Note: For ease of outpatient administration, the total daily dose may be administered as a 24-hour continuous infusion (AHA [Baddour 2015]; IDSA [Berbari 2015]; IDSA [Osmon 2013]; Walton 2007).
Actinomycosis, severe or extensive: IV: 10 to 20 million units/day as a continuous infusion or in divided doses every 4 to 6 hours for 4 to 6 weeks followed by appropriate long-term oral therapy (Brook 2008; Brook 2020).
Bloodstream infection:
Pathogen-directed therapy for Enterococcus spp. (off-label use): IV: 18 to 30 million units/day as a continuous infusion or in divided doses every 4 hours; use as part of an appropriate combination regimen in the setting of suspected endocarditis or critical illness (IDSA [Mermel 2009]; Murray 2020). Duration of therapy is 7 to 14 days for uncomplicated infection (ie, fever resolution within 72 hours and absence of metastatic focus of infection or endovascular hardware) (IDSA [Mermel 2009]). Some experts recommend a duration of 5 to 7 days for uncomplicated infection if blood cultures clear within 24 hours (Murray 2020).
Pathogen-directed therapy for Listeria monocytogenes: IV: 24 million units/day in divided doses every 4 hours; use in combination with gentamicin for nonpregnant patients. Duration should be individualized based on patient factors, source and extent of infection, and clinical response. Penicillin is usually continued for at least 2 weeks; patients who are immunocompromised warrant a longer course (eg, at least 3 to 6 weeks) (Gelfand 2020; Hof 1997).
Pathogen directed therapy for beta-hemolytic streptococci: IV: 18 to 24 million units/day in divided doses every 4 hours. Duration of therapy is generally 14 days; some experts suggest a shorter course (eg, 10 days) for patients with rapid clearance of bacteremia and clinical improvement (Barshak 2022; Wessels 2020).
Pathogen-directed therapy for group D streptococci (Streptococcus bovis/Streptococcus equinus complex) (alternative agent): IV: 12 to 24 million units/day in divided doses every 4 hours. Duration of therapy is 14 days in the absence of other clinical manifestations (Hoen 2020).
Botulism, wound (adjunctive agent following antitoxin administration): IV: 18 to 20 million units/day in divided doses every 4 to 6 hours in combination with wound debridement; duration depends on extent of the wound (Pegram 2020; manufacturer's labeling).
Diphtheria (adjunctive agent following antitoxin administration) (alternative agent): IV: 2 to 3 million units/day in divided doses every 4 to 6 hours for 10 to 12 days (manufacturer's labeling).
Endocarditis, treatment:
Enterococcus, native or prosthetic valve (penicillin-susceptible/gentamicin-susceptible) (off-label use): IV: 18 to 30 million units/day as a continuous infusion or in divided doses every 4 hours in combination with an aminoglycoside (eg, gentamicin). Duration is usually 6 weeks; for patients with native valve endocarditis and symptoms <3 months, antibiotic therapy may be given for 4 weeks. Note: Reserve this regimen for patients with CrCl >50 mL/minute (AHA [Baddour 2015]). For native-valve endocarditis due to ampicillin-susceptible Enterococcus faecalis, some experts prefer a different beta-lactam combination regimen (Chu 2020).
Viridans group streptococci and Streptococcus gallolyticus (S. bovis):
Native valve: Highly penicillin-susceptible (minimum inhibitory concentration [MIC] ≤0.12 mcg/mL): IV: 12 to 18 million units/day as a continuous infusion or in divided doses every 4 or 6 hours for 4 weeks; for patients with uncomplicated infection, rapid response to therapy, and no underlying disease, an alternative is 12 to 18 million units/day as a continuous infusion or in divided doses every 4 hours in combination with gentamicin for 2 weeks (AHA [Baddour 2015]).
Native valve: Relatively penicillin-resistant (MIC >0.12 to <0.5 mcg/mL): IV: 24 million units/day as a continuous infusion or in divided doses every 4 or 6 hours for 4 weeks in combination with gentamicin for the first 2 weeks (AHA [Baddour 2015]).
