Fosfomycin

 Risk Factor: BM
 Class: ANTI-INFECTIVES / Antibiotics/Anti-infectives

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Fosfomycin is a synthetic, broad-spectrum, bactericidal phosphonic acid antibiotic given as a single 3-g oral dose of the trometamol salt for the treatment of uncomplicated urinary tract infections (acute cystitis) in women (1). Outside of the United States, other salt forms (calcium salt for oral administration, disodium salt for IM or IV dosing) are also available. Following absorption, fosfomycin tromethamine is rapidly converted to the free acid, fosfomycin.

Studies in male and female rats found no effect on fertility or impairment of reproductive performance (1). No teratogenic effects were observed in pregnant rats administered doses up to 1000 mg/kg/day, about 9 and 1.4 times the human dose (HD) based on body weight and mg/m2, respectively (1). In pregnant rabbits, fetotoxicity was observed at doses up to 1000 mg/kg/day, about 9 and 2.7 times the HD, respectively, a maternally toxic dose in the rabbit.

The placental transfer of fosfomycin, following a single 1-g IM dose (1420 mg/kg), was studied in a group of women at term in active labor (2). Samples of maternal and fetal blood were obtained before delivery at 30, 90, and 120210 minutes after the dose in 7, 8, and 7 women, respectively. Mean maternal blood concentrations of fosfomycin at the three time intervals were 14.24, 23.32, and 15.86 g/mL, respectively, while those in the fetal blood were 1.58, 5.35, and 11.5 g/mL, respectively.

Although the above study was conducted with IM dosing, the results appear to be comparable to those expected after oral dosing. The mean maximum maternal serum concentration of fosfomycin, after a single 3-g oral dose of fosfomycin tromethamine under fasting conditions, was 26.1 g/mL within 2 hours (1). As should be expected because of the normal physiologic changes that occur during gestation, pregnant women will have lower peak levels. In four pregnant women at 2832 weeks' gestation after a single 3-g oral dose, the mean peak serum level at 2 hours was 20.5 g/mL (3).

A number of reports have described the use of fosfomycin during human pregnancy. Although appropriate precautions had been taken to exclude and prevent pregnancies during clinical trials, three women conceived shortly after enrolling and all received a single 3-g oral dose of fosfomycin (H.A. Schneier, personal communication, Forest Laboratories, 1997). The dose was apparently consumed about 3 days before conception in one case, 8 days after the last menstrual period (i.e., probably before conception) in a second, and 14 days after the last menstrual period (i.e., assumed to be around the time of conception) in a third. The first woman was lost to follow-up and the other two delivered healthy male newborns who were developing normally at 3 years of age.

In a case of stillbirth reported by the manufacturer to the FDA, the mother was hospitalized following a car accident and approximately 10 days later received a single 3-g oral dose of fosfomycin for a urinary tract infection (H.A. Schneier, personal communication, Forest Laboratories, 1997). About 5 days later, ultrasound demonstrated no fetal heartbeat and an induced abortion was performed. The cause of death was thought to be caused by progressive multiple placental infarctions and fetal hypotrophy.

Several published reports have studied the efficacy and safety of oral fosfomycin during pregnancy (3,4,5,6,7,8,9,10,11,12,13 and 14). The drug has been used in all trimesters of pregnancy without apparent harm to the fetus or newborn.

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (15). Of 1,067 exposed pregnancies, fosfomycin was taken during the 1st trimester in two, both concluding with normal, full-term infants.

In summary, the lack of teratogenicity in animals and the apparently safe use of fosfomycin during human pregnancy appear to indicate that the drug presents a low risk, if any, to the fetus. Because the number of 1st trimester human exposures is limited, however, treatment would be best delayed until after the period of organogenesis.

Breast Feeding Summary

No reports describing the use of fosfomycin during human lactation have been located. Because of its relatively low molecular weight (about 259) and its transfer across the placenta, passage into milk should be anticipated. The risk to a nursing infant from this exposure is unknown, but modification of the infant's bowel flora may occur.

References

1. Product information. Monurol. Forest Laboratories, 2001.
2. Ferreres L, Paz M, Martin G, Gobernado M. New studies on placental transfer of fosfomycin. Chemotherapy 1977;23(Suppl 1):1759.
3. De Cecco L, Ragni N. Urinary tract infections in pregnancy: Monuril single-dose treatment versus traditional therapy. Eur Urol 1987;13(Suppl 1):10813.
4. Ragni N. Fosfomycin trometamol single dose versus pipemidic acid 7 days in the treatment of bacteriuria in pregnancy. Clinical report, 29 November 1990. Data on file, Forest Laboratories.
5. Reeves DS. Treatment of bacteriuria in pregnancy with single dose fosfomycin trometamol: a review. Infection 1992;20(Suppl 4):S313S6.
6. Moroni M. Monuril effectiveness and tolerability in the treatment and prevention of urinary tract infections. Clinical report. Data on file, Forest Laboratories.
7. Paladini A, Paladini AA, Balbi C, Carati L. Efficacy and safety of fosfomycin trometamol in the treatment of bacteriuria in pregnancy. Clinical report. Data on file, Forest Laboratories.
8. Ragni N, Pivetta C, Paccagnella F, Foglia G, Del Bono GP, Fontana P. Urinary tract infections in pregnancy. In Neu HC, Williams JD, eds. New Trends in Urinary Tract Infections. International Symposium Rome 1987. Basel:Karger, 1988:197206.
9. Zinner S. Fosfomycin trometamol versus pipemidic acid in the treatment of bacteriuria in pregnancy. Chemotherapy 1990;36(Suppl 1):502.
10. Marone P, Concia E, Catinella M, Andreoni M, Guaschino S, Marino L, Grossi F, Cellani F. Fosfomycin trometamol in the treatment of urinary tract infections during pregnancy. A multicenter study. 3rd International Congress, Infections in Obstetrics and Gynecology, Pavia, Italy, 1988.
11. Thoumsin H, Aghayan M, Lambotte R. Fosfomycin trometamol versus nitrofurantoin in multiple dose in pregnant women. Preliminary results. Infection 1990;18(Suppl 2):S94S7.
12. Moroni M. Monurol in lower uncomplicated urinary tract infections in adults. Eur Urol 1987;13(Suppl 1):1014.
13. De Andrade J, Mendes Carvalho Lopes C, Carneiro daSilva D, Champi Ribeiro MG, Souza JEMR. Fosfomycin trometamol single-dose in the treatment of uncomplicated urinary tract infections in cardiac pregnant or non pregnant women. A controlled study. J Bras Ginec 1994;104:34551.
14. Gobernado M, Perez de Leon A, Santos M, Mateo C, Ferreres L. Fosfomycin in the treatment of gynecological infections. Chemotherapy 1977;23(Suppl 1):28792.
15. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:8829.