Tetracyclines, chloramphenicol, erythromycin, clindamycin, and metronidazole.

The tetracyclines are effective in the treatment of Chlamydia, Mycoplasma pneumoniae, and rickettsial infections and also can be used for gonococcal infections in patients unable to tolerate penicillin. These drugs may cause gastrointestinal irritation, diarrhea, phototoxic dermatitis, and vestibular damage, and fatal reactions due to hepatotoxicity have occurred in pregnant women. Chloramphenicol has a broad spectrum of bacteriostatic activity, but its association with suppression of the bone marrow and aplastic anemia has relegated it to a historical role. Erythromycin is the drug of choice for the treatment of infections caused by M. pneumoniae, Legionella species, group A beta-hemolytic streptococci, and Streptococcus pneumoniae. The frequency of serious adverse effects associated with the use of erythromycin is low; dose-related epigastric distress may occur. Clindamycin is bactericidal to most nonenterococcal gram-positive aerobic bacteria and many anaerobic microorganisms. Although historically it was a frequent cause of antibiotic-associated diarrhea and colitis, clindamycin is considered an excellent alternative to beta-lactam antibiotics for treatment of many staphylococcal infections, and it has therapeutic utility in anaerobic infections and in several protozoan infections in immunosuppressed patients. Metronidazole is efficacious for treating nonpulmonary anaerobic infections, various parasitic infections (trichomoniasis, amebiasis, and giardiasis), nonspecific vaginitis, and Clostridium difficile-mediated colitis. With use of metronidazole, mild side effects such as epigastric discomfort, diarrhea, reversible neutropenia, and allergic-type cutaneous reactions may occur.     

Comparative penetration of metronidazole, clindamycin, chloramphenicol, cefoxitin, ticarcillin, and moxalactam into bone.

The concentrations of metronidazole, clindamycin, chloramphenicol, cefoxitin, ticarcillin, and moxalactam in the serum, femurs, and scapulae of normal rats were measured microbiologically 0.5, 1, 1, and 4 h after intravenous injection of 15-, 15-, 20-, 40-, 75-, and 30-mg/kg doses of the respective drugs. By 0.5 h metronidazole reached levels of 3.0 micrograms/g in compact femoral bone and 2.7 micrograms/g in cancellous scapular bone. Clindamycin and chloramphenicol reached levels of 8.1 and 6.1 micrograms/g, respectively, at 0.5 h. Cefoxitin penetrated bone to a level of 2.6 micrograms/g, whereas ticarcillin and moxalactam failed to reach significant levels in bone after single intravenous doses.     

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.     

Influence of metronidazole, chloramphenicol, clindamycin and penicillin G on growth and neuraminidase activity of Bacteroides fragilis

The effects of subinhibitory concentrations of metronidazole, chloramphenicol, clindamycin and penicillin G on cell growth and neuraminidase activity of Bacteroides fragilis were tested in six strains from clinical specimens and two type collection strains. All showed significant inhibition of cell growth at one half the MIC after 24 h incubation. Metronidazole at one quarter the MIC was significantly inhibitory after 24 and 48 h incubation. The neuraminidase activity remained unaltered, in comparison with controls, when metronidazole and clindamycin were tested. Chloramphenicol reduced the enzyme activity at both one half and one quarter the MIC. On the other hand, penicillin G enhanced the neuraminidase activity, although the difference was not statistically significant. These in-vitro effects may simulate the behaviour of the bacteria in abscesses in vivo.     

Clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis: a prospective double-blind clinical trial.