Native valve: Penicillin-resistant (MIC ≥0.5 mcg/mL): IV: 18 to 30 million units/day as a continuous infusion or in divided doses every 4 or 6 hours in combination with gentamicin. The duration of this regimen is not well established; infectious diseases consultation recommended (AHA [Baddour 2015]).
Prosthetic valve: Highly penicillin-susceptible (MIC ≤0.12 mcg/mL): IV: 24 million units/day as a continuous infusion or in divided doses every 4 or 6 hours for 6 weeks (with or without concomitant gentamicin for the first 2 weeks) (AHA [Baddour 2015]). Some experts prefer giving in combination with gentamicin for all patients without contraindications (Karchmer 2020).
Prosthetic valve: Relatively or fully penicillin-resistant (MIC >0.12 mcg/mL): IV: 24 million units/day as a continuous infusion or in divided doses every 4 or 6 hours in combination with gentamicin for 6 weeks (AHA [Baddour 2015]). For relatively resistant strains, some experts prefer a shorter duration of the gentamicin component (≥2 weeks) (Karchmer 2020).
Leptospirosis, severe (off-label use): IV: 1.5 million units every 6 hours for 7 days (Panaphut 2003; Suputtamongkol 2004; Watt 1988).
Lyme disease (Borrelia spp. infection) (alternative agent) (off-label use):
Carditis, severe disease (patients who are symptomatic, have second- or third-degree atrioventricular block, or have first-degree atrioventricular block with PR interval ≥300 msec): IV: 18 to 24 million units/day in divided doses every 4 hours until high-grade atrioventricular block resolved and PR interval <300 msec; may switch to oral therapy to complete a total of 14 to 21 days (Hu 2021; IDSA/AAN/ACR [Lantos 2021]).
Acute neurologic disease (eg, meningitis, radiculopathy), patients requiring hospitalization: IV: 18 to 24 million units/day in divided doses every 4 hours for 14 to 21 days (Halperin 2013; IDSA/AAN/ACR [Lantos 2021]; Sanchez 2016).
Late neurologic disease: IV: 18 to 24 million units/day in divided doses every 4 hours for 14 to 28 days (IDSA/AAN/ACR [Lantos 2021]); some experts favor a duration of 28 days (Hu 2021).
Recurrent arthritis after adequate oral regimen: IV: 18 to 24 million units/day in divided doses every 4 hours for 14 days; may extend to 28 days if inflammation is not resolving (IDSA/AAN/ACR [Lantos 2021]).
Meningitis, bacterial:
Pathogen-directed therapy for Cutibacterium acnes, L. monocytogenes, Neisseria meningitidis (with MIC <0.1 mcg/mL), Streptococcus agalactiae, or Streptococcus pneumoniae (with MIC ≤0.06 mcg/mL): IV: 4 million units every 4 hours (Hof 1997; IDSA [Tunkel 2004]; IDSA [Tunkel 2017]). For treatment of L. monocytogenes, use as part of an appropriate combination regimen (Drevets 1994; Hof 1997; IDSA [Tunkel 2004]). Treatment duration is 7 to 21 days, depending on causative pathogen(s) and clinical response (IDSA [Tunkel 2004]; IDSA [Tunkel 2017]).
Neurosyphilis (including ocular and otosyphilis ): Note: Penicillin desensitization and treatment is recommended in patients with a history of severe penicillin allergy (CDC [Workowski 2021]).
IV: 18 to 24 million units/day as a continuous infusion or in divided doses every 4 hours for 10 to 14 days. For late neurosyphilis (syphilis exposure >1 year ago), may consider administration of penicillin G benzathine following initial IV penicillin G aqueous therapy to provide a comparable total duration of therapy for late syphilis (CDC [Workowski 2021]).
Odontogenic soft tissue infection, pyogenic (alternative agent): IV: 2 to 4 million units every 4 to 6 hours in combination with metronidazole; following clinical improvement, transition to oral step-down therapy and continue antibiotics until resolution, typically for a total of 7 to 14 days (Chow 2022).
Osteomyelitis and/or discitis (off-label use):
Pathogen-directed therapy for C. acnes, Enterococcus spp. (penicillin-susceptible), or beta-hemolytic streptococci: IV: 20 to 24 million units/day as a continuous infusion or in divided doses every 4 hours, generally for ≥6 weeks depending on patient-specific factors such as organism, extent of infection, debridement, and clinical response. Shorter courses are appropriate if the affected bone is completely resected (eg, by amputation) (IDSA [Berbari 2015]; Osmon 2020).
