Bicillin L-A

Drug overview for BICILLIN L-A (penicillin g benzathine):

Generic name: PENICILLIN G BENZATHINE (PEN-i-SIL-in BEN-za-theen)
Drug class: Beta-Lactams
Therapeutic class: Anti-Infective Agents

Penicillin G benzathine, a natural penicillin, is a beta-lactam antibiotic. The drug is the benzathine tetrahydrate salt of penicillin G and is a long-acting formulation of penicillin G.

Penicillin G benzathine is used only for the treatment of mild to moderately severe infections caused by organisms that are susceptible to the low, prolonged concentrations of penicillin G provided by IM penicillin G benzathine and for prophylaxis of certain infections caused by these organisms. When high, sustained concentrations of penicillin G are required for the treatment of severe infections, parenteral penicillin G potassium or sodium should be used. The fixed combinations of penicillin G benzathine and penicillin G procaine are used for the treatment of moderately severe to severe infections caused by susceptible streptococci (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections).

The fixed combinations should not be used for initial treatment of severe pneumococcal infections, including pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, or arthritis. In addition, fixed combinations of penicillin G benzathine and penicillin G procaine should not be used for the treatment of syphilis, yaws, bejel, pinta, or gonorrhea. For additional information on the uses of penicillin G benzathine, see Uses in the Natural Penicillins General Statement 8:12.16.04.

DRUG IMAGES

BICILLIN L-A 600,000 UNIT/ML
BICILLIN L-A 2,400,000 UNITS
BICILLIN L-A 1,200,000 UNITS

The following indications for BICILLIN L-A (penicillin g benzathine) have been approved by the FDA:

Indications:
Bejel
Latent bejel
Latent early syphilis
Latent late syphilis
Latent yaws
Neurosyphilis
Pharyngitis due to Streptococcus pyogenes
Pinta
Primary genital syphilis
Rheumatic fever prevention
Secondary syphilis
Symptomatic congenital syphilis
Syphilis
Tertiary bejel
Tertiary syphilis
Tertiary yaws
Tonsillitis due to Streptococcus pyogenes
Yaws

Professional Synonyms:
Asymptomatic early syphilis
Asymptomatic late bejel
Asymptomatic late syphilis
Asymptomatic late yaws
Bouba
Carate
Early latent syphilis
Enfermedad azul
Epidemic sore throat
Frambesia
Late bejel
Late latent bejel
Late latent syphilis
Late latent yaws
Late syphilis
Late yaws
Mal del pinto
Parangi
Pharyngitis due to group A beta-hemolytic streptococci
Pharyngitis due to Streptococcus epidemicus
Pian
Rheumatic fever prophylaxis
Septic sore throat
Spotted sickness
Streptococcal pharyngitis
Streptococcus pyogenes tonsillitis
Syphilitic chancre

The following dosing information is available for BICILLIN L-A (penicillin g benzathine):

Dosing
Administration
BICILLIN L-A
Generic

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

Dosage of the fixed combinations containing penicillin G benzathine and penicillin G procaine (Bicillin(R) C-R, Bicillin(R) C-R 900/300) usually is expressed in terms of the total (sum) of penicillin G units of penicillin G benzathine and penicillin G units of penicillin G procaine.

The American Academy of Pediatrics (AAP) states that the usual dosage of IM penicillin G benzathine for the treatment of mild to moderate infections in pediatric patients beyond the neonatal period is a single dose of 300,000-600,000 units in those weighing less than 27 kg or a single dose of 900,000 units in those weighing 27 kg or more. AAP states that IM penicillin G benzathine is inappropriate for the treatment of severe infections.

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin(R) C-R) is used in pediatric patients beyond the neonatal period, AAP recommends a single IM dose of 600,000 penicillin G units in those weighing less than 14 kg and a single IM dose of 900,000 to 1.2 million penicillin G units in those weighing 14-27 kg. If this fixed-combination preparation is used in those weighing 27 kg or more, AAP recommends a single dose of 2.4 million penicillin G units.

