Penicillin G Potassium (penicillin G potassium)

Dosage of penicillin G potassium and penicillin G sodium usually is expressed in terms of penicillin G units, but also has been expressed as mg of penicillin G.

In patients with impaired renal function, doses and/or frequency of administration of penicillin G may need to be modified in response to the degree of impairment.

The manufacturers state that dosage of IM or IV penicillin G potassium or sodium should be adjusted in patients with severe renal impairment. These manufacturers and others recommend that patients with creatinine clearance less than 10 mL/minute per 1.73 m2 receive a loading dose of penicillin G using the usually recommended dose followed by 50% of the usually recommended dose given every 8-10 hours. In uremic patients with creatinine clearance greater than 10 mL/minute per 1.73 m2, the manufacturers and others recommend a loading dose of penicillin G using the usually recommended dose followed by 50% of the usually recommended dose given every 4-5 hours.

Alternatively, some clinicians suggest that if the usual dosing interval for penicillin G potassium or sodium in patients with normal renal function (creatinine clearance greater than 50 mL/minute) is every 6 or 8 hours, then the usual dose should be given every 8-12 hours in those with creatinine clearance of 10-50 mL/minute or every 12-18 hours in those with creatinine clearance less than 10 mL/minute.

Some clinicians suggest a maximum daily dosage of 4-10 million penicillin G units in adults with severe renal failure.

In patients with impaired hepatic function in addition to impaired renal function, further dosage reductions may be advisable.

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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)

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.

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 Cephalosporins & Penicillins/Probenecid

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

MECHANISM OF ACTION: Probenecid impairs the clearance of some cephalosporins and penicillins via inhibition of renal anion transporters in the proximal tubule.(49) It has also been hypothesized that probenecid may affect tissue distribution of cephalosporins.(1-5)

CLINICAL EFFECTS: The concurrent administration of probenecid may result in increased maximum concentration (Cmax), area-under-curve (AUC), and half-life of the cephalosporin or penicillin.(49) While this may improve antibiotic efficacy,(46-48) increased levels may also increase the risk for antibiotic-associated nephrotoxicity.(4)

PREDISPOSING FACTORS: Underlying renal dysfunction may increase the risk for nephrotoxicity.

PATIENT MANAGEMENT: In patients receiving the combination to improve antibiotic efficacy, monitor for antibiotic adverse effects and consider monitoring renal function. In patients receiving probenecid therapy to prevent or treat hyperuricemia, exposure to the antibiotic will be increased. A decrease in antibiotic dose or frequency may be required. The US manufacturer of piperacillin-tazobactam states probenecid should not be coadministered with piperacillin-tazobactam unless the benefit outweighs the risk.(50)

DISCUSSION: Concurrent use of probenecid with a cephalosporin or penicillin may cause an increase in the Cmax, AUC, and an increased elimination half life of the antibiotic.(6-8,49) This may be beneficial or necessary in difficult to treat infections,(46-48) but an increased risk for adverse effects should be expected. Antibiotics not dose adjusted for concurrent use with probenecid may be associated with an increased risk for adverse effects, such as nephrotoxicity. Probenecid administered concurrently with piperacillin-tazobactam prolongs the half-life of piperacillin by 21% and tazobactam by 71%. In a study in 8 healthy males, concurrent administration of probenecid (1 g) with piperacillin (1 g IM) increased piperacillin's Cmax and AUC by 30% and 60%. Renal clearance was reduced by 40%.(51) The cephalosporins affected by probenecid include cefazolin,(9-11) cephacetrile,(12,13) cephaloglycin,(14,15) cephalexin,(16-21) cephradine, (22-23) cefoxitin,(24-28) cefadroxil(29), cefaclor,(23) cefamandole,(30) ceftizoxime,(31,32) cefuroxime,(33,34) cefprozil,(35) cefonicid,(36) cefmetazole,(37) cefmenoxime,(38) and cefditoren.(39) Probenecid has been shown not to affect moxalactam,(4,40,41) ceforanide, (4,42), cefoperazone, ceftazidime(4,34,43) or ceftriaxone.(4)

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.

• Clostridioides difficile infection

There are no moderate contraindications for this drug.

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Less Frequent

• Anaphylaxis
• Hypotension

Rare or Very Rare

• Abnormal desquamation
• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Agranulocytosis
• Anemia
• Angioedema
• Bronchospastic pulmonary disease
• Clostridioides difficile infection
• Crystalluria
• DRESS syndrome
• Enterocolitis
• Eosinophilia
• Exfoliative dermatitis
• Hemolytic anemia
• Hyperkalemia
• Hypersensitivity drug reaction
• Interstitial nephritis
• Jarisch-herxheimer reaction
• Laryngismus
• Leukopenia
• Maculopapular rash
• Neutropenic disorder
• Phlebitis after infusion
• Seizure disorder
• Serum sickness
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thrombophlebitis
• Thrombotic thrombocytopenic purpura
• Toxic epidermal necrolysis

More Frequent

• Diarrhea
• Nausea

Less Frequent

• Oral candidiasis
• Pruritus of skin
• Skin rash
• Stomatitis
• Vomiting
• Vulvovaginal candidiasis

Rare or Very Rare

• Acute abdominal pain
• Arthralgia
• Fever
• Fungal infection
• Furred tongue
• Glossitis
• Headache disorder
• Hyperreflexia
• Injection site sequelae
• Malaise
• Muscle fasciculation
• Myalgia
• Tongue discoloration
• Urticaria

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Reproduction studies evaluating penicillin G in mice, rats, and rabbits have not revealed evidence of impaired fertility or harm to the fetus. Although experience with use of penicillins during pregnancy has not shown any evidence of adverse effects on the fetus, there are no adequate or controlled studies using penicillin G in pregnant women.

Some clinicians state that penicillin G is considered low risk and safe for use during pregnancy. The drug is included in the US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of syphilis during pregnancy.

The manufacturers state that penicillin G potassium or sodium should be used during pregnancy only when clearly needed.

Penicillin G is distributed into milk. Some clinicians state that penicillin G is usually considered compatible with breast-feeding. The manufacturers and others state that penicillin G potassium or sodium should be used with caution in nursing women.

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