Sulfamethoxazole and Trimethoprim (Page 6 of 7)

12.4 Microbiology

Mechanism of Action

Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para -aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim injection blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.

Resistance

In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either trimethoprim or sulfamethoxazole alone.

Antimicrobial Activity

Trimethoprim/sulfamethoxazole has been shown to be active against most isolates of the following microorganisms, both in in vitro and in clinical infections [see Indications and Usage (1)].

Aerobic gram-negative bacteria

Escherichia coli

Klebsiella species

Enterobacter species

Morganella morganii

Proteus mirabilis

Proteus species

Proteus vulgaris

Shigella flexneri

Shigella sonnei

Other Microorganisms

Pneumocystis jirovecii

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for trimethoprim/sulfamethoxazole against isolates of similar genus or organism group. However, the efficacy of trimethoprim/sulfamethoxazole in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive bacteria

Streptococcus pneumoniae

Aerobic gram-negative bacteria

Haemophilus influenzae

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole twice a day).

Mutagenesis

In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.

Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes.

Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded.

Impairment of Fertility

No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim, doses roughly two times the recommended human daily dose on a body surface area basis.

15 REFERENCES

1. Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis carinii pneumonia. Ann Intern Med. June 1980;92:762-769.

2. Al-Khatib SM, LaPointe N, Kramer JM, Califf RM. What Clinicians Should Know About the QT Interval. JAMA. 2003;289(16):2120-2127.

3. Boyer EW, Stork C, Wang RY. Review: The Pharmacology and Toxicology of Dofetilide. Int J Med Toxicol. 2001;4(2):16.

4. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. Oct 1994;170(4):912-7.

5. London NJ, Garg SJ, Moorthy RS, Cunningham ET. Drug-induced uveitis. J Ophthalmic Inflamm Infect. 2013;3:43.

6. Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol. 1999;45:209–212.

7. Margassery S, Bastani B. Life threatening hyperkalemia and acidosis secondary to trimethoprimsulfamethoxazole treatment. J. Nephrol. 2001;14(5):410-414.

8. Moh R, et al. Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Côte d’Ivoire. Antivir Ther. 2005;10(5):615-24.

9. Kosoglou T, Rocci ML Jr, Vlasses PH. Trimethoprim alters the disposition of procainamide and Nacetylprocainamide. Clin Pharmacol Ther. Oct 1988;44(4):467-77.

10. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973;128 (Suppl): S657-S663.

11. Grose WE, Bodey GP, Loo TL. Clinical Pharmacology of Intravenously Administered Trimethoprim-Sulfamethoxazole. Antimicrob Agents Chemother. Mar 1979;15:447-451.

12. Siber GR, Gorham C, Durbin W, Lesko L, Levin MJ. Pharmacology of Intravenous Trimethoprim-Sulfamethoxazole in Children and Adults. Current Chemotherapy and Infectious Diseases. American Society for Microbiology, Washington, D.C. 1980; Vol. 1, pp. 691-692.

16 HOW SUPPLIED/STORAGE AND HANDLING

Sulfamethoxazole and trimethoprim injection, USP is supplied as follows:

5 mL Single Dose Vial containing 80 mg trimethoprim (16 mg/mL) and 400 mg sulfamethoxazole (80 mg/mL) for infusion with 5% dextrose in water.

5 mL Vial: NDC 70069-361 -01

5 mL Vial (Box of 10): NDC 70069-361 -10

10 mL Multiple Dose Vial; Each 5 mL containing 80 mg trimethoprim (16 mg/mL) and 400 mg sulfamethoxazole (80 mg/mL) for infusion with 5% dextrose in water.

10 mL Vial: NDC 70069-362 -01

10 mL Vial (Box of 10): NDC 70069-362 -10

30 mL Multiple Dose Vial; Each 5 mL containing 80 mg trimethoprim (16 mg/mL) and 400 mg sulfamethoxazole (80 mg/mL) for infusion with 5% dextrose in water.

30 mL Vial (Box of 1): NDC 70069-363 -01

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. DO NOT REFRIGERATE.

17 PATIENT COUNSELING INFORMATION

Embryo–fetal Toxicity

Advise female patients of reproductive potential that sulfamethoxazole and trimethoprim injection can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Hypersensitivity and Other Serious or Fatal Reactions

Advise patients to stop taking sulfamethoxazole and trimethoprim injection immediately if they experience any clinical signs such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Lactation

Advise nursing women to avoid breastfeeding during treatment with sulfamethoxazole and trimethoprim injection.

Antibacterial Resistance

Counsel patients that antibacterial drugs including sulfamethoxazole and trimethoprim injection should only be used to treat bacterial infections. It does not treat viral infections (e.g., the common cold).

Instruct patients to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.

Diarrhea

Advise patients that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

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Somerset Therapeutics, LLC

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Made in India

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ST-STM/P/01

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