Penicillin G benzathine and fixed combinations containing penicillin G benzathine and penicillin G procaine are administered only by deep IM injection. Special precaution should be taken to avoid inadvertent intravascular or intra-arterial administration of penicillin G benzathine or fixed combinations of penicillin G benzathine and penicillin G procaine or injection into or near major peripheral nerves or blood vessels because this may result in severe and/or permanent neurovascular damage. (See Cautions: Adverse Effects.) Penicillin G benzathine and fixed combinations containing penicillin G benzathine and penicillin G procaine must not be given IV or admixed with IV solutions because inadvertent IV administration of penicillin G benzathine has been associated with cardiorespiratory arrest and death.

Dosing information for BICILLIN L-A
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
BICILLIN L-A 600,000 UNIT/ML	Maintenance	Adults inject 1 milliliter (600,000 unit) by intramuscular route every 2 weeks
BICILLIN L-A 1,200,000 UNITS	Maintenance	Adults inject 2 milliliters (1.2 million units) by intramuscular route once
BICILLIN L-A 2,400,000 UNITS	Maintenance	Adults inject 4 milliliters (2.4 million units) by intramuscular route once

No generic dosing information available.

The following drug interaction information is available for BICILLIN L-A (penicillin g benzathine):

Contraindicated
Severe
Moderate

There are 1 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Live Typhoid Vaccine/Antimicrobials 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)	VIVOTIF

Drug Interaction

Drug Names

Live Typhoid Vaccine/Antimicrobials

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)

VIVOTIF

There are 2 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Methotrexate/Penicillins 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)	JYLAMVO, METHOTREXATE, METHOTREXATE SODIUM, OTREXUP, RASUVO, TREXALL, XATMEP
Fecal Microbiota Spores/Antibiotics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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.	VOWST

Drug Interaction

Drug Names

Methotrexate/Penicillins

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)

JYLAMVO, METHOTREXATE, METHOTREXATE SODIUM, OTREXUP, RASUVO, TREXALL, XATMEP

Fecal Microbiota Spores/Antibiotics

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

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.

