Chronic Granulomatous Disease: Mode of Action of Sulfamethoxazole/Trimethoprim

Gmünder, Felix K.; Seger, Reinhard

doi:10.1203/00006450-198112000-00017

Cited by 41 publications

(19 citation statements)

References 15 publications

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“…Rifampin (16,21), erythromycin (16,21), clindamycin (16,21), trimethoprim-sulfamethoxazole (12), and ciprofloxacin (4) have been shown to be concentrated within human leukocytes. The uptake for clindamycin is quite pronounced, with intracellular concentrations being 20 to 50 times greater than extracellular concentrations (16).…”

Section: Discussionmentioning

confidence: 99%

Effect of quinolones and other antimicrobial agents on cell-associated Legionella pneumophila

Havlichek

Saravolatz

Pohlod

1987

Antimicrob Agents Chemother

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We evaluated the in vitro susceptibility of Legionella pneumophila ATCC 33152 (serogroup I) to 13 antibiotics alone and in combination with rifampin (0.1 mg/liter) by three methods. Extracellular susceptibility was determined by MIC determinations and time kill curves in buffered yeast extract broth, while intracellular susceptibility was determined by peripheral human monocytes in RPMI 1640 culture medium. Antibiotic concentrations equal to or greater than the broth dilution MIC inhibited or killed L. pneumophila by-the time kill method, except this was not the case for trimethoprim-sulfamethoxazole. Antibiotic concentrations below the broth dilution MIC did not inhibit Legionella growth. The only antibiotic-rifampin combinations which produced improved killing of L. pneumophila by the time kill method were those in which the logarithmic growth of L. pneumophila occurred during the experiment (rosoxacin, amifloxacin, cinoxacin, trimethoprimsulfamethoxazole, clindamycin, and doxycycline). Neither direct MICs nor time kill curve assays accurately predicted intracellular L. pneumophila susceptibility. Rifampin, erythromycin, ciprofloxacin, rosoxacin, enoxacin, amifloxacin, gentamicin, clindamycin, and doxycycline all inhibited intracellular L. pneumophila growth at readily achievable concentrations in serum. Cefoxitin and thienamycin showed no inhibition of growth, although they were present extracellularly at concentrations that were 20 to 1,000 times their broth dilution MICs. Clindamycin was the only antibiotic that was able to inhibit intracellular L. pneumophila growth at an extracellular concentration below its MIC. The gentamicin (5 mg/liter)-rifampin combination was the only antibiotic-rifampin combination which demonstrated decreased cell-associated Legionella survival in this model of in vitro susceptibility.

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Section: Discussionmentioning

confidence: 99%

Effect of quinolones and other antimicrobial agents on cell-associated Legionella pneumophila

Havlichek

Saravolatz

Pohlod

1987

Antimicrob Agents Chemother

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“…We have found in the literature only a few other data on C/E ratios for TMP in PMNs. Koga (32) reported a value of 6.10 Ϯ 0.63, Jacobs and Wilson (27) reported a value of 4, Gründer and Seger (17) reported a value of 4.1 Ϯ 0.6 (they used 5 g of TMP per ml), and Höger et al (25) reported a value of 3.15 (they used 10 g of TMP per ml); however, the last three groups of investigators did not indicate the intracellular volumes of their PMNs, and this makes it difficult to compare their results with ours. There is also the value of Climax et al (7) of 0.5 g of TMP per ml per 10 7 cells, but this is difficult to analyze and to transform into a C/E ratio because they provided no information about the exact starting concentration or the intracellular volumes of the PMNs.…”

Section: Discussionmentioning

confidence: 99%

“…At pH 6, the uptake was lower, and at pH 8, it was higher. Lipid-soluble drugs with pK a values of Ӎ7.3, such as BMP and TMP at plasma pH (Ӎ7.3), exist as 50% in the ionized form and 50% in the nonionized form, and only the nonprotonated portions of these lipid-soluble molecules diffuse across the lipid cell membrane of PMNs (17,52,61). At pH 6 these drugs are mainly ionized (protonated), with reduced diffusion across the membranes, while at pH 8 drugs with pK a values of Ӎ7.3 are mainly nonionized, and their diffusions across the membranes are greater than those at an environmental pH of 7.3.…”

Section: Discussionmentioning

confidence: 99%

Penetration of brodimoprim into human neutrophils and intracellular activity

Braga

Sasso

Maci

et al. 1996

Antimicrob Agents Chemother

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The entry of an antibiotic into phagocytes is a prerequisite for its intracellular bioactivity against susceptible facultative or obligatory intracellular microorganisms. Brodimoprim is a dimethoxybenzylpyrimidine that has recently entered into clinical use, and its uptake into and elimination from human polymorphonuclear neutrophils (PMNs), together with its effects on normal phagocytic and antimicrobial mechanisms, have been investigated. Brodimoprim uptake by PMNs was determined by a velocity-gradient centrifugation technique under various experimental conditions and was expressed as the ratio of the intracellular to the extracellular drug concentration (C/E) in comparison with the C/E of trimethoprim, which was used as a control drug. After incubation with 7.5 micrograms of brodimoprim per ml, PMNs accumulated brodimoprim (C/E, 74.43 +/- 12.35 at 30 min) more avidly than trimethoprim (C/E, 20.97 +/- 6.61 at 30 min). The cellular uptake of brodimoprim was not affected by temperature, 2,4-dinitrophenol, or potassium fluoride and was increased with an increase in the pH of the medium. It was reduced in formaldehyde-killed PMNs. The efflux of brodimoprim was very rapid (46% after 5 min). The liposolubility of brodimoprim was about three times that of trimethoprim, as was the uptake. Therefore, a possible passive transmembrane diffusion mechanism might be proposed. Brodimoprim did not decrease either phagocytosis or phagocyte-mediated bactericidal activity, nor did it affect oxidative burst activity, as investigated by luminol-amplified chemiluminescence. On the basis of the pharmacokinetic data for brodimoprim, the concentration of 7.5 micrograms/ml was chosen as the highest concentration attainable in serum by oral therapy, and at this concentration of brodimoprim, the amount of drug that penetrated into PMNs was able to maintain its antimicrobial activity without interfering with the functions of the PMNs.

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“…The mainstay of therapy is adequate anti‐microbial prophylaxis. The most common antibiotic used for chemoprophylaxis is cotrimoxazole, which has broad activity against the pathogens encountered in CGD, is lipophilic and is thus concentrated inside cells, and is well tolerated because it does not affect anaerobic gut flora [90–92]. No randomized controlled trials of cotrimoxazole have been performed but a number of small studies have shown a reduction in the incidence of serious infections in patients on regular prophylaxis [93–96].…”

Section: Clinical Managementmentioning

confidence: 99%