Treatment of acute toxoplasmosis with intravenous clindamycin

Dannemann, Brian; McCutchan, J. A.; Israelski, Dennis; Antoniskis, Diana; Leport, Catherine; Luft, Benjamin J.; Chiu, John T.; Vildé, J. L.; Nussbaum, Joseph; Orellana, Manuel; Heseltine, Peter N. R.; Leedom, John M.; Clumeck, Nathan; Morlat, P.; Remington, Jack S.

doi:10.1007/bf01964461

Cited by 21 publications

(18 citation statements)

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Section: Introductionmentioning

confidence: 99%

“…The lincosamide antibiotics seem to be most useful against the bacteria classified as Gram-positive cocci. In addition, clindamycin is helpful against protozoans such as Toxoplasma and Mycoplasma as well as many anaerobic bacteria (Luft and Remington, 1988;Dannemann et al, 1991;Mazur et al, 1999).In humans, absorption of clindamycin is rapid and virtually complete (90%) following oral administration (DeHaan et al, 1972;Metzler et al, 1973). Concentrations of clindamycin in the serum increase linearly with increased dose, and levels exceed the minimum inhibitory concentration for most indicated organisms for at least 6 h following administration of the recommended dose.…”

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In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

Wynalda¹,

Hutzler²,

Koets³

et al. 2003

Drug Metab Dispos

102

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This article is available online at http://dmd.aspetjournals.org ABSTRACT: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 Soxidation 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 6␤-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 (ϳ26%) by coincubation with clindamycin (100 M). 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 (methyl 7-chloro-6,7,8-trideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-1-threo-D-galacto-octopyranoside monohydrochloride) is an antibiotic of the "lincosamide" class (Brodasky et al., 1968). The lincosamide antibiotics seem to be most useful against the bacteria classified as Gram-positive cocci. In addition, clindamycin is helpful against protozoans such as Toxoplasma and Mycoplasma as well as many anaerobic bacteria (Luft and Remington, 1988;Dannemann et al., 1991;Mazur et al., 1999).In humans, absorption of clindamycin is rapid and virtually complete (90%) following oral administration (DeHaan et al., 1972;Metzler et al., 1973). Concentrations of clindamycin in the serum increase linearly with increased dose, and levels exceed the minimum inhibitory concentration for most indicated organisms for at least 6 h following administration of the recommended dose. Clindamycin is widely distributed throughout the body and has an average biological half-life of 2.4 h. The major bioactive metabolites excreted in urine and feces are clindamycin sulfoxide and N-desmethylclindamycin (Seaberg et al., 1984;Flaherty et al., 1988;Gatti et al., 1998).To date, there are no published reports tha...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

Wynalda¹,

Hutzler²,

Koets³

et al. 2003

Drug Metab Dispos

102

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“…Clindamycin (a lincosamide) and several macrolide antibiotics have proven effective for the treatment of AIDS-toxoplasmosis, usually in combination with pyrimethamine (6,13,15). These compounds are known to block protein synthesis in bacteria by interacting with the peptidyl transferase domain of 23S rRNA (5), but their target in T. gondii and related parasites remains unclear (1).…”

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In vitro assays elucidate peculiar kinetics of clindamycin action against Toxoplasma gondii

Fichera

Bhopale

Roos

1995

Antimicrob Agents Chemother

181

129

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In order to characterize the delayed effect of clindamycin and macrolide antibiotics against Toxoplasma gondii tachyzoites (E. R. Pfefferkorn and S. E. Borotz, Antimicrob. Agents Chemother. 38:31-37, 1994), we have carefully examined the replication of parasites as a function of time after drug addition. Intracellular tachyzoites treated with up to 20 M clindamycin (>1,000 times the 50% inhibitory concentration) exhibit doubling times indistinguishable from those of controls (ϳ7 h). Drug-treated parasites emerge from infected cells and establish parasitophorous vacuoles inside new host cells as efficiently as untreated controls, but replication within the second vacuole is dramatically slowed. Growth inhibition in the second vacuole does not require continued presence of drug, but it is dependent solely on the concentration and duration of drug treatment in the first (previous) vacuole. The susceptibility of intracellular parasites to nanomolar concentrations of clindamycin contrasts with that of extracellular tachyzoites, which are completely resistant to treatment, even through several cycles of subsequent intracellular replication. This peculiar phenotype, in which drug effects are observed only in the second infectious cycle, also characterizes azithromycin and chloramphenicol treatment, but not treatment with cycloheximide, tetracycline, or anisomycin. These findings provide new insights into the mode of clindamycin and macrolide action against T. gondii, although the relevant target for their action remains unknown.The protozoan parasite Toxoplasma gondii is a ubiquitous human pathogen long recognized as a source of congenital neurological abnormalities (19). In recent years, this parasite has also acquired considerable notoriety as an opportunistic infection associated with AIDS (16). The ability of T. gondii parasites to persist as latent cysts in the tissues of infected patients mandates chronic treatment for infected AIDS patients, to guard against recrudescence. Unfortunately, the traditional therapeutic regimen of pyrimethamine plus sulfonamides (18) is not always suitable for prolonged treatment, because of the emergence of sulfa hypersensitivity and other adverse side effects (12,14,27).Clindamycin (a lincosamide) and several macrolide antibiotics have proven effective for the treatment of AIDS-toxoplasmosis, usually in combination with pyrimethamine (6, 13, 15). These compounds are known to block protein synthesis in bacteria by interacting with the peptidyl transferase domain of 23S rRNA (5), but their target in T. gondii and related parasites remains unclear (1). Early difficulties in establishing a functional in vitro system to study clindamycin and macrolide action against T. gondii (4, 9, 17) can now be explained by the long lag period between drug administration and effect (20,21). Nanomolar drug concentrations block parasite replication, but only 2 to 3 days after treatment-a remarkable delay, considering that the tachyzoite undergoes ϳ8 generations in this time.In order to more precisely e...

