Unasyn (ampicillin sodium/sulbactam sodium)

Ampicillin/sulbactam is commercially available for parenteral administration as a sterile powder containing a 2:1 ratio of ampicillin to sulbactam. The ampicillin component is provided as ampicillin sodium and the sulbactam component is provided as sulbactam sodium; potency of each component is expressed in terms of the base.

Dosage of ampicillin/sulbactam usually is expressed in terms of the total (sum) of the dosage of both components of the fixed combination (i.e., dosage of ampicillin plus dosage of sulbactam); pediatric dosage of ampicillin/sulbactam also has been expressed in terms of the ampicillin content.

The manufacturer's dosage recommendations for adults are the same for IM and IV administration; however, higher serum concentrations usually are attained with IV administration of the drug, and this route generally is preferred, especially for severe infections.

Because the pharmacokinetics of both ampicillin and sulbactam are affected to the same degree in patients with renal impairment, the recommended 2:1 ratio of the drugs remains the same regardless of the degree of renal impairment.

The manufacturer recommends that patients with renal impairment receive the usually recommended doses of ampicillin/sulbactam, but doses should be given less frequently than usual and the dosing intervals should be based on the patient's creatinine clearance. The manufacturer recommends that patients with creatinine clearances of 30 mL/minute per 1.73 m2 or greater receive 1.5 g (1 g of ampicillin and 0.5 g of sulbactam) to 3 g (2 g of ampicillin and 1 g of sulbactam) of the drug every 6-8 hours and that patients with creatinine clearances of 15-29 or 5-14 mL/minute per 1.73 m2 receive these doses every 12 or 24 hours, respectively.

Because ampicillin and sulbactam are removed by hemodialysis, some clinicians suggest that patients undergoing hemodialysis receive 1.5 g (1 g of ampicillin and 0.5 g of sulbactam) to 3 g (2 g of ampicillin and 1 g of sulbactam) once every 24 hours and that the dose preferably should be given immediately after dialysis.

No dosing information is available for this tab.

For further information on these and other drug interactions reported with aminopenicillins, see Drug Interactions in the Aminopenicillins General Statement 8:12.16.08. In addition, while not all drug interactions reported with other penicillins have been reported with aminopenicillins, the possibility that they could occur with these drugs should be considered.

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.

Selected Penicillins/Selected Anticoagulants (Vit K Antag)

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

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Large doses of parenterally administered penicillins and oral amoxicillin appear to increase the risk of bleeding during concurrent administration of anticoagulants.

PREDISPOSING FACTORS: Renal failure may predispose patients to penicillin-induced coagulation abnormalities. A study suggests that various inflammatory syndromes or the nature of the infection can affect INR levels. The risk for bleeding episodes may be greater in patients with additional disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor patient INR for an increase in the hypoprothrombinemic response to anticoagulants during concomitant administration of penicillins. Adjust the dose of warfarin accordingly. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: High dose parenteral administration of penicillins and oral amoxicillin have been reported to cause an increase in the hypoprothrombinemic effects of warfarin producing bleeding. Significant clinical effects have been reported with combined administration of warfarin and either carbenicillin or penicillin G. There have been several case reports and retrospective reviews documenting increased acenocoumarol and warfarin effects, including bleeding, following the addition of amoxicillin, with and without clavulanic acid, to therapy. In a randomized controlled trial, adult ambulatory patients that had no recent and ongoing infectious or inflammatory conditions received warfarin to a target INR between 2 and 3 with amoxicillin-clavulanic acid (1 gram twice daily for seven days) or placebo. The results showed the mean maximum INR increase from baseline to day 10 did not differ between amoxicillin/clavulanic acid (0.22 +/- 0.3) and the placebo period (0.24 +/- 0.6, p = 0.94). No patient experienced an INR of greater than 3.5. No bleeding events were reported during the entire study. A prospective cross-sectional observational study in 120 patients evaluated warfarin drug interactions, particularly with high-dose amoxicillin/clavulanate. The study found that patients on amoxicillin/clavulanate had a relative risk of having an INR >=4 of 4.8 compared to patients not on amoxicillin/clavulanate (95% CI 2.1-11.3, p < 0.001). This risk was primarily driven by patients on high-dose amoxicillin/clavulanate, who were 5.8 times more likely to have INR >=4 (95% CI 3.5-9.6, p<0.001). Significantly more patients on high-dose than normal dose amoxicillin/clavulanate had an INR value >= 4 (87.5% v. 28.9%, respectively). Nine out of ten patients who experienced bleeding during hospitalization were prescribed amoxicillin/clavulanate. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with penicillins (OR=1.59; 95% CI 1.14-2.20) and amoxicillin (OR=1.78; 95% CI 1.14-2.79). A case-control nested cohort study of Medicare beneficiaries with warfarin prescriptions was evaluated for antibiotic use and warfarin toxicity in older adults. An increased risk of bleeding was associated with penicillins with an adjusted odds ratio of 1.92. Parenteral penicillins linked to this monograph include: almecillin, amdinocillin, amoxicillin, ampicillin, azlocillin, bacampicillin, carbenicillin, cyclacillin, hetacillin, mezlocillin, penicillin, penicillin G, penicillin V, phenethicillin, piperacillin, and ticarcillin. Oral penicillins linked to this monograph include: amoxicillin and penicillin.