VOWST

There are 3 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Oral Contraceptives/Penicillins 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.	2-METHOXYESTRADIOL, AFIRMELLE, ALTAVERA, ALYACEN, AMETHIA, AMETHYST, APRI, ARANELLE, ASHLYNA, AUBRA, AUBRA EQ, AUROVELA, AUROVELA 24 FE, AUROVELA FE, AVIANE, AYUNA, AZURETTE, BALCOLTRA, BALZIVA, BEYAZ, BLISOVI 24 FE, BLISOVI FE, BRIELLYN, CAMILA, CAMRESE, CAMRESE LO, CAZIANT, CHARLOTTE 24 FE, CHATEAL, CHATEAL EQ, CRYSELLE, CYRED, CYRED EQ, DASETTA, DAYSEE, DEBLITANE, DESOGESTR-ETH ESTRAD ETH ESTRA, DIETHYLSTILBESTROL, DOLISHALE, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, ELINEST, ELLA, EMZAHH, ENPRESSE, ENSKYCE, ERRIN, ESTARYLLA, ESTRADIOL, ESTRADIOL BENZOATE, ESTRADIOL CYPIONATE, ESTRADIOL HEMIHYDRATE, ESTRADIOL HEMIHYDRATE MICRO, ESTRADIOL MICRONIZED, ESTRADIOL VALERATE, ESTRIOL, ESTRIOL MICRONIZED, ESTRONE, ETHINYL ESTRADIOL, ETHYNODIOL-ETHINYL ESTRADIOL, FALMINA, FEMLYV, FINZALA, GEMMILY, HAILEY, HAILEY 24 FE, HAILEY FE, HEATHER, ICLEVIA, INCASSIA, ISIBLOOM, JAIMIESS, JASMIEL, JENCYCLA, JOLESSA, JOYEAUX, JULEBER, JUNEL, JUNEL FE, JUNEL FE 24, KAITLIB FE, KALLIGA, KARIVA, KELNOR 1-35, KELNOR 1-50, KURVELO, LARIN, LARIN 24 FE, LARIN FE, LAYOLIS FE, LEENA, LESSINA, LEVONEST, LEVONORG-ETH ESTRAD ETH ESTRAD, LEVONORG-ETH ESTRAD-FE BISGLYC, LEVONORGESTREL-ETH ESTRADIOL, LEVORA-28, LO LOESTRIN FE, LO-ZUMANDIMINE, LOESTRIN, LOESTRIN FE, LOJAIMIESS, LORYNA, LOW-OGESTREL, LUTERA, LYLEQ, LYZA, MARLISSA, MERZEE, MIBELAS 24 FE, MICROGESTIN, MICROGESTIN 24 FE, MICROGESTIN FE, MILI, MONO-LINYAH, NATAZIA, NECON, NEXTSTELLIS, NIKKI, NORA-BE, NORETHIN-ETH ESTRA-FERROUS FUM, NORETHINDRON-ETHINYL ESTRADIOL, NORETHINDRONE, NORETHINDRONE-E.ESTRADIOL-IRON, NORGESTIMATE-ETHINYL ESTRADIOL, NORTREL, NYLIA, NYMYO, OCELLA, ORTHO TRI-CYCLEN, ORTHO-NOVUM, PHILITH, PIMTREA, PORTIA, QUARTETTE, RECLIPSEN, RIVELSA, SAFYRAL, SETLAKIN, SHAROBEL, SIMLIYA, SIMPESSE, SLYND, SPRINTEC, SRONYX, SYEDA, TARINA 24 FE, TARINA FE, TARINA FE 1-20 EQ, TAYTULLA, TILIA FE, TRI-ESTARYLLA, TRI-LEGEST FE, TRI-LINYAH, TRI-LO-ESTARYLLA, TRI-LO-MARZIA, TRI-LO-MILI, TRI-LO-SPRINTEC, TRI-MILI, TRI-NYMYO, TRI-SPRINTEC, TRI-VYLIBRA, TRI-VYLIBRA LO, TRIVORA-28, TULANA, TURQOZ, TYBLUME, TYDEMY, VELIVET, VESTURA, VIENVA, VIORELE, VOLNEA, VYFEMLA, VYLIBRA, WERA, WYMZYA FE, YASMIN 28, YAZ, ZARAH, ZOVIA 1-35, ZUMANDIMINE
Selected Anticoagulants (Vit K antag)/Selected Penicillins 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.	ANISINDIONE, DICUMAROL, JANTOVEN, WARFARIN SODIUM
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)	PROBENECID, PROBENECID-COLCHICINE

Severe List
Clostridioides difficile infection

The following adverse reaction information is available for BICILLIN L-A (penicillin g benzathine):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 35 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/Very Rare
Abnormal hepatic function tests Acute generalized exanthematous pustulosis Anaphylaxis Bloody stools Cardiac arrest Cellulitis Cerebrovascular accident Clostridioides difficile infection Dermal necrosis DRESS syndrome Dyspnea Eosinophilia Exfoliative dermatitis Gangrene Hemolytic anemia Hypersensitivity angiitis Hypotension Intestinal ischemic necrosis Kidney disease with reduction in glomerular filtration rate (GFr) Laryngeal edema Leukopenia Lymphadenopathy Methemoglobinemia Myelitis Myoglobinuria Neurogenic bladder Priapism Renal failure Rhabdomyolysis Seizure disorder Serum sickness Stevens-johnson syndrome Thrombocytopenic disorder Toxic epidermal necrolysis Vasculitis