Bacterial vaginosis is common among patients seen by gynecologists. Several types of therapy have been proposed. The purpose of this prospective, randomized, double-blind clinical trial was to examine the efficacy of clindamycin vaginal cream for the treatment of bacterial vaginosis. Sixty patients with symptoms of bacterial vaginosis were randomized into the study, and 46 completed the protocol. Twenty-three patients received 2% clindamycin vaginal cream (5 g applied intravaginally at bedtime for 7 days), with placebo oral tablets twice daily for 7 days. The other 23 patients received oral metronidazole tablets (500 mg twice a day for 7 days) and placebo vaginal cream (5 g intravaginally for 7 days). The cure rates for the two regimens were comparable. Twenty-two (97%) of the patients treated with clindamycin vaginal cream had improvement or cure at the first follow-up visit versus 19 (83%) of those taking metronidazole. There was no statistically significant difference between the two results. Side effects for both regimens were comparable. We conclude that 2% clindamycin vaginal cream offers similar efficacy and safety to standard oral metronidazole therapy for bacterial vaginosis.     

Synergistic effects between amoxicillin, metronidazole, and the hydroxymetabolite of metronidazole against Actinobacillus actinomycetemcomitans.

Interactions between metronidazole and amoxicillin, metronidazole and its hydroxymetabolite, and amoxicillin and the hydroxymetabolite of metronidazole were investigated with checkerboard titrations in combination with accurately determined MICs and MBCs. Actinobacillus actinomycetemcomitans was used as the test organism. Synergism was found for all three combinations. Fractional inhibitory concentration indices and fractional bactericidal concentration indices varied from 0.3 to 0.7. These synergistic interactions between these antibiotics may explain the efficacy of the combination of metronidazole and amoxicillin in various bacterial infections, including periodontal disease.     

Clindamycin

Clindamycin is an excellent, well tolerated, effective antimicrobial agent that can be used clinically in the treatment of specific anaerobic infections as well as clinical situations when both S. aureus and anaerobes occur together.     

Tetracyclines, chloramphenicol, erythromycin, and clindamycin

The tetracyclines are effective in the treatment of Chlamydia, Mycoplasma pneumoniae, and rickettsial infections and may also be used for gonococcal infections in patients unable to tolerate penicillins. These drugs may cause gastrointestinal irritation, photo-toxic dermatitis, diarrhea, vestibular damage, and hepatotoxicity in pregnant women. Chloramphenicol is used primarily for anaerobic infections, Haemophilus influenzae meningitis, and typhoid fever. The most important toxic effect of chloramphenicol is bone marrow suppression, which can be dose related or idiosyncratic. Erythromycin is the drug of choice for the treatment of infections caused by M. pneumoniae, Legionella species, group A beta-hemolytic streptococci, and Streptococcus pneumoniae. The frequency of serious untoward effects associated with the use of erythromycin is low; epigastric distress may occur. Clindamycin is active against Bacteroides fragilis and other anaerobic microorganisms. Pseudomembranous enterocolitis has developed in as many as 10% of patients taking this drug. The use of clindamycin should be discontinued promptly if diarrhea occurs.     

Metabolism and metronidazole uptake in Trichomonas vaginalis isolates with different metronidazole susceptibilities.

Three Trichomonas vaginalis isolates with low in vivo susceptibilities to metronidazole (95% curative dose, greater than 3 X 100 mg kg-1 in subcutaneous infections in mice) were compared with strain ATCC 30001 and with four isolates exhibiting high in vivo susceptibilities (95% curative dose, less than 3 X 15 mg kg-1). Activity of pyruvate:ferredoxin oxidoreductase, anaerobic fermentation, and anaerobic intracellular accumulation of [14C]metronidazole label showed no significant isolate-dependent differences which could be correlated with drug susceptibility. The results suggest that processes providing electrons for metronidazole activation are not defective in the resistant strains. Aerobiosis, known to inhibit the antimicrobial action of metronidazole, inhibited accumulation of label more strongly in resistant isolates than in susceptible ones. No differences were detected, however, between resistant and susceptible isolates in respiration, aerobic fermentation, and the specific activity of NADH and NADPH oxidases, the main terminal oxidases of T. vaginalis. These findings suggest that the production of electrons is not diminished under aerobic conditions. The inhibitory effect of aerobic conditions on metronidazole activation, possibly due to competition for the electrons, is markedly enhanced in the resistant isolates compared to the susceptible ones. The mechanism of this effect, however, remains unknown.     

