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PubMed1998

Transdermal absorption of clindamycin and tretinoin from topically applied anti-acne formulations in man.

The percutaneous absorption of clindamycin was studied in healthy male volunteers, comparing two investigative clindamycin (% w/v)/tretinoin (0.025% w/v) gels, containing clindamycin phosphate ester and clindamycin HCl, respectively, relative to a clindamycin phosphate lotion (1% clindamycin; Dalacin T). Formulations were applied daily for 5 days on the face, according to a balanced complete block design. Redness of the skin was scored visually, and blood and urine were collected. Clindamycin plasma levels did not exceed the limit of quantification (5 ng mL(-1)) with the clindamycin phosphate formulations, but one volunteer who received the clindamycin HCl/tretinoin gel showed plasma levels of up to 13 ng mL(-1). Clindamycin urinary excretion for 12 h after application of the clindamycin phosphate/tretinoin gel was comparable to the values of the reference lotion, whereas the clindamycin HCl/tretinoin gel gave significantly higher values. Erythema appeared to be associated with increased urinary excretion. The formulations were tolerated well. In a separate clinical pilot study in acne patients, the transdermal uptake of tretinoin and clindamycin from the clindamycin phosphate/tretinoin gel was monitored. Plasma samples were collected after 4 and 12 weeks of daily treatment. None of the study plasma samples contained measurable tretinoin levels. Clindamycin levels were not quantifiable in the majority (87%) of samples, the highest plasma level was 11 ng mL(-1). The chemical form of clindamycin proved to modulate skin irritation and percutaneous uptake of clindamycin from a gel formulation in healthy subjects. There was no indications for a notable transdermal uptake of tretinoin during daily application of the gel in patients, nor for an enhancing effect of tretinoin on clindamycin uptake.

Acne Vulgaris↗
PubMed2003

In vitro metabolism of clindamycin in human liver and intestinal microsomes.

Incubations with human liver and gut microsomes revealed that the antibiotic, clindamycin, is primarily oxidized to form clindamycin sulfoxide. In this report, evidence is presented that the S-oxidation of clindamycin is primarily mediated by CYP3A. This conclusion is based upon several lines of in vitro evidence, including the following. 1) Incubations with clindamycin in hepatic microsomes from a panel of human donors showed that clindamycin sulfoxide formation correlated with CYP3A-catalyzed testosterone 6beta-hydroxylase activity; 2) coincubation with ketaconazole, a CYP3A4-specific inhibitor, markedly inhibited clindamycin S-oxidase activity; and 3) when clindamycin was incubated across a battery of recombinant heterologously expressed human cytochrome P450 (P450) enzymes, CYP3A4 possessed the highest clindamycin S-oxidase activity. A potential role for flavin-containing monooxygenases (FMOs) in clindamycin S-oxidation in human liver was also evaluated. Formation of clindamycin sulfoxide in human liver microsomes was unaffected either by heat pretreatment or by chemical inhibition (e.g., methimazole). Furthermore, incubations with recombinant FMO isoforms revealed no detectable activity toward the formation of clindamycin sulfoxide. Beyond identifying the drug-metabolizing enzyme responsible for clindamycin S-oxidation, the ability of clindamycin to inhibit six human P450 enzymes was also evaluated. Of the P450 enzymes examined, only the activity of CYP3A4 was inhibited (approximately 26%) by coincubation with clindamycin (100 microM). Thus, it is concluded that CYP3A4 appears to account for the largest proportion of the observed P450 catalytic clindamycin S-oxidase activity in vitro, and this activity may be extrapolated to the in vivo condition.

Clindamycin↗
PubMed1988

Effects of clindamycin and metronidazole on the intestinal colonization and translocation of enterococci in mice.