Rare/Very Rare

Abnormal hepatic function tests
Acute generalized exanthematous pustulosis
Anaphylaxis
Bloody stools
Cardiac arrest
Cellulitis
Cerebrovascular accident
Clostridioides difficile infection
Dermal necrosis
DRESS syndrome
Dyspnea
Eosinophilia
Exfoliative dermatitis
Gangrene
Hemolytic anemia
Hypersensitivity angiitis
Hypotension
Intestinal ischemic necrosis
Kidney disease with reduction in glomerular filtration rate (GFr)
Laryngeal edema
Leukopenia
Lymphadenopathy
Methemoglobinemia
Myelitis
Myoglobinuria
Neurogenic bladder
Priapism
Renal failure
Rhabdomyolysis
Seizure disorder
Serum sickness
Stevens-johnson syndrome
Thrombocytopenic disorder
Toxic epidermal necrolysis
Vasculitis

There are 37 less severe adverse reactions.

More Frequent	Less Frequent
Diarrhea Headache disorder Nausea	Skin rash Vomiting

Rare/Very Rare
Acute cognitive impairment Blurred vision Dizziness Drowsy Ecchymosis Edema Erectile dysfunction Euphoria Fatigue Fever General weakness Hyperhidrosis Injection site abscess Injection site sequelae Localized edema Maculopapular rash Nervousness Pain Pallor Palpitations Paresthesia Periostitis Proteinuria Pruritus of skin Skin atrophy Skin ulcer Symptoms of anxiety Syncope Tachycardia Tremor Urticaria Vasodilation of blood vessels

Rare/Very Rare

Acute cognitive impairment
Blurred vision
Dizziness
Drowsy
Ecchymosis
Edema
Erectile dysfunction
Euphoria
Fatigue
Fever
General weakness
Hyperhidrosis
Injection site abscess
Injection site sequelae
Localized edema
Maculopapular rash
Nervousness
Pain
Pallor
Palpitations
Paresthesia
Periostitis
Proteinuria
Pruritus of skin
Skin atrophy
Skin ulcer
Symptoms of anxiety
Syncope
Tachycardia
Tremor
Urticaria
Vasodilation of blood vessels

The following precautions are available for BICILLIN L-A (penicillin g benzathine):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

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 benzathine in pregnant women. Some clinicians state that IM penicillin G benzathine 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 benzathine and fixed combinations containing penicillin G benzathine and penicillin G procaine should be used during pregnancy only when clearly needed.

Drug/Drug Class	Severity	Precaution Description	Pregnancy Category Description
Penicillin G Benzathine	B		Animal studies have failed to demonstrate a risk to the fetus but there are no well-controlled studies in pregnant women; or animal reproduction studies have shown an adverse effect (other than decrease in fertility), but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).

Penicillin G is distributed into milk. Some clinicians state that IM penicillin G benzathine usually is considered compatible with breast-feeding. The manufacturers and others state that penicillin G benzathine and fixed combinations of penicillin G benzathine and penicillin G procaine should be used with caution in nursing women.

Precaution Exists
Precaution exists. (No data or inconclusive human data.) Use of this drug by breast feeding mothers should be evaluated carefully.

Drug Name	Excretion Potential	Effect on Infant	Notes
Penicillin G Benzathine	Excreted.This drug is known to be excreted in human breast milk.	It is not known whether this drug has an adverse effect on the nursing infant. (No data or inconclusive human data)	May cause sensitization, diarrhea or rash in nursing infant.

No enhanced Geriatric Use information available for this drug.

Precaution Exists
Geriatric management or monitoring precaution exists.

