Ampicillin Trihydrate (ampicillin trihydrate)

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Selected Antibiotics/Cholera Vaccine Live

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Antibiotics with activity against Vibrio cholerae may attenuate the immunization response to the live cholera vaccine.(1)

CLINICAL EFFECTS: Concurrent or recent antibiotic use may make the cholera vaccine ineffective.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of live cholera vaccine states that it should not be administered to patients who have received antibiotics within 14 days prior to vaccination.(1) If antimalarial prophylaxis with chloroquine is required, administer the live cholera vaccine at least 10 days before beginning chloroquine.(1) Antibiotics linked to this monograph are: macrolides, quinolones, tetracyclines, ampicillin, cefprozil, chloramphenicol, furazolidone, sulfamethoxazole-trimethoprim, and sulfametrole-trimethoprim.(2,3)

DISCUSSION: Antibiotics with activity against Vibrio cholerae may attenuate the immunization response to the live cholera vaccine, rendering the vaccine ineffective.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Penicillins/Methotrexate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Penicillins may compete with the renal tubular secretion of methotrexate.

CLINICAL EFFECTS: The concurrent use of methotrexate and penicillins may result in elevated levels of methotrexate and methotrexate toxicity, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: Patients receiving concurrent therapy with methotrexate and penicillins should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The dose and duration of leucovorin rescue therapy may need to be increased.

DISCUSSION: Elevated methotrexate levels, signs of methotrexate toxicity, and death have been reported following the concurrent use of methotrexate (both low dose and high dose) and penicillin derivatives. In a patient being treated with high-dose methotrexate (8 G/m2), the concurrent use of amoxicillin resulted in a 56% decrease in the clearance of methotrexate and signs of methotrexate toxicity.(1) There are two cases of methotrexate toxicity following the addition of amoxicillin to low-dose methotrexate therapy (7.5 mg-10 mg weekly) for psoriasis. In another case, a patient was found to have a toxic methotrexate level 12 days after her last dose of weekly methotrexate (7.5 mg). The patient had been treated with amoxicillin followed by flucloxacillin.(2) In a case report, dicloxacillin decreased methotrexate clearance 93%.(4) Flucloxacillin was shown to increase the area-under-curve (AUC) of methotrexate by 7.3% in a study in 10 subjects.(5) In a case report, a patient on low-dose methotrexate (5 mg) developed methotrexate pneumonia following the addition of flucloxacillin to his regimen.(5) In a patient being treated with high-dose methotrexate (12 G/m2), the concurrent use of mezlocillin increased the half-life of methotrexate from 10.1 to 27.2 hours.(6) In a case report, a patient developed methotrexate toxicity following the addition of penicillin V potassium to his methotrexate (50 mg weekly).(7) In a case report, penicillin decreased methotrexate clearance 36%.(4) In one report, leucovorin rescue therapy had to be continued for 192 hours following the concurrent use of methotrexate (3 G/m2) and piperacillin. During cycles without concurrent piperacillin, leucovorin rescue therapy was only required for 72 hours.(8) There are two reports of neutropenia and death following the concurrent use of piperacillin and low-dose methotrexate (2.5 mg three times weekly in one patient, 5 mg weekly in another) for psoriasis. One of these patients also received flucloxacillin. (3) In another case report, the concurrent use of piperacillin decreased methotrexate clearance by 67%.(4) In a case report, ticarcillin decreased methotrexate clearance by 60%.(4)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Amoxicillin, Ampicillin, Bendamustine/Allopurinol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Allopurinol, amoxicillin, ampicillin, and bendamustine have been documented to cause cases of Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN), and Drug reaction with eosinophilia and systemic symptoms (DRESS).(1)

CLINICAL EFFECTS: Concurrent administration of allopurinol with amoxicillin, ampicillin or bendamustine may result in an increased incidence of rash which may be severe.

PREDISPOSING FACTORS: Patients who are HLA-B*58:01 positive may be at increased risk.