A Double-Blind, Randomized Comparison of Aztreonam Plus Clindamycin with Tobramycin Plus Clindamycin in Abdominal Infections

Seventy patients with intraabdominal infections were randomly assigned in double-blinded fashion to receive either the combination of tobramycin plus clindamycin (TM/C) or aztreonam plus clindamycin (AZ/C). Thirty-four patients received AZ/C and 36 were given TM/C. Average ages were 62 years (TM/C) and 66 years (AZ/C). In approximately one-half of both groups, the source of infection was perforated colon or perforated appendix. There were no significant differences in demographic factors between these groups, although those given AZ/C had a more serious long-term prognosis due to underlying diseases. The average lengths of treatment were 10 days (TM/C) and 9 days (AZ/C). Clinical response to therapy did not differ, as 84% of the TM/C patients and 78% of the AZ/C patients had satisfactory clinical responses. The two regimens differed in adverse effects, as an elevated PT/PTT was more frequently (p < 0.05) observed in AZ/C. All PT/PTT elevations responded to injections of vitamin K, and no serious bleeding occurred. Choice between these regimens depends on differences in cost and the risk of adverse effects, as both regimens appear equally effective for treatment of abdominal infections in conjunction with appropriate surgical intervention.     

Clindamycin, A New Antibiotic in Otolaryngological Infections

Clindamycin, a new semi-synthetic derivative of lincomycin was evaluated in the treatment of otorhinolaryngological infections in 65 patients. Excellent or good clinical and bacteriological response was seen in all cases. Liver function and hematological examinations were unaffected by the antibiotic. Side effects were seen in three patients who developed mild diarrhea not necessitating discontinuation of therapy.     

Hemodialysis clearance of metronidazole and its metabolites.

Metronidazole is now being used with increasing frequency for various infectious conditions in patients with renal failure. It is commonly administered to septic patients who have developed acute renal failure requiring hemodialysis. The hemodialysis clearances of metronidazole and its metabolites were evaluated in nine renal failure patients on maintenance hemodialysis. The mean +/- standard deviation clearance and the extraction ratio were 106.9 +/- 16.3 ml/min and 0.65 +/- 0.08, respectively, when regenerated cellulose dialysis membrane was used. The clearance and the extraction ratio with the use of cuprophan membrane were 72.1 +/- 17.3 ml/min and 0.44 +/- 0.12, respectively. The clearances and extraction ratios for the metabolites were similar to those of the parent drug. For both metronidazole and the hydroxy metabolite, the clearance and the extraction ratio demonstrated a statistically significant difference between the regenerated cellulose membrane and the cuprophan membrane. In summary, metronidazole and its metabolites were found to be highly dialyzable with different clearances depending on the specific type of membrane used. However, owing to the relatively wide therapeutic index of the drug, dosage supplementation may be necessary only in seriously ill patients to ensure therapeutic effect.     

Comparative effects of omeprazole, amoxycillin plus metronidazole versus omeprazole, clarithromycin plus metronidazole on the oral, gastric and intestinal microflora in Helicobacter pylori-infected patients.

Fourteen patients with Helicobacter pylori infection were treated with 20 mg omeprazole, 1 g amoxycillin and 400 mg metronidazole bd for 7 days (OAM), and 16 patients were treated with 20 mg omeprazole, 250 mg clarithromycin and 400 mg metronidazole bd for 7 days (OCM). Saliva, gastric biopsies and faecal samples were collected before, during (day 7) and 4 weeks after treatment in order to analyse alterations of the normal microflora and to determine antimicrobial susceptibility. Both treatment regimens resulted in marked quantitative and qualitative alterations. A selection of resistant streptococcal strains were noticed in both treatment groups, most apparent in the OCM group where a shift from susceptible to resistant strains was recorded. In the OAM group, six patients had overgrowth of resistant enterobacteriaceae during treatment compared with none in the OCM group, in the gastric microflora. The MICs for Enterococcus spp. and Enterobacteriaceae in faeces increased significantly during treatment in both groups. Nine patients in the OAM group became intestinally colonized by yeasts during treatment. The total anaerobic microflora was strongly suppressed in both treatment groups, although most pronounced in the OCM group, where the frequency of clarithromycin-resistant bacteroides strains increased from 2 to 76% during treatment, and remained at 59% 4 weeks post-treatment. Even if the treatment outcome was better in the OCM group (100%) than in the OAM group (71%), the amoxycillin-based treatment might be preferable from an ecological point of view, since the qualitative alterations in terms of emergence and persistence of resistant strains seemed to be most pronounced in the clarithromycin-treated group.     

