Co-trimoxazole
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Co-trimoxazole is the fixed combination of the two antibiotically effective drugs trimethoprim and sulfamethoxazole in the dose ratio of 1: 5.
Clinical information
Application areas (indications)
Cotrimoxazole is an antibiotic drug mixture that is used to treat infectious diseases caused by pathogens that are sensitive to them. These include in particular infections of the upper and lower respiratory tract, including Pneumocystis jirovecii pneumonia ; ENT infections with the exception of streptococcal angina; Kidney and urinary tract infections ; Infections of the female and male genital organs including prostatitis , ulcus molle and lymphogranuloma venereum ; Infections of the gastrointestinal tract , including typhoid , paratyphoid serotypes A and B, shigellosis and travelers' diarrhea, and salmonella enteritis with septic disease progression in immunocompromised patients. Other indications include brucellosis , nocardiosis , non-genuinely mycotic mycetoma and South American blastomycosis . The combination of trimethoprim + sulfamethoxazole was added to the World Health Organization's list of indispensable drugs by the World Health Organization (WHO) in 1977.
Another application is in the treatment of granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis or Wegener's disease) as a therapeutic attempt in the initial stage. The mechanism of action is still unknown.
Type and duration of application
The usual dose for adults is 2 × 960 mg per day (800 mg each of sulfamethoxazole and 160 mg of trimethoprim). In Pneumocystis carinii pneumonia, the dose is up to 5 times the standard dose. For long-term use, 480 mg of co-trimoxazole are usually used twice a day. In case of renal insufficiency, the dose may need to be reduced. The use of co-trimoxazole is contraindicated in the advanced stages of renal insufficiency .
Contraindications (contraindications)
In addition to known hypersensitivity to sulfonamides, trimethoprim or related substances, erythema multiforme , abnormal blood count changes, a congenital glucose-6-phosphate dehydrogenase deficiency in the red blood cells , kidney damage or high-grade kidney insufficiency with creatinine clearance of less than 15 ml / min, severe Liver damage or liver dysfunction and acute porphyria are absolute contraindications. Likewise, cotrimoxazole must not be used in premature babies or in newborns with hyperbilirubinaemia or glucose-6-phosphate dehydrogenase deficiency of the erythrocytes.
Drug interactions
Both active components of co-trimoxazole can interact with other drugs. Sulphamethoxazole can lead to an increase in the anti-coagulant effect of 4-hydroxycoumarins . An intensification of the blood sugar lowering effect of sulfonylureas by sulfamethoxazole can also be observed. Trimethoprim is associated with an inhibition of excretion and thus with an increase in the effect of phenytoin , cardiac glycosides and procainamide . The relevance of a possible influence on the free plasma concentration of concomitantly administered methotrexate or on the effectiveness of the birth control pill , however, is questionable.
Adverse effects (side effects)
Co-trimoxazole has a favorable safety profile with a well-defined and therefore calculable spectrum of side effects . The most common undesirable effects of cotrimoxazole with around 3 to 8% include disorders of the digestive system such as nausea, vomiting and loss of appetite and, less often, diarrhea, glossitis and stomatitis . The liver toxicity of co-trimoxazole is comparable to that of other antibiotics.
Skin reactions occur with a frequency of about 3 to 4%. These include maculopapular rash , hives , diffuse erythema , morbilliform lesions, erythema multiforme , purpura, and photosensitization , among others . Serious skin reactions, such as Stevens-Johnson syndrome or Lyell syndrome , are rare.
Serious blood count disorders, such as anemia , granulocytopenia , agranulocytosis and thrombocytopenia , are less common . There have also been isolated reports of mental disorders, particularly in older patients. In addition, high doses of co-trimoxazole can lead to an increase in potassium levels. Cardiac arrhythmias are also possible by extending the QTc time .
Pharmacological properties
Mechanism of action (pharmacodynamics)
The active components of co-trimoxazole, sulfamethoxazole and trimethoprim, inhibit the bacterial biosynthesis of tetrahydrofolic acid , the biologically active form of folic acid . This is essential for the formation of thymidine and the purine bases and thus for the synthesis of DNA . Like other sulfonamides, sulfamethoxazole competitively inhibits the enzyme folic acid synthetase at the binding site for the natural substrate para-aminobenzoic acid . As a structural analogue of dihydrofolic acid, trimethoprim inhibits another enzyme that is important for bacterial folic acid metabolism, dihydrofolate reductase .
The combination produces a synergistic effect , at least in vitro . The inhibition of folic acid synthesis in two places results in an expanded spectrum of activity and a delayed development of resistance.
Absorption and distribution in the body (pharmacokinetics)
Due to the very good bioavailability of almost 100%, cotrimoxazole can almost always be administered orally as a tablet. However, preparations for intravenous use are also available without this resulting in a significant pharmacokinetic difference.
From a pharmacokinetic point of view, the two active ingredients are good combination partners, since the half-lives are similar (trimethoprim 10–11 hours, sulfamethoxazole 9–11 hours).
Both active ingredients are mainly excreted via the kidneys, with a relevant proportion of sulfamethoxazole being metabolized beforehand in the liver.
toxicology
Overdose
Co-trimoxazole can be toxic from a dose of 3000 mg. Overdose symptoms can be diagnosed with one or more symptoms as well as health problems:
- Ataxia
- Nausea and vomiting
- Liver division
- immunodeficiency
- Difficulty breathing
- Leukopenia
- cramps
- Psychosis
- depressions
- Sweats
- nausea
- skin rash
- toxic jaundice
Furthermore, from a dose of 5000 mg co-trimoxazole, permanent brain damage, kidney failure, severe liver damage and, in women, permanent infertility are known.
Classification of the effect on bacteria
Both components and the combination have a bacteriostatic effect . The combination can only have a bactericidal effect on very sensitive microorganisms .
chemistry
Sulfamethoxazole is a substance from the group of sulfonamides , which are structurally similar to para-aminobenzoic acid (PABA).
Trimethoprim is a substance from the diaminopyrimidine group and is structurally similar to dihydrofolic acid .
Trade names
Bactrim (A, CH), Drylin (D), Escoprim (CH), Eusaprim (D, A), Kepinol (D), Lagatrim (CH), Nopil (CH), TMS forte (D), numerous generics (D, A, CH)
Individual evidence
- ↑ a b c Technical information Kepinol. Dr. R. Pfleger Chemical Factory GmbH. Status: January 2008.
- ^ GP Wormser, GT Keusch, RC Heel: Co-trimoxazole (trimethoprim-sulfamethoxazole): an updated review of its antibacterial activity and clinical efficacy . In: Drugs . 24, No. 6, December 1982, pp. 459-518. PMID 6759092 .
- ^ WHO Model List of Essential Medicines. (PDF) accessed on March 24, 2014.
- ↑ a b c d e f PA Masters, TA O'Bryan, J Zurlo, DQ Miller, N Joshi: Trimethoprim-sulfamethoxazole revisited . In: Arch Intern Med . 163, No. 4, February 2003, pp. 402-410. PMID 12588198 .
- ↑ H Jick, LE Derby: A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and cephalexin for uncommon serious drug toxicity . In: Pharmacotherapy . 15, No. 4, 1995, pp. 428-432. PMID 7479194 .
- ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 512.
- ↑ Thomas Karow, Ruth Lang-Roth: General and Special Pharmacology and Toxicology: Lecture-oriented presentation and clinical guide for study and practice 2019 . Pulheim, 2018, p. 830.
