations, administration of antimicrobial agents for prophylaxis should be limited, in general, to the perioperative time period. Doses given more than an hour before or 3 hours after a surgical procedure have not been shown to increase effectiveness, and such an approach increases the cost and the probability of toxicity and superinfection. Investigation of antimicrobial prophylaxis necessitates adequate evaluation of potential advantages and disadvantages in prospective double-blind fashion.

General principles of antimicrobial therapy.

Use of antimicrobial agents must be tailored to the individual patient, site of infection, and etiologic organism. The choice of drug should be based on efficacy, safety, low toxicity, and acceptable cost. Empiric therapy should be broad enough to cover the pathogens that are suspected of causing the infection, based on the site of infection and the type of host. Definitive therapy may differ from initial therapy and should be started as soon as specific laboratory and clinical data are available. Cautious conservatism is advocated with regard to the use of new antimicrobial agents. The effects of the agents on the microbial ecology and hospital environment should be considered. Judicious use is necessary to prevent antimicrobial pollution.

The penicillins.

The penicillin family of antibiotics is ever expanding and remains an important part of our antimicrobial armamentarium. These medications generally have bactericidal activity, excellent distribution throughout the body, low toxicity, and efficacy against infections due to susceptible organisms. The clinical introduction of aqueous penicillin G for treatment of streptococcal and staphylococcal infections was an important pharmacologic landmark. The emergence of penicillinase-producing staphylococci prompted the development of the penicillinase-resistant penicillins (methicillin, oxacillin, nafcillin, and others), in which the acyl side chain prevented disruption of the beta-lactamase ring. The aminopenicillins (ampicillin, amoxicillin, and others) were later developed because of the need for gram-negative antimicrobial activity. Their spectrum included Escherichia coli, Proteus mirabilis, Shigella, Salmonella, Listeria, and Haemophilus. The search for a penicillin with even further antimicrobial activity against the Enterobacteriaceae and Pseudomonas aeruginosa led to the development of the carboxypenicillins, ureidopenicillins, and piperazine penicillins. Recently, the combination of a beta-lactamase inhibitor (clavulanic acid or sulbactam) and an amino-penicillin or ticarcillin has resulted in further extension of their antibacterial spectra. The development of an ideal penicillin that is nonsensitizing, bioavailable, beta-lactamase-resistant, rapidly bactericidal, nontoxic, and inexpensive and that has high affinity to penicillin-binding proteins and no inoculum effect remains the goal.

Clindamycin versus chloramphenicol in treatment of anaerobic infections: a prospective, randomized, double-blind study.

Seventy patients with substantiated anaerobic infections were treated parenterally with clindamycin or chloramphenicol in a prospective, double-blind, randomized study. No significant differences in clinical response or toxicity were noted between the two groups of patients.

Candida pseudotropicalis fungemia and invasive disease in an immunocompromised patient.

A case of Candida pseudotropicalis fungemia and invasive disease in an immunocompromised patient is reported. Multiple blood cultures taken over a 2-week period were positive, and histopathological slides of postmortem spleen and kidney tissue showed tissue invasion by the organism. The source of the yeast infection was determined to be the urinary tract. This is the first report of C. pseudotropicalis fungemia documented by culture.

Treatment of streptomycin-susceptible and streptomycin-resistant enterococcal endocarditis.

Fifty-six patients with enterococcal endocarditis received 4 weeks of antimicrobial therapy with penicillin G and streptomycin (36 patients) or, if infections were streptomycin resistant, penicillin and gentamicin (20 patients). Compared with patients who had symptoms for less than 3 months, patients with symptoms for more than 3 months had a higher relapse rate (0% versus 44%; p less than 0.001) and mortality (2.5% versus 25%; p less than 0.001). Patients with mitral valve endocarditis had a significantly higher relapse rate (25%) than patients with aortic valve infections (0%) (p less than 0.01). Gentamicin-associated nephrotoxicity was more frequent (p less than 0.001) among patients treated with greater than 3 mg/kg d of gentamicin than among those treated with 3 mg or less (100% versus 20%). Relapse and mortality rates did not differ significantly between patients treated with low-dose or high-dose gentamicin regimens. Patients who have had symptoms of enterococcal endocarditis for more than 3 months or patients with mitral valve infection should receive at least 6 weeks of antimicrobial therapy, but patients without these high-risk factors can be treated for 4 weeks.