Prosthetic joint infection (off-label use):
Pathogen-directed therapy for C. acnes, Enterococcus spp. (penicillin-susceptible), or Streptococcus spp.: IV: 20 to 24 million units/day as a continuous infusion or in divided doses every 4 hours (IDSA [Osmon 2013]). Duration varies but is generally 4 to 6 weeks depending on patient-specific factors, infection site, and intervention (Berbari 2022; IDSA [Osmon 2013]). Note: For enterococcal infections, the addition of an aminoglycoside is optional (IDSA [Osmon 2013]), but some experts prefer other regimens in the setting of retained hardware unless an aminoglycoside-impregnated implant is present, in which case beta-lactam monotherapy is likely sufficient (Berbari 2022).
Rat bite fever:
Uncomplicated infection: IV: 200,000 units every 4 hours; if patient clinically improves, may switch to an oral antibiotic after 5 to 7 days to complete a 14-day course (CDC 2005; Elliott 2007; King 2022; Roughgarden 1965).
Serious invasive infection (including bacteremia, meningitis, endocarditis, and other focal organ involvement): IV: 12 to 18 million units/day as a continuous infusion or in divided doses every 4 to 6 hours; may increase dose to 24 million units/day in patients with an isolate that is not highly penicillin-susceptible (eg, MIC >0.1 mcg/mL) or in patients with prosthetic valve endocarditis. Duration depends on site of infection and extent of disease (eg, 4 weeks for endocarditis) (King 2022).
Skin and soft tissue infection, streptococcal (group A Streptococcus, beta-hemolytic streptococci) (off-label use):
Erysipelas: IV: 2 to 4 million units every 4 to 6 hours. Total duration of therapy is ≥5 days (including oral step-down therapy); may extend to 14 days depending on severity and clinical response (IDSA [Stevens 2014]; Spelman 2022). Note: Some experts favor other regimens unless a streptococcal- or penicillin-susceptible infection has been microbiologically confirmed (Spelman 2022).
Necrotizing soft tissue infection: Note: Use in conjunction with early and aggressive surgical exploration and debridement of necrotic tissue.
IV: 4 million units every 4 hours in combination with clindamycin. Once the patient is clinically and hemodynamically stable for 48 to 72 hours, can give penicillin monotherapy. Total duration is individualized and depends on need for further debridement and patient clinical status (IDSA [Stevens 2014]; Stevens 2021).
Streptococcus (group B), maternal prophylaxis for prevention of neonatal disease (off-label use): IV: 5 million units as a single dose at onset of labor or prelabor rupture of membranes, then 2.5 to 3 million units every 4 hours until delivery (ACOG 2020).
Tetanus (Clostridium tetani infection) (adjunctive agent following tetanus immune globulin and vaccine administration) (alternative agent): IV: 2 to 4 million units every 4 to 6 hours for 7 to 10 days (Sexton 2020; manufacturer's labeling).
Toxic shock syndrome, streptococcal: IV: 4 million units every 4 hours in combination with clindamycin. Duration of therapy depends on extent and severity of infection and response to treatment; treat patients who are bacteremic for ≥14 days (Stevens 2021; Walker 2014).
Manufacturer's labeling:
Uremic patients with CrCl >10 mL/minute/1.73 m2: Administer a usual recommended dose followed by 50% of the usual recommended dose every 4 to 5 hours.
CrCl <10 mL/minute/1.73 m2: Administer a normal dose followed by 50% of the normal dose every 8 to 10 hours.
Alternative recommendation:
GFR >50 mL/minute: No dosage adjustment necessary (Aronoff 2007).
GFR 10-50 mL/minute: Administer 75% of the normal dose (Aronoff 2007).
GFR <10 mL/minute: Administer 20% to 50% of the normal dose (Aronoff 2007).