The intestinal colonization and translocation of enterococci was studied in mice treated intramuscularly with metronidazole or clindamycin, with or without oral streptomycin. Treatment with metronidazole resulted in selective elimination of strictly anaerobic cecal bacteria, with a 100-fold increase in the numbers of aerobic and facultative gram-negative bacilli and a 10,000-fold increase in the numbers of aerobic and facultative gram-positive species. Clindamycin had a similar effect on the cecal flora except that the numbers of aerobic and facultative gram-positive bacteria decreased at least 10-fold. The predominating gram-positive species in the cecal flora or metronidazole-treated mice was an enterococcus, but this organism could not be recovered from the ceca of clindamycin-treated mice. Translocating bacteria (primarily gram-negative enteric bacteria) were recovered from the mesenteric lymph nodes of the majority of mice given metronidazole or clindamycin. Gram-positive bacteria were not recovered from the mesenteric lymph nodes of 20 clindamycin-treated mice, whereas 26% of 19 metronidazole-treated mice had translocating enterococci. With addition of streptomycin to the metronidazole and clindamycin regimens, mice treated with metronidazole-streptomycin became colonized predominantly with an enterococcus, and this was the only translocating species recovered from 13% of 23 mice; however, enterococci could not be detected in the ceca of clindamycin-streptomycin-treated mice, and Bacillus spp. were recovered from the mesenteric lymph nodes of 8% of 24 mice, reflecting the composition of the cecal flora. The apparent elimination of enterococci from the ceca of clindamycin and clindamycin-streptomycin-treated mice was inconsistent with the observation that the average (n=6) peak levels of clindamycin in blood and ceca were 25 and 21 microgram/ml, respectively, whereas the in vitro MIC was 128 microgram/ml. However, this apparent in vivo activity of clindamycin against enterococci was not evident in mice given 10(9) oral enterococci; the concentrations of cecal enterococci in both clindamycin-streptomycin- and metronidazole-streptomycin-treated mice were 10(10) to 10(11) enterococci per g, with translocating enterococci recovered from approximately half of these antibiotic-treated mice. Thus antibiotic therapy with metronidazole, clindamycin, metronidazole-streptomycin, and clindamycin-streptomycin resulted in a wide variation in the cecal population levels and translocation frequencies of enterococci. This variation appeared to be related to the discrepancy between the in vivo and in vitro activities of clindamycin against enterococci.

Animals↗
PubMed1993

Effect of clindamycin on intracellular replication, protein synthesis, and infectivity of Toxoplasma gondii.

We studied the effects of clindamycin and a combination of clindamycin and pyrimethamine on the proliferation of Toxoplasma gondii in cultured mammalian cells and the effect of clindamycin on the parasite's RNA and protein syntheses. Infected macrophages were treated for 48 h with clindamycin or a combination of clindamycin and pyrimethamine, and the 50% inhibitory concentrations for parasite growth were 32.50 +/- 1.30 and 10.78 +/- 0.56 micrograms/ml, respectively. A modified susceptibility assay was also used to measure the effect of low concentrations of clindamycin on T. gondii. Macrophages and bovine turbinate cells were infected with low numbers of tachyzoites and were exposed to low concentrations of clindamycin for 5 days. In these systems, a concentration of 10 ng of clindamycin per ml inhibited 50% of the growth of the parasite in macrophages, while it completely prohibited the growth of the parasite in epithelial cells. When free tachyzoites were preexposed to clindamycin for 4 h, the reduction of parasite infectivity was proportional to the amount of drug; 100 ng of clindamycin per ml reduced the infectivity of T. gondii to 46.5% +/- 8.5% of that of the untreated control. A concentration of 40 micrograms of clindamycin per ml reduced protein synthesis by 56.2% +/- 6.0% but had no effect on RNA synthesis after a 4-h exposure of free tachyzoites of T. gondii to the drug. Our results show that long-term exposure to low concentrations of clindamycin reduces the level of replication of T. gondii, that clindamycin affects the protein synthesis of free parasites, and that clindamycin impairs the ability of tachyzoites to infect host cells.

Animals↗
PubMed1996

Clindamycin therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant Streptococcus pneumoniae.