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There are no contraindication contraindications for this drug.

• Cholestatic hepatitis
• Clostridioides difficile infection
• Kidney disease with reduction in glomerular filtration rate (GFr)

There are no moderate contraindications for this drug.

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Less Frequent

• Anaphylaxis
• Dyspnea
• Serum sickness

Rare or Very Rare

• Acute coronary syndrome
• Acute generalized exanthematous pustulosis
• Acute pancreatitis
• Agranulocytosis
• Allergic dermatitis
• Anemia
• Angioedema
• Cholestasis
• Cholestatic hepatitis
• Clostridioides difficile infection
• DRESS syndrome
• Edema
• Enterocolitis
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Exfoliative dermatitis
• Hemolytic anemia
• Hepatitis
• Hepatocellular damage
• Hyperbilirubinemia
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypokalemia
• Hypotension
• Increased alanine transaminase
• Increased alkaline phosphatase
• Increased aspartate transaminase
• Increased risk of bleeding due to coagulation disorder
• Interstitial nephritis
• Jaundice
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Kounis syndrome
• Leukopenia
• Linear immunoglobulin A bullous dermatosis
• Multiple organ failure
• Non-infective meningitis
• Obstructive hyperbilirubinemia
• Pancytopenia
• Qualitative platelet disorder
• Seizure disorder
• Stevens-johnson syndrome
• Symmetrical drug-related intertriginous and flexural exanthema
• Thrombocytopenic disorder
• Thrombocytosis
• Thrombophlebitis
• Thrombotic thrombocytopenic purpura
• Toxic epidermal necrolysis

More Frequent

• Cough
• Diarrhea
• Gastrointestinal irritation
• Headache disorder
• Loose stools
• Oral candidiasis
• Vulvovaginal candidiasis

Less Frequent

• Constipation
• Contact dermatitis
• Insomnia
• Nausea
• Phlebitis after infusion
• Pruritus of skin
• Skin rash
• Upper respiratory infection
• Urticaria
• Vomiting

Rare or Very Rare

• Acute abdominal pain
• Acute cognitive impairment
• Agitation
• Back pain
• Black tarry stools
• Chills
• Crystalluria
• Dental discoloration
• Dizziness
• Dysgeusia
• Dyspepsia
• Fever
• Flatulence
• Furred tongue
• Gastritis
• Glossitis
• Hematuria
• Injection site sequelae
• Malaise
• Mucocutaneous candidiasis
• Myalgia
• Stomatitis
• Symptoms of anxiety
• Tremor
• Vaginitis

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There are no adequate or controlled studies using ampicillin/sulbactam in pregnant women. Reproduction studies in mice, rats, and rabbits using ampicillin and sulbactam doses up to 10 times the usual human dose have not revealed evidence of impaired fertility or harm to the fetus due to ampicillin/sulbactam. Because animal reproduction studies are not always predictive of human response, ampicillin/sulbactam should be used during pregnancy only when clearly needed.

Although the clinical importance is unclear, administration of ampicillin alone to pregnant women has resulted in a transient decrease in plasma concentrations of total conjugated estriol, estriol glucuronide, conjugated estrone, and estradiol; this effect also may occur following administration of ampicillin/sulbactam. IV administration of ampicillin to guinea pigs has resulted in decreased uterine tone and decreased frequency, height, and duration of uterine contractions. It is not known whether use of ampicillin/sulbactam in humans during labor or delivery could have any immediate or delayed adverse effects on the fetus, prolong the duration of labor, or increase the likelihood of forceps delivery, other obstetrical intervention, or resuscitation of the neonate.

Because ampicillin and sulbactam are distributed into milk in low concentrations, ampicillin/sulbactam should be used with caution in nursing women.

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