Drug Name	Narrative	REN	HEP	CARDIO	NEURO	PULM	ENDO
Penicillin G Benzathine	Renal-May need to adjust dosage	Y	N	N	N	N	N

The following icd codes are available for BICILLIN L-A (penicillin g benzathine)'s list of indications:

Bejel
A65	Nonvenereal syphilis
Latent bejel
A65	Nonvenereal syphilis
Latent early syphilis
A50.1	Early congenital syphilis, latent
A51.5	Early syphilis, latent
Latent late syphilis
A50.6	Late congenital syphilis, latent
A52.8	Late syphilis, latent
Latent yaws
A66.8	Latent yaws
Neurosyphilis
A50.4	Late congenital neurosyphilis [juvenile neurosyphilis]
A50.40	Late congenital neurosyphilis, unspecified
A50.41	Late congenital syphilitic meningitis
A50.42	Late congenital syphilitic encephalitis
A50.43	Late congenital syphilitic polyneuropathy
A50.44	Late congenital syphilitic optic nerve atrophy
A50.45	Juvenile general paresis
A50.49	Other late congenital neurosyphilis
A52.1	Symptomatic neurosyphilis
A52.10	Symptomatic neurosyphilis, unspecified
A52.11	Tabes dorsalis
A52.12	Other cerebrospinal syphilis
A52.13	Late syphilitic meningitis
A52.14	Late syphilitic encephalitis
A52.15	Late syphilitic neuropathy
A52.16	Charcot's arthropathy (tabetic)
A52.17	General paresis
A52.19	Other symptomatic neurosyphilis
A52.2	Asymptomatic neurosyphilis
A52.3	Neurosyphilis, unspecified
Pharyngitis due to streptococcus pyogenes
J02.0	Streptococcal pharyngitis
Pinta
A67	Pinta [carate]
A67.0	Primary lesions of pinta
A67.1	Intermediate lesions of pinta
A67.2	Late lesions of pinta
A67.3	Mixed lesions of pinta
A67.9	Pinta, unspecified
Primary genital syphilis
A51.0	Primary genital syphilis
Rheumatic fever prevention
B95.0	Streptococcus, group a, as the cause of diseases classified elsewhere
J02.0	Streptococcal pharyngitis
J03.00	Acute streptococcal tonsillitis, unspecified
Secondary syphilis
A51.3	Secondary syphilis of skin and mucous membranes
A51.31	Condyloma latum
A51.32	Syphilitic alopecia
A51.39	Other secondary syphilis of skin
A51.4	Other secondary syphilis
A51.41	Secondary syphilitic meningitis
A51.42	Secondary syphilitic female pelvic disease
A51.43	Secondary syphilitic oculopathy
A51.44	Secondary syphilitic nephritis
A51.45	Secondary syphilitic hepatitis
A51.46	Secondary syphilitic osteopathy
A51.49	Other secondary syphilitic conditions
Symptomatic congenital syphilis
A50	Congenital syphilis
A50.0	Early congenital syphilis, symptomatic
A50.01	Early congenital syphilitic oculopathy
A50.02	Early congenital syphilitic osteochondropathy
A50.03	Early congenital syphilitic pharyngitis
A50.04	Early congenital syphilitic pneumonia
A50.05	Early congenital syphilitic rhinitis
A50.06	Early cutaneous congenital syphilis
A50.07	Early mucocutaneous congenital syphilis
A50.08	Early visceral congenital syphilis
A50.09	Other early congenital syphilis, symptomatic
A50.2	Early congenital syphilis, unspecified
A50.3	Late congenital syphilitic oculopathy
A50.30	Late congenital syphilitic oculopathy, unspecified
A50.31	Late congenital syphilitic interstitial keratitis
A50.32	Late congenital syphilitic chorioretinitis
A50.39	Other late congenital syphilitic oculopathy
A50.4	Late congenital neurosyphilis [juvenile neurosyphilis]
A50.40	Late congenital neurosyphilis, unspecified
A50.41	Late congenital syphilitic meningitis
A50.42	Late congenital syphilitic encephalitis