Prophylactic use of antimicrobial agents.

A major shortcoming in many studies of prophylactic antimicrobial agents has been lack of adequate evaluation of potential advantages and disadvantages in prospective double-blind investigations. Recent data demonstrated that certain bowel preparations given orally and antimicrobial agents applied topically or given parenterally prevent postoperative infections. Several studies have shown that if topically and parenterally administered antimicrobial agents are used, they should be given only during the surgical procedure. Antimicrobial therapy initiated after an operation is generally not indicated for prophylaxis and, in fact, increases the potential disadvantages of prophylaxis. There is no evidence that combinations of orally, topically, and parenterally administered antimicrobial agents reduce infection rates below those achieved by the use of any one route of prophylactic antimicrobial administration.

Antituberculous agents. Isoniazid, rifampin, streptomycin, ethambutol, and pyrazinamide.

Effective antituberculous drugs have radically improved the prognosis of the patient with active tuberculosis. Surgical therapy is rarely needed, and sanitoriums have largely vanished. Triple-drug therapy may be indicated initially for cavitary pulmonary disease, meningitis, miliary disease, and moderate to severe renal disease. Short-course therapy twice or three times weekly with isoniazid and rifampin may be used in cavitary pulmonary disease and probably in these other serious infections as well. Isoniazid alone is adequate for prophylaxis. The major cause of therapeutic failure is noncompliance of the patient in taking the medication regularly. The second major cause of treatment failure is resistance of tubercle bacilli to the antimicrobial agents used. When treatment failure is apparent, careful reassessment by physicians experienced in the treatment of tuberculosis is indicated. A single drug should never be added to a failing regimen.

General principles of antimicrobial therapy.

The initial treatment of suspected life-threatening bacterial infection should be sufficiently broad to cover the likely causative agents. Definitive therapy depends on microbial isolation, identification, and, when indicated, in vitro susceptibility tests. Parenteral therapy should be used, at least initially, and optimal doses are necessary. The dose is particularly important when aminoglycosides are administered; a concern for potential side effects with use of these agents had engendered a tendency to administer inadequate doses. The problems leading to recurrence or persistence of fever during antimicrobial therapy include failure to diagnose and drain abscesses, superinfection, drug fever, and clinical or microbiologic errors. Combinations of antibiotics are indicated in severe infections due to Pseudomonas aeruginosa, enterococcal group D streptococci, and Cryptococcus neoformans. Laboratory assistance for the selection of antimicrobial therapy can be valuable but is not always necessary because certain microorganisms--for example, Streptococcus pneumoniae and S. pyogenes--have stable, predictable susceptibilities. Cautious conservatism is advocated with regard to the use of new antimicrobial agents.

The penicillins.

The penicillins as a group are the most frequently and widely used of the antimicrobial agents because they are effective, low in toxicity, and relatively inexpensive. Effectiveness is due to the bactericidal action, the excellent distribution throughout the body spaces, and the wide spectrum of activity. Knowledge of the variation in spectrum of activity of the various types of penicillins is needed for effective use of the appropriate drug against individual infections. Allergenicity is the most frequent and serious problem associated with the use of penicillins. Individual penicillins, however, do have different side effects. The older penicillins are so inexpensive that the cost of their use need hardly be considered, whereas the newer penicillins are expensive and should be used only when they are clearly more effective for treatment than are drugs such as penicillin G.

Enterococcal endocarditis.

Ten to twenty percent of all cases of bacterial endocarditis are caused by enterococci. The enterococci are penicillin-resistant group D streptococci that can be distinguished from other streptococci by certain biochemical reactions, including growing the bile or 6.5% sodium chloride. In patients with enterococcal endocarditis, the portal of entry often is the genitourinary tract. Therapy is difficult; combination chemotherapy with penicillin G or ampicillin and an aminoglycoside is required. Although specimen streptomycin is preferred, occasional strains of enterococci are resistant to this agent, and gentamicin must be substituted. The minimal duration of therapy is 4 weeks.