Should isoniazid be used in retreatment of tuberculosis despite acquired isoniazid resistance?

The use of high-dose isoniazid in retreatment regimens for tuberculosis, despite acquired isoniazid resistance, could possibly improve therapeutic results if all or part of the organisms were resistant to only low concentrations of that drug. Furthermore, organisms resistant to low concentrations of isoniazid have been shown, on occasion, to be resistant to 2 of the retreatment drugs, ethionamide and pyrazinamide, whereas higher degrees of isoniazid resistance are associated with susceptibility to these drugs. Use of high-dose isoniazid might improve results in retreatment with ethionamide and pyrazinamide by eliminating any organisms with low degrees of isoniazid resistance that have associated ethionamide and pyrazinamide resistance. Two clinical trials concerning this topic have been reported. A controlled retreatment trial with various combinations of ethionamide, cycloserine, and pyrazinamide with and without conventional "low" doses of isoniazid (300 mg per day) showed no benefit when isoniazid was added. However, a noncontrolled trial using ethionamide and pyrazinamide with and without high doses of isoniazid, 1 to 1.5 g per day, showed marked benefit with the added isoniazid. In view of these conflicting data, the use of high-dose isoniazid in retreatment regimens needs further study, which could probably be carried out in the developing countries.     

Inhaled antimicrobial therapies for respiratory infections

Inhaled antimicrobial therapy is attractive because of its potential to provide high concentrations of antimicrobials to the site of active respiratory infections while avoiding systemic toxicity. Many antimicrobials have been used in inhaled preparations, including aminoglycosides, colistin sodium, cephalosporins, penicillins, vancomycin, amphotericin B, and several antiviral compounds. This review highlights available data on inhaled antimicrobials, antifungals, and antivirals for the prevention and treatment of infections of the respiratory tract.     

Diagnostic dilemma and therapeutic non-compliance in a case of intracranial tuberculoma

A case of extensive intracranial tuberculoma is presented. The patient had been treated for 5 years with a standard antituberculosis regimen but she had been grossly non-compliant. This had led to emergence of multi-resistant Mycobacterium tuberculosis producing progressive disease and extensive cranial nerve damage and proptosis. The unusual CT and angiographic appearances cast doubt on the original diagnosis and a brain biopsy was necessary. Mycobacterium tuberculosis resistant to isoniazid, rifampicin, ethambutol, ethionamide, pyrazinamide, clofazimine and PAS was cultured from the brain biopsy specimen and from an associated groin abscess. A novel regimen of isoniazid, cycloserine, amikacin and ciprofloxacin produced clinical improvement of symptoms and radiological resolution.     

Hepatitis in leprosy patients treated by a daily combination of dapsone, rifampin, and a thioamide

A 13% incidence of hepatitis was observed among 54 cases of multibacillary leprosy treated daily with the three-drug combination of dapsone, rifampin, and a thioamide (ethionamide or prothionamide). No hepatitis was observed among 109 cases of paucibacillary leprosy treated daily with the two-drug combination of dapsone and rifampin. Symptoms were jaundice in five cases and nausea plus vomiting associated with a significant increase of transaminase levels in two cases. In five cases, the symptoms appeared during the first two months of therapy and in two cases, later. Discontinuing treatment with rifampin and the thioamide but not dapsone resulted in recovery. When rifampin was resumed without the thioamide, the hepatitis did not recur. Viral etiology could be eliminated in six cases. Neither sex, age, weight nor the fact that the patient was a new case or a relapse case appeared to be a contributing factor. Hepatotoxicity caused by administration of a thioamide might have been potentiated by the concurrent administration of rifampin.     

Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use

Although there are reports of cases of acute renal failure occurring in cystic fibrosis (CF) patients, usually in association with the use of nephrotoxic antibiotic therapy, there have been no studies of renal function in this patient group. We hypothesized that long-term use of intravenous (IV) nephrotoxic antibiotics (aminoglycosides and colistin sulphomethate) may contribute to renal disease in CF patients. In a prospective study, we assessed creatinine clearance as an index of renal function with two techniques (24-hr urine collections and the Cockroft-Gault formula) in a group of 80 stable adult CF outpatients chronically infected with Pseudomonas aeruginosa but with no history of preceding renal disease. Using a multiple linear regression model, we evaluated their renal function in terms of their lifetime IV use of aminoglycosides and colistin. Between 31% (Cockroft-Gault formula method) and 42% (24-hr urine collection method) of patients had a creatinine clearance below normal range. Using either method, there was a strong correlation between aminoglycoside use and diminishing renal function (r=- 0.32, P=0.0055), which was potentiated by the coadministration of colistin (r=- 0.42, P <0.0002). However, there was no correlation with colistin when used in combination with other antibiotics alone (r=0.18, P=NS). Repeated IV aminoglycoside use in CF is associated with long-term renal damage. Although this effect is potentiated by colistin, colistin on its own in moderate doses does not appear to be nephrotoxic. IV aminoglycosides should be used cautiously in CF patients, with regular monitoring of renal function.     

The use of antimicrobial agents for noninfectious diseases

Antimicrobial agents are used in the treatment of a variety of noninfectious diseases. Therapeutic action may be directed against the host immune system as well as against the microbe. Some actions conventionally classified as toxic may be therapeutically or diagnostically desirable under unusual clinical circumstances. Antibiotics are used for both their antimicrobial and antiinflammatory properties to treat several dermatologic and immune-mediated diseases. Tetracycline fluorescence indicates necrotic or malignant tissue and the depth of dermal burns. Tetracycline's affinity for new bone tissue formation has applications in both research and diagnostic assessments. Radiolabeled tetracycline can act as an imaging agent for the gall bladder and kidney. The sulfonamides and sulfones, chloramphenicol, metronidazole, and some aminoglycosides also have been demonstrated to have unusual therapeutic and diagnostic efficacy, albeit by mechanisms not always understood. Although not all reported unconventional applications of antimicrobial agents remain in use, sharpening awareness of their multifaceted actions should encourage broader understanding of all agents traditionally confined to specific uses.     

Antimicrobial drugs, microorganisms, and phagocytes

The literature on the interaction between antimicrobial drugs, microorganisms, and phagocytes is reviewed. Critical assessment of the methods used in various studies is indispensable in the interpretation of results. The available data seldom permit firm conclusions, but a number of interactions can be postulated. Chemotaxis is influenced by beta-lactam antibiotics, which induce an increased release of chemoattractants from bacteria; inhibitors of protein synthesis (erythromycin, tetracyclines) reduce the release of chemoattractants. Rifampin and tetracyclines inhibit chemotactic activity of granulocytes. Phagocytosis is diminished by tetracyclines and bacitracin. Intracellular killing is impaired by trimethoprim and sulfamethoxazole. Antimicrobial drugs that inhibit protein synthesis alter the surface of bacteria, changing the opsonic requirements for phagocytosis. Antimicrobial agents that act on the cell wall or disrupt the organization of the outer membrane of gram-negative bacteria increase bacterial vulnerability to the lethal action of granulocytes. Cellular enzymes of granulocytes act synergistically with a variety of drugs. Synergism between monocytes and penicillins has also been shown. The degree of penetration of an antimicrobial drug into phagocytic cells is not correlated with the intracellular activity of the drug. Polymyxin B, colistin, rifampin, vancomycin, clindamycin, and quinolones kill bacteria phagocytosed by granulocytes. Penicillins, rifampin, and chloramphenicol show microbicidal activity against bacteria ingested by monocytes or macrophages.     

Mechanisms of bacterial resistance to antibiotics

The three fundamental mechanisms of antimicrobial resistance are (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that are antimicrobial targets, and (3) changes in membrane permeability to antibiotics. Antibiotic resistance can be either plasmid mediated or maintained on the bacterial chromosome. The most important mechanism of resistance to the penicillins and cephalosporins is antibiotic hydrolysis mediated by the bacterial enzyme beta-lactamase. The expression of chromosomal beta-lactamase can either be induced or stably depressed by exposure to beta-lactam drugs. Methods to overcome resistance to beta-lactam antibiotics include the development of new antibiotics that are stable to beta-lactamase attack and the coadministration of beta-lactamase inhibitors with beta-lactam drugs. Resistance to methicillin, which is stable to gram-positive beta-lactamase, occurs through the alteration of an antibiotic target protein, penicillin-binding protein 2. Production of antibiotic-modifying enzymes and synthesis of antibiotic-insensitive bacterial targets are the primary resistance mechanisms for the other classes of antibiotics, including trimethoprim, the sulfonamides, the aminoglycosides, chloramphenicol, and the quinolone drugs. Reduced antibiotic penetration is also a resistance mechanism for several classes of antibiotics, including the beta-lactam drugs, the aminoglycosides, chloramphenicol, and the quinolones.     