Comparison of Clindamycin, Erythromycin, and Methicillin in Streptococcal Infections in Monkeys

Intravenous inoculation of a group A hemolytic streptococcus caused lethal infections in all of eight untreated monkeys. Intramuscular injections of clindamycin-2-phosphate in a daily dose of 25 mg/kg given in equal morning and afternoon doses for 10 days resulted in survival of all of eight monkeys. Similar results were observed with the same dose schedule of clindamycin hydrochloride given intragastrically; no fatalities occurred among eight monkeys. In monkeys receiving erythromycin stearate intragastrically or methicillin intramuscularly, three of eight and four of eight monkeys, respectively, died. Duration of both illness and positive blood cultures was greater in the erythromycin- and methicillin-treated survivors than in the clindamycin-treated monkeys. The differences in results between clindamycin and erythromycin could not be correlated with serum antibacterial activity levels, which were similar, or with minimal inhibitory concentrations, which were 0.02 mug/ml with both antibiotics. With methicillin, however, the minimal inhibitory concentration was 0.16 mug/ml and serum antibacterial activity varied from titers of less than 1:2 to 1:8. As in previous studies of staphylococcal infections in monkeys with the same antibiotics, in vitro susceptibility data and serum antibacterial activity did not completely correlate with in vivo results.     

Clindamycin in a murine model of toxoplasmic encephalitis.

We investigated the efficacy of clindamycin in a murine model of toxoplasmic encephalitis using direct intracerebral inoculation. Clindamycin reduced mortality from 40% in normal mice and 100% in cortisone-treated mice to 0% in both groups. Although we were unable to document appreciable levels of clindamycin in the brains of infected mice, the histological features of cerebral infection were markedly altered. The formation of large numbers of cysts and the intense inflammatory response seen in the brains of normal mice and the unchecked infection and tissue necrosis in the brains of cortisone-treated mice were absent in the brains of clindamycin-treated mice. Enumeration of cysts in the brains of mice 10 weeks after infection revealed a significantly lower number in the clindamycin-treated mice. Spread of infection to other organs was also decreased during clindamycin administration. These observations suggest that clindamycin may have a role in the therapy of toxoplasmic encephalitis.     

Virulence of Entamoeba histolytica trophozoites. Effects of bacteria, microaerobic conditions, and metronidazole

The association of axenically grown trophozoites of Entamoeba histolytica strains HK-9 or HM-1:IMSS with various types of gram-negative bacteria for relatively short periods markedly increased their virulence, as evidenced by their ability to destroy monolayers of tissue-cultured cells. Interaction of trophozoites with bacteria that were heat inactivated, glutaraldehyde fixed, or disrupted by sonication, or bacteria treated with inhibitors of protein synthesis, did not augment amebic virulence. Lethally irradiated bacteria, however, retained their stimulative properties and trophozoites that ingested bacteria were protected from the toxic effects of added hydrogen peroxide. An increase in virulent properties of amebae was also found in experiments carried out under microaerobic conditions (5% O2, 10% CO2). The augmentation of amebic virulence due to association with bacteria was specifically blocked by metronidazole, but not by tetracycline or aminoglycosides, and the rate of metronidazole uptake in stimulated trophozoites was two to three times higher. The results obtained suggest that virulence of axenically grown E. histolytica trophozoites may depend to a considerable extent on the cell's reducing power. Both microaerobic conditions and the association with bacteria apparently stimulate the electron transport system of the ameba. Bacteria may function as broad range scavengers for oxidized molecules and metabolites through the contribution of enzymatic systems, components, or products.