Clavulanate Potassium Risk Summary

Last Updated on Mon, 04 Sep 2023 | Drug Safety

Risk Factor: BM
Class: Anti-infectives / Antibiotics/anti-infectives

Fetal Risk Summary

Clavulanic acid is a b-lactamase inhibitor produced by Streptomyces clavuligerus that is combined, as the potassium salt, with the penicillin antibiotics, amoxicillin or ticarcillin, to broaden their antibacterial spectrum of activity. No adverse fetal effects were observed in mice, rats, and pigs administered potassium clavulanate in combination with amoxicillin or ticarcillin during gestation (1,2,3,4 and 5).



Following a single oral dose of amoxicillin (250 mg) and potassium clavulanate (125 mg) in humans, both agents crossed the placenta to the fetus (6,7). Cord blood levels were found 1 hour after the dose with peak levels occurring at 23 hours. In one study, the mean peak maternal serum and umbilical cord blood levels occurred at 2 hours with values of 2.20 and 1.23 g/mL, respectively (fetal:maternal ratio 0.56) (7). Both amoxicillin and potassium clavulanate have been demonstrated in the amniotic fluid (6,7 and 8), with peak concentrations of clavulanate (0.44 g/mL) measured 5.5 hours after administration (7). A study using in vitro perfused human placentas demonstrated the transfer of potassium clavulanate when concentrations on the maternal side were 1013 g/mL, but not at 26 g/mL (8). A fetal/maternal gradient of 1:1 was obtained at the higher concentrations.

Several studies have described the use of amoxicillin and potassium clavulanate for various infections in pregnant women (7, 9,10 and 11). No adverse effects in the fetus or newborn attributable to the combination were observed (see also Amoxicillin and Ticarcillin).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 556 newborns had been exposed to clavulanic acid (presumably in combination with penicillins) during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 24 (4.3%) major birth defects were observed (24 expected). Specific data were available for six defect categories, including (observed/expected) 5/6 cardiovascular defects, 2/1 oral clefts, 1/2 polydactyly, 0/1 limb reduction defects, 1/1 hypospadias, and 2/0.3 spina bifida. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother's disease, concurrent drug use, and chance may be involved.

Breast Feeding Summary

Both amoxicillin and ticarcillin are excreted into breast milk (see Amoxicillin and Ticarcillin), but data pertaining to potassium clavulanate have not been located. Excretion probably occurs because of the low molecular weight (about 237). The effects of the b-lactamase inhibitor on the nursing infant are unknown.

References

  1. Baldwin JA, Schardein JL, Koshima Y. Reproduction studies of BRL14151K and BRL25000. I. Teratology studies in rats. Chemotherapy (Tokyo) 1983;31(Suppl 2):23851.
  2. Baldwin JA, Schardein JL, Koshima Y. Reproduction studies of BRL14151K and BRL25000. II. Peri- and post-natal studies in rats. Chemotherapy (Tokyo) 1983;31(Suppl 2):25262.
  3. Hirakawa T, Suzuki T, Sano Y, Tamura K, Koshima Y, Hiura KI, Fujita K, Hardy TL. Reproduction studies of BRL14151K and BRL25000. III. Fertility studies in rats. Chemotherapy (Tokyo) 1983;31(Suppl 2):26372.
  4. James PA, Hardy TL, Koshima Y. Reproduction studies of BRL 25000. IV. Teratology in pig. Chemotherapy (Tokyo) 1983;31(Suppl 2):2749.
  5. Tasker TCG, Cockburn A, Jackson D, Mellows G, White D. Safety of ticarcillin/potassium clavulanate. J Antimicrob Chemother 1986;17:22532.
  6. Matsuda S, Tanno M, Kashiwagura T, Seida A. Fundamental and clinical studies on BRL25000 (clavulanic acid-amoxicillin) in the field of obstetrics and gynecology. Chemotherapy (Tokyo) 1982;30(Suppl 2):53847.
  7. Takase Z, Shirafuji H, Uchida M. Clinical and laboratory studies on BRL25000 (clavulanic acid-amoxicillin) in the field of obstetrics and gynecology. Chemotherapy (Tokyo) 1982;30(Suppl 2):57986.
  8. Fortunato SJ, Bawdon RE, Swan KF, Bryant EC, Sobhi S. Transfer of Timentin (ticarcillin and clavulanic acid) across the in vitro perfused human placenta: comparison with other agents. Am J Obstet Gynecol 1992;167:15959.
  9. Matsuda S. Augmentin treatment in obstetrics and gynaecology. Augmentin: Proceedings of an International Symposium, Montreux, Switzerland. July 1981. Leigh DA, Robinson OPW, ed. Excerpta Medica 1982:17991.
  10. Mayer HO, Jeschek H, Kowatsch A. Augmentin in the treatment of urinary tract infection in pregnant women and pelvic inflammatory disease. Proceedings of the European Symposium on Augmentin, Scheveningen, June 1982, 1983:20717.
  11. Pedler SJ, Bint AJ. Comparative study of amoxicillin-clavulanic acid and cephalexin in the treatment of bacteriuria during pregnancy. Antimicrob Agents Chemother 1985;27:50810.

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Readers' Questions

  • juliane brandt
    What is the safety concern with clavulanate and what is the preferred ratio?
    8 months ago
    • Clavulanate is a beta-lactamase inhibitor that is commonly used in combination with certain antibiotics, such as amoxicillin, to enhance their effectiveness. While clavulanate is generally safe and well-tolerated, there are a few safety concerns associated with its use. One of the safety concerns with clavulanate is its potential to cause liver damage. In rare cases, clavulanate may lead to hepatotoxicity, which is characterized by elevated liver enzymes and, in severe cases, liver failure. Patients with pre-existing liver conditions or those who have experienced liver problems while taking clavulanate in the past are at higher risk. Another possible safety concern is the risk of allergic reactions. Some individuals may be hypersensitive to clavulanate, leading to allergic reactions that range from mild rash or hives to severe allergic symptoms like swelling, difficulty breathing, and anaphylaxis. Regarding the preferred ratio, the most commonly used ratio of clavulanate to amoxicillin in the combination product is 1:2. This means that for every 125 mg of clavulanate, there are 250 mg of amoxicillin. This ratio is often prescribed to ensure an optimal balance between the antibiotic activity of amoxicillin and the beta-lactamase inhibitory effects of clavulanate. However, the specific ratio may vary depending on the clinical condition being treated and the individual patient's needs. It is crucial to follow the dosage instructions prescribed by a healthcare professional.