Intermittent chemotherapy of experimental leprosy in mice

In this study we assess the degree of prolonged bacteriostasis of Mycobacterium leprae after temporary exposure to ehtionamide or thiacetazone, and relate this to their efficacy when administered intermittently to mice with experimental leprosy infections. The results show that temporary exposure of M. leprae to either of these drugs results in a prolonged bacteriostatic effect, but that efficacy is rapidly lost as the interval between doses is increased. Using the mouse foot pad system, growth of M. leprae is not inhibited by thiacetazone when the frequency of administration is less than three times weekly. When ethionamide is administered once weekly, growth of M. leprae is inhibited but bactericidal activity is lost. When ethionamide is administered in combination with continuous dapsone therapy, either continuously or three times weekly, the bactericidal activity of the drug combination is greater than when either drug is administered alone. However, when ethionamide is administered once weekly in combination with continuous dapsone treatment, the bactericidal effect is identical to that when dapsone is given alone: that is, ethionamide makes no contribution to the combination.     

Management of anaerobic infections.

Anaerobic infections are reviewed with emphasis on management. Most anaerobic pulmonary infections respond to penicillin G, even when Bacteroides fragilis (penicillin-resistant) is present. Clindamycin is suitable in penicillin-sensitive patients. Intraabdominal infections have a complex flora usually involving anaerobes, especially B. fragilis. It is desirable to use antimicrobial therapy to cover potential pathogens of all types. Surgical drainage and debridement are extremely important considerations. Anaerobic bacteria were found in 72% of 200 patients with female genital tract infections and were the exclusive isolates in 30%. Surgical therapy is primary, but antimicrobial and anticoagulant therapy are also important. A variety of soft-tissue infections involve anaerobes. Surgery is the major therapeutic approach. Anaerobic endocarditis is uncommon but may be difficult to manage. Chloramphenicol is ordinarily the drug of choice for brain abscess. New antimicrobial agents, which are under investigation and are promising, include new penicillins, new cephalosporins, new tetracyclines, and metronidazole.     

The clinical use of colistin in patients with cystic fibrosis.

Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis. Current data supports the use of intravenous colistimethate for the treatment of acute pulmonary exacerbations involving MDR P. aeruginosa and inhaled therapy for initial colonization. The frequency of nephrotoxicity and severity of neurotoxicity seem to be substantially less than previously believed. In addition, recent pharmacokinetic and pharmacodynamic data suggests new intravenous dosing regimens may enhance efficacy while minimizing toxicities; such regimens deserve further evaluation. Pre- and post-treatment spirometry is recommended at initiation of inhaled colistin therapy to identify sensitized individuals. Judicious use of colistin where the benefits have been clearly documented will retain this as a useful agent in the management of P. aeruginosa infections in patients with cystic fibrosis.     

A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy

In 1982-1984 we conducted a six-month clinical trial in 50 previously untreated lepromatous leprosy patients randomly assigned to directly observed monotherapy with one of two thioamides, ethionamide or prothionamide, each given six times a week at doses of either 250 mg or 500 mg. The findings of this study have only recently been analyzed, and the potential for the use of these thioamides in leprosy patients placed in perspective. However, because of the small number of patients included in this study, the results must be interpreted with some caution. Clinical improvement was noted in 74% of the patients treated with ethionamide and in 83% of those treated with prothionamide. Therapy was well tolerated and drug-related hepatotoxicity did not require discontinuation of therapy. The 500-mg dose of both ethionamide and prothionamide resulted in loss in Mycobacterium leprae viability more rapidly than did the 250-mg dose, and prothionamide at both dose levels was superior to the equivalent dose of ethionamide. Overall killing of M. leprae in this study was found to be similar to that obtained previously with dapsone and clofazimine, but less than was obtained with rifampin, minocycline, clarithromycin, pefloxacin, and ofloxacin.     