A50.43	Late congenital syphilitic polyneuropathy
A50.44	Late congenital syphilitic optic nerve atrophy
A50.45	Juvenile general paresis
A50.49	Other late congenital neurosyphilis
A50.5	Other late congenital syphilis, symptomatic
A50.51	Clutton's joints
A50.52	Hutchinson's teeth
A50.53	Hutchinson's triad
A50.54	Late congenital cardiovascular syphilis
A50.55	Late congenital syphilitic arthropathy
A50.56	Late congenital syphilitic osteochondropathy
A50.57	Syphilitic saddle nose
A50.59	Other late congenital syphilis, symptomatic
A50.7	Late congenital syphilis, unspecified
A50.9	Congenital syphilis, unspecified
Syphilis
A50	Congenital syphilis
A50.0	Early congenital syphilis, symptomatic
A50.01	Early congenital syphilitic oculopathy
A50.02	Early congenital syphilitic osteochondropathy
A50.03	Early congenital syphilitic pharyngitis
A50.04	Early congenital syphilitic pneumonia
A50.05	Early congenital syphilitic rhinitis
A50.06	Early cutaneous congenital syphilis
A50.07	Early mucocutaneous congenital syphilis
A50.08	Early visceral congenital syphilis
A50.09	Other early congenital syphilis, symptomatic
A50.1	Early congenital syphilis, latent
A50.2	Early congenital syphilis, unspecified
A50.3	Late congenital syphilitic oculopathy
A50.30	Late congenital syphilitic oculopathy, unspecified
A50.31	Late congenital syphilitic interstitial keratitis
A50.32	Late congenital syphilitic chorioretinitis
A50.39	Other late congenital syphilitic oculopathy
A50.4	Late congenital neurosyphilis [juvenile neurosyphilis]
A50.40	Late congenital neurosyphilis, unspecified
A50.41	Late congenital syphilitic meningitis
A50.42	Late congenital syphilitic encephalitis
A50.43	Late congenital syphilitic polyneuropathy
A50.44	Late congenital syphilitic optic nerve atrophy
A50.45	Juvenile general paresis
A50.49	Other late congenital neurosyphilis
A50.5	Other late congenital syphilis, symptomatic
A50.51	Clutton's joints
A50.52	Hutchinson's teeth
A50.53	Hutchinson's triad
A50.54	Late congenital cardiovascular syphilis
A50.55	Late congenital syphilitic arthropathy
A50.56	Late congenital syphilitic osteochondropathy
A50.57	Syphilitic saddle nose
A50.59	Other late congenital syphilis, symptomatic
A50.6	Late congenital syphilis, latent
A50.7	Late congenital syphilis, unspecified
A50.9	Congenital syphilis, unspecified
A51	Early syphilis
A51.0	Primary genital syphilis
A51.1	Primary anal syphilis
A51.2	Primary syphilis of other sites
A51.3	Secondary syphilis of skin and mucous membranes
A51.31	Condyloma latum
A51.32	Syphilitic alopecia
A51.39	Other secondary syphilis of skin
A51.4	Other secondary syphilis
A51.41	Secondary syphilitic meningitis
A51.42	Secondary syphilitic female pelvic disease
A51.43	Secondary syphilitic oculopathy
A51.44	Secondary syphilitic nephritis
A51.45	Secondary syphilitic hepatitis
A51.46	Secondary syphilitic osteopathy
A51.49	Other secondary syphilitic conditions
A51.5	Early syphilis, latent
A51.9	Early syphilis, unspecified
A52	Late syphilis
A52.0	Cardiovascular and cerebrovascular syphilis
A52.00	Cardiovascular syphilis, unspecified
A52.01	Syphilitic aneurysm of aorta
A52.02	Syphilitic aortitis
A52.03	Syphilitic endocarditis
A52.04	Syphilitic cerebral arteritis
A52.05	Other cerebrovascular syphilis
A52.06	Other syphilitic heart involvement
A52.09	Other cardiovascular syphilis