End-stage renal disease on intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days) (Heintz 2009): Administer a normal dose followed by either 25% to 50% of normal dose every 4 to 6 hours or 50% to 100% of normal dose every 8 to 12 hours. For mild-to-moderate infections, administer 0.5 to 1 million units every 4 to 6 hours or 1 to 2 million units every 8 to 12 hours. For neurosyphilis, endocarditis, or serious infections, administer up to 2 million units every 4 to 6 hours; administer after dialysis on dialysis days or supplement with 500,000 units after dialysis. Note: Dosing dependent on the assumption of 3-times-weekly, complete IHD sessions.
Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:
CVVH: Loading dose of 4 million units, followed by 2 million units every 4 to 6 hours.
CVVHD: Loading dose of 4 million units, followed by 2 to 3 million units every 4 to 6 hours.
CVVHDF: Loading dose of 4 million units, followed by 2 to 4 million units every 4 to 6 hours.
There are no dosage adjustments provided in the manufacturer's labeling. However, the manufacturer's labeling recommends further adjustment of doses adjusted for renal impairment in patients with both renal and hepatic impairment.
(For additional information see "Penicillin G (intravenous and short-acting intramuscular): Pediatric drug information")
General dosing, susceptible infection (non-CNS): Infants, Children, and Adolescents: IM, IV: 100,000 to 300,000 units/kg/day in divided doses every 4 to 6 hours; maximum daily dose: 24 million units/day (Red Book [AAP 2021]).
Anthrax, systemic (including meningitis); treatment: Note: Consult public health officials for event-specific recommendations.
Infants, Children, and Adolescents: IV: 400,000 units/kg/day in divided doses every 4 hours; maximum dose: 4 million units/dose. Use as part of an appropriate combination regimen for ≥14 days if meningitis is excluded or ≥14 to 21 days if meningitis cannot be excluded, and until patient clinically stable. Note: May transition to oral step-down therapy when clinically appropriate to complete course if meningitis has been excluded. Treatment must be followed by prophylaxis for a total antibiotic course of 60 days (AAP [Bradley 2014]).
Diphtheria: Infants, Children, and Adolescents: IM, IV: 150,000 to 250,000 units/kg/day in divided doses every 6 hours for 7 to 10 days (manufacturer's labeling). AAP suggests a duration of 14 days (Red Book [AAP 2021]).
Endocarditis, bacterial; treatment: Children and Adolescents: IV: 200,000 to 300,000 units/kg/day in divided doses every 4 hours; maximum daily dose: 24 million units/day; treat for ≥4 weeks; longer durations may be necessary; may use in combination with gentamicin for some resistant organisms (AHA [Baltimore 2015]). Note: For endocarditis from rat-bite fever/haverhill fever, the manufacturer recommends a lower dose of 150,000 to 250,000 units/kg/day in divided doses every 4 hours; maximum daily dose: 20 million units/day.
Lyme disease (Borrelia spp. infection) (alternative agent): Infants, Children, and Adolescents: IV: 200,000 to 400,000 units/kg/day in divided doses every 4 hours; maximum daily dose: 24 million units/day. Duration of therapy depends on clinical syndrome; treat meningitis or radiculopathy for 14 to 21 days (IDSA/AAN/ACR [Lantos 2021]).
Meningitis, including healthcare-associated ventriculitis and meningitis: Infants, Children, and Adolescents: IV: 300,000 to 400,000 units/kg/day divided every 4 to 6 hours; maximum dose: 4 million units/dose; maximum daily dose: 24 million units/day (IDSA [Tunkel 2004]; IDSA [Tunkel 2017]; Red Book [AAP 2021]).
Pneumonia, community-acquired (CAP): Infants >3 months and Children:
Empiric treatment or S. pneumoniae (moderate to severe; MICs to penicillin ≤2.0 mcg/mL): IV: 200,000 to 250,000 units/kg/day divided every 4 to 6 hours (IDSA/PIDS [Bradley 2011]).
Group A Streptococcus (moderate to severe): IV: 100,000 to 250,000 units/kg/day divided every 4 to 6 hours (IDSA/PIDS [Bradley 2011]).
Skin and soft tissue infections (Streptococcal infection or necrotizing infections due to Clostridium or Streptococcus species): Infants, Children, and Adolescents: IV: 60,000 to 100,000 units/kg/dose every 6 hours; maximum dose: 4 million units/dose; adult dose: 2 to 4 million units every 4 to 6 hours. For necrotizing infections, use in combination with clindamycin and continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014]).