Although penicillin resistance among Streptococcus pneumoniae strains is increasing in many areas, resistance to clindamycin remains low. In our well-characterized rabbit meningitis model, we conducted experiments to evaluate the bacteriologic efficacy of clindamycin after a penicillin- and cephalosporin-resistant S. pneumoniae strain was intracisternally inoculated. Animals received a loading intravenous dose of 30 mg of clindamycin per kg of body weight and then two doses of 20 mg/kg given 5 h apart. In addition to clindamycin, some animals received dexamethasone (DXM) with or without ceftriaxone. The concentrations of clindamycin in cerebrospinal fluid were from 8.9 to 12.8% of the concomitant concentrations in serum and were unaffected by DXM administration. Mean changes in CFU (log10 per milliliter) at 10 and 24 h were -3.7 and -6.1, respectively, for clindamycin-treated rabbits, -3.6 and -6.3 for clindamycin-DXM-treated rabbits, -3.9 and -5.8, respectively, for clindamycin-ceftriaxone-treated rabbits, and -5.0 and -6.7, respectively, for clindamycin-ceftriaxone-DXM-treated rabbits. By 24 h all but one of the cultures of cerebrospinal fluid (that from a clindamycin-DXM-treated rabbit) were sterile. Because of the potential risk for clindamycin-treated rabbits to develop macrolide-lincosamide resistance, we attempted, unsuccessfully, to induce clindamycin resistance in vitro in two S. pneumoniae strains. Although clindamycin therapy might be effective in selected patients with multiple-drug-resistant pneumococcal meningitis who have failed conventional treatments, clinical experience is necessary before it can be recommended.

Animals↗
PubMed1991

Adjunctive clindamycin therapy for preterm labor: results of a double-blind, placebo-controlled trial.

A double-blind, placebo-controlled, randomized trial was conducted to evaluate the efficacy, safety, and tolerance of a course of clindamycin (administered for 3 days intravenously and 4 days orally) among hospitalized women with preterm labor at less than or equal to 34 weeks' gestation who were treated with tocolytics. One hundred three woman-perinate pairs were analyzed. Univariate analysis demonstrated that pregnancies were continued longer in women treated with clindamycin than in women who received placebo (clindamycin-treated group, 35 days; placebo-treated group, 25 days; p = 0.02). Survival analysis showed that pregnancy continued at least 35.5 days in 50% of clindamycin-treated women versus 20 days for control women (p = 0.03). Obstetric and microbiologic parameters associated with treatment outcomes were also sought. Women with bacterial vaginosis more often delivered preterm (p = 0.03; relative risk, 1.4; 95% confidence interval, 1.04 to 2.0). Among women with bacterial vaginosis, trends for increased duration of pregnancy (clindamycin-treated group, 36 days; placebo-treated group, 19 days), increased birth weight (clindamycin-treated group, 2634 gm; placebo-treated group, 2256 gm), and increased mean gestational age at delivery (clindamycin-treated group, 35 weeks; placebo-treated group, 34 weeks) were associated with clindamycin treatment. Women with either group B streptococcus, Chlamydia trachomatis, Trichomonas vaginalis, or Staphylococcus aureus were more likely to have preterm premature rupture of membranes (p = 0.01). Clindamycin treatment of these women reduced the incidence of preterm premature rupture of membranes to that of uninfected subjects. Stratification by gestational age at enrollment showed clindamycin treatment to be associated with an increased interval to delivery only among mothers enrolled before 33 weeks' gestation (clindamycin-treated group, 40 days; placebo-treated group, 28 days; p less than 0.05). Treatment with clindamycin appeared safe and well tolerated, with benefits limited to women who were less than or equal to 32 weeks' gestation.

Chemotherapy, Adjuvant↗
PubMed1986

Stability of clindamycin phosphate with aztreonam, ceftazidime sodium, ceftriaxone sodium, or piperacillin sodium in two intravenous solutions.

In admixtures containing clindamycin and either aztreonam, ceftazidime, ceftriaxone, or piperacillin in either 5% dextrose injection (D5W) or 0.9% sodium chloride injection (NS), the stability of each drug was studied. Each of the following combinations of drugs was added to 100-mL glass bottles of base solution: clindamycin phosphate 0.9 g and aztreonam 2.0 g, clindamycin phosphate 0.9 g and ceftazidime sodium 2.0 g, clindamycin phosphate 1.2 g and ceftriaxone sodium 2.0 g, and clindamycin phosphate 0.9 g and piperacillin sodium 4.0 g. Duplicate samples were prepared. Admixtures containing each single drug were also tested. Samples were visually inspected and tested for pH and drug concentration immediately after mixing and at 1, 4, 8, 12, 24, and 48 hours of storage in room temperature and light. Drug concentrations were determined by high-performance liquid chromatographic assay methods. Ceftriaxone retained greater than 90% of its original concentration for 24 hours in single-drug admixtures in NS, for eight hours with clindamycin in NS, and for one hour with clindamycin in D5W. Ceftazidime retained greater than 90% potency for 24 hours with clindamycin in D5W. In all other test admixtures, all drugs were stable for 48 hours. Under the conditions studied, clindamycin is compatible in the admixtures tested with aztreonam and piperacillin. Admixtures of clindamycin and ceftazidime in D5W should be used within 24 hours at room temperature. Clindamycin and ceftriaxone can be mixed in NS if administered within eight hours, but ceftriaxone is stable for only one hour in combination with clindamycin in D5W.