A52.1	Symptomatic neurosyphilis
A52.10	Symptomatic neurosyphilis, unspecified
A52.11	Tabes dorsalis
A52.12	Other cerebrospinal syphilis
A52.13	Late syphilitic meningitis
A52.14	Late syphilitic encephalitis
A52.15	Late syphilitic neuropathy
A52.16	Charcot's arthropathy (tabetic)
A52.17	General paresis
A52.19	Other symptomatic neurosyphilis
A52.2	Asymptomatic neurosyphilis
A52.3	Neurosyphilis, unspecified
A52.7	Other symptomatic late syphilis
A52.71	Late syphilitic oculopathy
A52.72	Syphilis of lung and bronchus
A52.73	Symptomatic late syphilis of other respiratory organs
A52.74	Syphilis of liver and other viscera
A52.75	Syphilis of kidney and ureter
A52.76	Other genitourinary symptomatic late syphilis
A52.77	Syphilis of bone and joint
A52.78	Syphilis of other musculoskeletal tissue
A52.79	Other symptomatic late syphilis
A52.8	Late syphilis, latent
A52.9	Late syphilis, unspecified
A53	Other and unspecified syphilis
A53.0	Latent syphilis, unspecified as early or late
A53.9	Syphilis, unspecified
A65	Nonvenereal syphilis
O98.1	Syphilis complicating pregnancy, childbirth and the puerperium
O98.11	Syphilis complicating pregnancy
O98.111	Syphilis complicating pregnancy, first trimester
O98.112	Syphilis complicating pregnancy, second trimester
O98.113	Syphilis complicating pregnancy, third trimester
O98.119	Syphilis complicating pregnancy, unspecified trimester
O98.12	Syphilis complicating childbirth
O98.13	Syphilis complicating the puerperium
Tertiary bejel
A65	Nonvenereal syphilis
Tertiary syphilis
A52	Late syphilis
A52.0	Cardiovascular and cerebrovascular syphilis
A52.00	Cardiovascular syphilis, unspecified
A52.01	Syphilitic aneurysm of aorta
A52.02	Syphilitic aortitis
A52.03	Syphilitic endocarditis
A52.04	Syphilitic cerebral arteritis
A52.05	Other cerebrovascular syphilis
A52.06	Other syphilitic heart involvement
A52.09	Other cardiovascular syphilis
A52.1	Symptomatic neurosyphilis
A52.10	Symptomatic neurosyphilis, unspecified
A52.11	Tabes dorsalis
A52.12	Other cerebrospinal syphilis
A52.13	Late syphilitic meningitis
A52.14	Late syphilitic encephalitis
A52.15	Late syphilitic neuropathy
A52.16	Charcot's arthropathy (tabetic)
A52.17	General paresis
A52.19	Other symptomatic neurosyphilis
A52.3	Neurosyphilis, unspecified
A52.7	Other symptomatic late syphilis
A52.71	Late syphilitic oculopathy
A52.72	Syphilis of lung and bronchus
A52.73	Symptomatic late syphilis of other respiratory organs
A52.74	Syphilis of liver and other viscera
A52.75	Syphilis of kidney and ureter
A52.76	Other genitourinary symptomatic late syphilis
A52.77	Syphilis of bone and joint
A52.78	Syphilis of other musculoskeletal tissue
A52.79	Other symptomatic late syphilis
A52.9	Late syphilis, unspecified
Tertiary yaws
A66.4	Gummata and ulcers of yaws
A66.5	Gangosa
A66.6	Bone and joint lesions of yaws
A66.7	Other manifestations of yaws
Tonsillitis due to streptococcus pyogenes
J03.0	Streptococcal tonsillitis
J03.00	Acute streptococcal tonsillitis, unspecified
J03.01	Acute recurrent streptococcal tonsillitis
Yaws
A66	Yaws
A66.0	Initial lesions of yaws
A66.1	Multiple papillomata and wet crab yaws
A66.2	Other early skin lesions of yaws
A66.3	Hyperkeratosis of yaws
A66.4	Gummata and ulcers of yaws
A66.5	Gangosa
A66.6	Bone and joint lesions of yaws
A66.7	Other manifestations of yaws
A66.8	Latent yaws
A66.9	Yaws, unspecified