Dapsone neuropathy--report of three cases and pathologic features of a motor nerve

We report the clinical features, electrophysiologic findings, and dapsone and isoniazid excretion studies in three young people who ingested excessive amounts (2-4 times the prescribed dose) of dapsone for hypopigmented macules and who developed, subacutely, progressive motor neuropathy a few months later. Pathologic studies on a biopsied motor nerve confirmed the electrophysiologic conclusion of distal motor axonopathy. All made a rapid recovery in a few months after dapsone was stopped, although electrical abnormalities persisted. One patient was a rapid acetylator of isoniazid.     

Inoculum effect

The inoculum effect (IE) is a laboratory phenomenon that is described as a significant increase in the minimal inhibitory concentration of an antibiotic when the number of organisms inoculated is increased. The IE generally occurs with beta-lactam antibiotics in relation to beta-lactamase-producing bacteria. An IE occurs with the first- and second-generation cephalosporins against Staphylococcus aureus and less often with the quinolones, beta-lactam-resistant penicillins, cefoxitin, and aminoglycosides. An IE occurs with the penicillins against the Enterobacteriaceae and Pseudomonas species, and a variable IE occurs with cephalosporins; however, no IE occurs with aminoglycosides, quinolones, imipenem, and chloramphenicol against these organisms. An IE occurs with beta-lactam antibiotics against Haemophilus influenzae and with the penicillins and the cephalosporins against penicillinase-producing Neisseria gonorrhoeae and Branhamella catarrhalis. An IE occurs with the penicillins and cephalosporins against the Bacteroides fragilis group; no IE occurs with cefoxitin and imipenem. Although certain antibiotics exhibit an IE, they are still capable of eradicating infections when administered appropriately. Thus, the clinical significance of this laboratory phenomenon has yet to be elucidated.     

Third generation cephalosporins

The third generation cephalosporins demonstrate greater potency, broader antibacterial spectrum, and more favorable pharmacologic characteristics than other cephalosporins. The majority of strains of E. coli, Klebsiella pneumoniae, and Proteus are susceptible, including strains resistant to aminoglycosides, anti-Pseudomonas penicillins, and other cephalosporins. Pseudomonas aeruginosa is susceptible to a subgroup of third generation agents including ceftazidime, cefoperazone, and the experimental agents cefpirome and cefpiramide. Penetration into the cerebrospinal fluid is excellent especially for cefotaxime, ceftazidime, ceftriaxone, and ceftizoxime. These agents are safe, sharing most of the known toxicities of other beta-lactam compounds. Their greatest use is in the therapy of difficult to treat gram-negative bacterial infections, including meningitis, nosocomial infections, and infections caused by Pseudomonas aeruginosa.     

Multiresistant nosocomial bacterial strains and their "in vitro" susceptibility to chloramphenicol and colistin

Objective: A multicenter study was conducted to obtain "in vitro" chloramphenicol and colistin susceptibility data on multiresistant hospital bacterial pathogens in Slovak Republic. Material and methods: During the period of April-June 2001, 628 clinical bacterial multiresistant isolates from patients with serious infections were selected in 10 hospitals and tested to a large scale of antibiotics by means of a microdilution method. The strains expressed either a significant resistance phenotype (ESBL, MRSA, CoNMRS, MLSB/c, efflux in Ps. aeruginosa), or were resistant to one or more preparations in at least half of reliable unrelated antibiotic groups (beta-lactams, aminoglycosides, quinolons, macrolides). Results: Both chloramphenicol and colistin retained significant "in vitro" activity against many multiresistant hospital bacterial pathogens. The highest activity of chloramphenicol was documented for isolates of Stenotrophomonas maltophilia (76,5 % susceptible, MIC50 = 4 mg/L, MIC90 = 16 mg/L) and of Staphylococcus aureus (76,2 % susceptible, MIC50 = 8 mg/L, MIC90 = 16 mg/L). In tested Pseudomonas aeruginosa (82,5 % susceptible, MIC50 = 2 mg/L, MIC90 = 16 mg/L) and Stenotrophomonas maltophilia (88,2 % susceptible, MIC50 = 1 mg/L, MIC90 = 8 mg/L) isolates colistin represented the most "in vitro" effective antibiotic. Colistin was the only "in vitro" effective antimicrobial in four of 120 multiresistant Pseudomonas aeruginosa isolates tested in our study. Conclusions: The study confirmed a good "in vitro" susceptibility of many multiresistant hospital bacterial pathogens to chloramphenicol and colistin in Slovak Republic. The clinical application of chloramphenicol and colistin might be reconsidered in infections caused by extremely resistant bacteria with prooved susceptibility to these antibiotics. It is important to consider, that the infection danger has to exceed the risk of antibiotic toxicity.     