Aztreonam↗
PubMed1975

Microbial kinetics of drug action against gram-positive and gram-negative organisms. II: Effect of clindamycin on Staphylococcus aureus and Escherichia coli.

Clindamycin-affected Staphylococcus aureus cultures show biphasic steady-state generation curves. An initial (phase I) generation of the clindamycin-affected Staph. aureus is followed by an ultimate (phase II) generation at the same dose level. The phase I apparent generation rate constant is greater than the phase II apparent generation rate constant and suggests the development of resistant Staph. aureus mutants to clindamycin action after a finite period of drug-bacteria contact at any subcompletely inhibitory concentration level. It is rationalized that the increased resistance to drug action in mutant strains is due to a comparatively reduced ribosomal binding affinity for clindamycin. In contrast, clindamycin-affected Escherichia coli cultures show monophasic steady-state generation curves at all concentration levels; E. coli cultures do not develop resistance to clindamycin action. The dependence of the apparent generation rate constant on drug concentration yields a sigmoidal curve, which is coincident by a potency factor for the phase I and phase II generations of clindamycin-affected Staph. aureus and suggests a common mechanism of action for both generation phases. That of clindamycin-affected E. coli yields an asymptote curve, which indicates a different mechanism of action. Clindamycin possesses both a bacteriostatic and a bactericidal action on initial and mutant resistant strains of Staph. aureus, whereas its action on E. coli is only bacteriostatic. Consequently, clindamycin has a minimum inhibitory concentration (MIC) against E. coli that is about 1000 times the MIC value against Staph. aureus at 37.5 degrees. The effect of pH changes in broth media on generation inhibition of both Staph. aureus and E. coli by clindamycin action indicates that the unprotonated fraction of drug concentration contributes to the activity, possibly because of its ready penetration through cell membranes.

Clindamycin↗
PubMed1987

Interactions of clindamycin with antibacterial defenses of the lung.

Clindamycin is speculated to have select advantages in the treatment of certain infections because biologically active antibiotic is internalized by macrophages and PMNs in vitro. By challenging pulmonary host defenses with various bacterial species as probes, we were able to evaluate clindamycin-phagocyte interaction in vivo. A murine model was developed using an implanted mini-osmotic pump to maintain constant clindamycin blood levels at 1/4 MIC (1 microgram/ml). Mice pretreated for 24 h with clindamycin killed a significantly greater percentage of intratracheally inoculated Bacteroides thetaiotaomicron in 4 h than did control animals (37 +/- 2% versus 7 +/- 5%). The enhancing effects of clindamycin on pulmonary defenses could not be duplicated by a 1-h preincubation of B. theta in 1/4 MIC of clindamycin before inoculation into untreated mice. Clindamycin blood levels of 1 microgram/ml did not alter the rate at which Pseudomonas aeruginosa (clindamycin-resistant) was killed by pulmonary defenses, suggesting that clindamycin did not cause nonspecific activation of phagocytic defenses. Both PMNs and alveolar macrophages lavaged from the lungs of clindamycin-treated mice contained bioassayable concentrated intracellular antibiotic. The presence of intracellular antibiotic was further supported by experiments in which the intrapulmonary killing of large numbers of Staphylococcus aureus (sensitive, but not resistant organisms) was significantly enhanced (89 +/- 5 versus 70 +/- 5%) by clindamycin pretreatment. In contrast, phagocytes lavaged from mice with constant 1/4 MIC (4 micrograms/ml) blood levels of penicillin G had no detectable intracellular antibiotic activity and did not augment the intrapulmonary killing of B. theta.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