Pharmacology and toxicology
The nitroimidazole antibiotic metronidazole is an antibacterial and antiprotozoal agent used in trichomonas infections, amebiasis, giardiasis, bactcrial vaginosis, and anaerobic infections. It acts as an electron acceptor in the metabolism of the bacteria, and causcs growth disturbances in the susceptible microorganism. Active metabolites that interact with and disrupt the DNA-synthesis are responsible for the effect. After oral and intravenous administration, concentrations as high as those in the mother are reached in the embryo/fetus. Significant systemic absorption occurs after vaginal application, exposing the fetus as well.
Because metronidazole is mutagenic in bactcrial tests and carcinogenic in some animals (review by Dobias 1994), it was feared that it could also be mutagenic and carcinogenic in huinans. Such cffects have not been reported. A 20-year ongoing study gave no indication of an elevated risk for malignancies after metronidazole therapy (Beard 1988). In a retrospective study, no increased risk of childhood cancer associated with in utero exposure to metronidazole was found; only a non-significant association with neuroblastoma was observed (Thapa 1998). Metronidazole does not appear to have teratogenic effects in the human, according to considerable experience (Caro-Paton 1997, Burtin 1995, Piper 1993). A recent prospective controlled study on 228 women exposed to metronidazole in pregnancy, 86% of whom with first-trimester exposure, confirmed these findings (Diav-Citrin 2001).
Metronidazole is now being recommended by some investigators for the treatment of bacterial vaginosis in pregnancies at high risk for preterm delivery, as a strategy to decrease this risk. For this purpose, oral therapy against possible subclinical genital upper tract infection seems to be more effective than intravaginal therapy (Dondcrs 2000, review by Jocsoef 1999). A review by Yudin confirms that vaginal treatment regimens of bacterial vaginosis arc ineffective in preventing preterm birth (Yudin 2005; see also Chapter 2.14).
Nimorazole and tinidazole, both registered for the treatment of trichomonas infections, amebiasis, and bacterial vaginosis, cannot be evaluated sufficiently because of lack of human data. The same applies to ornidazole.
Recommendation. If strongly indicated, metronidazole can be used In pregnancy. For treatment of trichomoniasis, a single oral dose of 2 g should be used. Parenteral administration Is only indicated for life-threatening anaerobic infections. Protracted vaginal treatment of vaginosis should be avoided because it is not considered effective enough; moreover, it exposes the fetus for longer. Metronidazole is preferred over nimorazole and tinidazole. Treatment with nimorazole, ornidazole or tinidazole during pregnancy does not require termination of pregnancy or invasive diagnostic procedures. However, a detailed fetal ultrasound may be considered after first-trimester exposure to these compounds.
2.6.13 Polypeptide antibiotics
Vancomycin, colistin, polymyxin B. and teicoplanine belong to the polypeptide antibiotics. Polypeptide antibiotics increase the permeability of the cytoplasma membrane of sensitive bacteria. They work against gram-positive bacteria.
For example, vancomycin is used against multiresistant staphylococcus. Experience with treatment in human prcgnancy is limited; neither malformations nor nephrotoxicity or auditory impairment were seen in neonates (Reyes 1989). There is a case report of a woman who became hypotensive when vancomycin was infused too rapidly during labor; the fetus exhibited a bradycardia during the hypotensive episode (Hill 1985).
Colistin and polymyxin B have as yet not shown teratogenic properties in humans, although documented experience is very limited (Kazy 2005). Experience with teicoplanine is insufficient for a risk assessment.
Recommendation. Vancomycin should only be used in case of life-threatening bacterial infections. Also, colistin, polymyxin B and (especially) the little-tested teicoplanine should only be used if compelllngly indicated. The use of these substances is not in itself an indication either for termination of pregnancy or for invasive diagnostic procedures.
2.6.14 Antimycotics in general
For the treatment of mycosis, topical therapy with the older agents is to be considered safe in pregnancy.
2.6.16 Clotrimazole and miconazole for topical use
There is less experience and fewer data with systemic agents. If systemic therapy is actually necessary, then there should be a carc-ful choice from this group of questionable drugs.
Lately it has become "fashionable" to use antimycotics for treatment of aspecific symptoms supposedly associated with the harmless presence of fungus in the stool; in pregnancy, at least, this should be omitted.
The treatment of asymptomatic colonization of the vagina is unnecessary (Sobel 2000).
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