Mechanism-independent method for predicting response to multidrug combinations in bacteria

Drugs are commonly used in combinations larger than two for treating bacterial infection. However, it is generally impossible to infer directly from the effects of individual drugs the net effect of a multidrug combination. Here we develop a mechanism-independent method for predicting the microbial growth response to combinations of more than two drugs. Performing experiments in both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria, we demonstrate that for a wide range of drugs, the bacterial responses to drug pairs are sufficient to infer the effects of larger drug combinations. To experimentally establish the broad applicability of the method, we use drug combinations comprising protein synthesis inhibitors (macrolides, aminoglycosides, tetracyclines, lincosamides, and chloramphenicol), DNA synthesis inhibitors (fluoroquinolones and quinolones), folic acid synthesis inhibitors (sulfonamides and diaminopyrimidines), cell wall synthesis inhibitors, polypeptide antibiotics, preservatives, and analgesics. Moreover, we show that the microbial responses to these drug combinations can be predicted using a simple formula that should be widely applicable in pharmacology. These findings offer a powerful, readily accessible method for the rational design of candidate therapies using combinations of more than two drugs. In addition, the accurate predictions of this framework raise the question of whether the multidrug response in bacteria obeys statistical, rather than chemical, laws for combinations larger than two.     

Chemotherapy of microbial diseases of the respiratory tract]

It is given a survey on the chemotherapy of the microbial diseases of the respiration tract. A chemotherapy is taken into consideration only for such cases in which a bacterial etiology is ascertained or is assumed with a great probability. The antimicrobial chemotherapy is of particular importance for the acute and chronic bronchitis, bronchiectases, pneumonias, pulmonary abscess and empyema of the pleura. The author deals with the special problems of bacteriological findings of the respiratory tract. The choice of the chemotherapeutic remedy is done in most cases according to the empirical points of view, in which cases development of resistance, side-effects and changing of the infection must be taken into consideration. Apart from the otherwise usual oral and parenteral application special forms of application, such as aerosol therapy and intrapleural instillation are used. It is referred to atypical pneumonias, such as the mycoplasma pneumonia which gives a good response to tetracyclines. Apart from the sulphonamides and trimethoprim penicillins, chloramphenicol, tetracyclines, cephalosporines, more rarely streptomycin and linkomycin are the most important antimicrobiotics.     

Gall-bladder perforation after long-term dapsone therapy

A 65-year-old man on maintenance dapsone therapy for dermatitis herpetiformis for 30 years was admitted to hospital with acute abdominal pain and vomiting. Investigations revealed a Heinz body haemolytic anaemia. Worsening symptoms prompted an emergency laparotomy that revealed a perforated gall bladder with pigmented biliary calculi. In previous reviews of the haematological abnormalities associated with dapsone therapy, life-threatening cholecystitis has not been described.     

In-vitro susceptibility of Mycobacterium avium complex to isoniazid and ethionamide

In this study, it was investigated whether or not Mycobacterium avium complex strains were inhibited by such low concentrations of isoniazid and ethionamide as possible in blood. The inhibitory concentrations were determined by the "Actual Count" method (Tsukamura, M.: Japan J. Tuberc. 12: 46-54, 1964), in which the inhibitory concentration was measured as a concentration that can inhibit the growth of 'countable' colony-forming units. The ratio of strains which were inhibited by such low concentrations as 0.2 microgram/ml isoniazid or 5 micrograms/ml ethionamide was 14%. The result suggests that there are some strains in which isoniazid or ethionamide are clinically effective, though their prevalence was low (14%).