PATIENT MANAGEMENT: Consider an alternative to amoxicillin, ampicillin, or bendamustine in patients with a history of serious skin rashes, such as SJS, TEN, or DRESS. Discontinue allopurinol at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction when used with amoxicillin or ampicillin or bendamustine. Instruct patients to seek medical attention for any peeling skin rash or blisters.(1)

DISCUSSION: In the Boston Collaborative Drug Surveillance Program, drug rash was seen in 22.4% of 67 hospitalized patients (relative risk 3.0) receiving concurrent allopurinol and ampicillin compared to 7.5% of 1257 patients receiving only ampicillin and 2.1% of 283 patients rceiving only allopurinol.(4) A hospital drug monitoring program found the observed risk of developing an exanthema with concurrent use is as follows: aminopenicillin without allopurinol 10.1%, aminopenicillin combined with allopurinol 7.2%, allopurinol without aminopenicillin 3.0%, or neither of the two drugs 1.5%.(6) A case-control study did not find a statistically significant increased risk of SJS with concurrent use of allopurinol and amoxicillin or ampicillin (allopurinol alone 4.4% vs. with amoxicillin 6.8%; allopurinol alone 0.1% vs. with ampicillin 2.7% at 1 month)(allopurinol alone 4.4% vs. with amoxicillin 5.7% or allopurinol alone 0.2% vs. with ampicillin 2.9% at 3 months).(8) In a retrospective study looking at mortality data, records were screened for administration of high risk drugs associated with SJS. Allopurinol and ampicillin was one of the drug combinations listed as contributing to mortality in patients (p = 0.049).(9)

Penicillins/Oral Contraceptives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens and progesterones are extensively excreted in bile, principally as glycuronide conjugates. Subsequently, they undergo enterohepatic circulation where bacterial hydrolysis occurs, allowing for reabsorption of the oral contraceptives through the bowel wall and eventual urinary excretion. Treatment with antibiotics destroys the gut flora and prevents steroid reabsorption, resulting in lower than normal concentrations of the contraceptive and excretion via the feces rather than the urine.

CLINICAL EFFECTS: May observe reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy. Reduced effects may be seen for several days after discontinuation of antibiotic therapy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception.

DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Reports of breakthrough bleeding and loss of contraceptive protection leading to unwanted pregnancies have occurred in women taking oral contraceptive agents who received concurrent ampicillin, amoxicillin, penicillin G, or oxacillin. Several studies have shown that the administration of ampicillin or penicillin to pregnant and nonpregnant women resulted in lowered urinary estrogen excretion, in some women as soon as three days after ampicillin therapy began. However in one small prospective study, plasma ethinyl estradiol concentrations showed a tendency to decrease during ampicillin administration on the third, fourth, and fifth morning of ampicillin administration, but were never lower than pretreatment values. In another small prospective study of women taking low dose combination contraceptives, concurrent ampicillin therapy neither altered the plasma levels nor the AUC of norethisterone and ethinyl estradiol. In addition, progesterone levels were in an anovulatory range. In another prospective study of 13 women taking long term oral contraceptive steroids, concurrent ampicillin was not associated with any significant changes in plasma concentrations of ethinyl estradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyl estradiol were noted in two women.

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There are no contraindication contraindications for this drug.

• Clostridioides difficile infection

There are no moderate contraindications for this drug.

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Less Frequent

• Anaphylaxis
• Exfoliative dermatitis
• Urticaria

Rare or Very Rare

• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Agranulocytosis
• Autoimmune hemolytic anemia
• Clostridioides difficile infection
• Crystalluria
• DRESS syndrome
• Drug-induced hepatitis
• Enterocolitis
• Eosinophilia
• Erythema multiforme
• Furred tongue
• Hypersensitivity angiitis
• Idiopathic thrombocytopenic purpura
• Interstitial nephritis
• Laryngeal edema
• Leukopenia
• Maculopapular rash
• Obstructive hyperbilirubinemia
• Seizure disorder
• Serum sickness
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis

More Frequent

• Diarrhea
• Nausea
• Skin rash
• Vomiting
• Vulvovaginal candidiasis

Less Frequent

• Abdominal pain with cramps
• Pruritus of skin

Rare or Very Rare

• Acute cognitive impairment
• Agitation
• Anemia
• Behavioral disorders
• Dental discoloration
• Dizziness
• Insomnia
• Mucocutaneous candidiasis
• Symptoms of anxiety

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