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“…The most effective therapy is the combination of pyrimethamine and sulfadiazine (6). Reports of successful treatment of cerebral toxoplasmosis with clindamycin-pyrimethamine (21) have prompted comparative trials, which are under way (5,18). However, all known therapeutic agents are active against the tachyzoite but not the cyst life form of the organism, and discontinuation of therapy is associated with relapse in 30 to 100% of AIDS patients with cerebral toxoplasmosis (22,26).…”

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confidence: 99%

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition

Chave

Munafo

Chatton

et al. 1992

Antimicrob Agents Chemother

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Toxoplasmic encephalitis is one of the leading causes of morbidity in patients with AIDS. Lifelong treatment is needed to prevent relapses, and primary prevention is desirable in high-risk patients, but the available drugs are often poorly tolerated. Azithromycin (AZM) has been considered a drug candidate because of its efficacy in the animal model and its kinetic properties, which would allow intermittent administration. The tolerability and kinetics of AZM and its effect on the disposition of zidovudine (ZVD) were therefore evaluated in a preliminary open study in nine human immunodeficiency virus-infected patients. AZM was administered once weekly for 5 weeks 2 h before the usual morning ZVD dose. The day before and on the first and fifth AZM dosings, blood samples were drawn every 30 min during 5 h for determination of the concentrations of ZVD and its glucuronide metabolite. Blood samples were drawn for AZM measurement over 72 and 360 h on the first and fifth AZM administrations, respectively, as well as before and 3 h after dosing on the second, third, and fourth AZM dosings. After the first and fifth administrations, maximum AZM concentrations in serum were 0.6 + 0.1 and 0.8 ± 0.2 ,uM (mean + standard error of the mean), respectively; times to peak concentration in serum were 3.7 ± 0.2 and 2.9 + 0.4 h, respectively; areas under the plasma concentration-time curves were 9.2 ± 1.6 and 9.3 + 2.0 ,ug h/ml, respectively; and half-lives were 61.0 + 5.4 and 63.8 ± 6.7 h, respectively.On days -1, 1, and 29, ZVD kinetic parameters were as follows: maximum concentrations in serum, 3.1 + 0.6, 4.3 + 0.6, and 4.2 + 0.9 ,uM, respectively; times to maximum concentration in serum, 1.1 + 0.4, 0.8 ± 0.2, and 1.2 ± 0.3 h, respectively; areas under the plasma concentration-time curves, 5.3 + 0.9, 5.9 + 0.6, and 5.7 + 0.8 ,ig. h/ml, respectively; and half-lives, 1.3 + 0.08, 1.4 ± 0.04, and 1.3 + 0.04 h, respectively. Except for transient mild abdominal cramps that occurred at 2 to 3 h postdose (6 of 45 exposures) and nausea (4 of 45 exposures), neither subjective nor objective side effects were observed. The kinetics of AZM were similar after the first and repeated administrations, and the disposition of ZVD was not altered by this treatment. The efficacy of AZM in preventing cerebral toxoplasmosis can therefore be safely tested in human immunodeficiency virus-infected patients concomitantly treated with zidovudine.

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Treatment of acute toxoplasmosis with intravenous clindamycin

Cited by 21 publications

References 2 publications

In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

In vitro assays elucidate peculiar kinetics of clindamycin action against Toxoplasma gondii

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition

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