Syphilis:
Congenital: Infants and Children: IV: 50,000 units/kg/dose every 4 to 6 hours for 10 days (CDC [Workowski 2015]).
Neurosyphilis (including ocular syphilis):
Infants and Children: IV: 50,000 units/kg/dose every 4 to 6 hours for 10 to 14 days; maximum daily dose: 24 million units/day.
Adolescents: IV: 3 to 4 million units every 4 hours or as a continuous infusion for 10 to 14 days; maximum daily dose: 24 million units/day (CDC [Workowski 2015]).
Tetanus; treatment: Infants, Children, and Adolescents: IV: 100,000 units/kg/day in divided doses every 6 hours in combination with tetanus immune globulin; maximum daily dose: 20 million units/day (Bradley 2021; manufacturer's labeling). Continue penicillin for 7 to 10 days (Red Book [AAP 2021]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children, and Adolescents: IM, IV:
Uremic patients with CrCl >10 mL/minute/1.73 m2: Administer a normal dose followed by 50% of the normal dose every 4 to 5 hours.
CrCl <10 mL/minute/1.73 m2: Administer a normal dose followed by 50% of the normal dose every 8 to 10 hours.
Hemodialysis: Dialyzable.
There are no dosage adjustments provided in the manufacturer's labeling; however, the manufacturer's labeling recommends further adjustment of doses adjusted for renal impairment in patients with both renal and hepatic impairment.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as potassium [preservative free]:
Generic: 20,000 units/mL (50 mL); 40,000 units/mL (50 mL); 60,000 units/mL (50 mL)
Solution Reconstituted, Injection, as potassium [preservative free]:
Pfizerpen: 5,000,000 units (1 ea); 20,000,000 units (1 ea)
Pfizerpen: 5,000,000 units (1 ea); 20,000,000 units (1 ea) [pyrogen free]
Generic: 5,000,000 units (1 ea); 20,000,000 units (1 ea)
Solution Reconstituted, Injection, as sodium [preservative free]:
Generic: 5,000,000 units (1 ea)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Generic: 1,000,000 units (1 ea); 10,000,000 units (1 ea)
Solution Reconstituted, Injection, as sodium:
Generic: 5,000,000 units (1 ea)
IM: Administer IM by deep injection in the upper outer quadrant of the buttock. Administer injection around-the-clock to promote less variation in peak and trough levels.
IV: Usually administered by intermittent infusion. In some centers, large doses may be administered by continuous IV infusion. Note: The 20 million unit dosage form may be administered by IV infusion only.
Intermittent IV: Infuse over 15 to 30 minutes.
Parenteral:
IM: Administer IM by deep injection in the upper outer quadrant of the buttock. Administer injection around-the-clock to promote less variation in peak and trough levels.
IV: Usually administered by intermittent infusion. In some centers, large doses may be administered by continuous IV infusion. The potassium or sodium content of the dose should be considered when determining the infusion rate.
Intermittent IV: Infuse over 15 to 30 minutes
Continuous IV infusion: Daily dose may be administered as a continuous infusion over 24 hours, or smaller increments (eg, 24 hour dose divided into two 12-hour infusions)
Anthrax: Treatment of anthrax caused by Bacillus anthracis.
Actinomycosis, severe or extensive: Treatment of actinomycosis (cervicofacial disease and thoracic and abdominal disease) caused by Actinomyces israelii.
Bloodstream infection: Treatment of bloodstream infection caused by Streptococcus spp., Listeria monocytogenes, Neisseria meningitidis, and Pasteurella multocida.
Botulism, wound: Treatment of botulism caused by Clostridium spp. as an adjunctive agent following antitoxin administration.
Diphtheria: Treatment of diphtheria caused by Corynebacterium diphtheriae as an adjunctive agent following antitoxin administration.
Endocarditis, treatment: Treatment of endocarditis caused by Streptococcus spp. and Erysipelothrix rhusiopathiae.
Meningitis, bacterial: Treatment of meningitis caused by L. monocytogenes, N. meningitidis, P. multocida, and Streptococcus spp.
Neurosyphilis (including ocular and otosyphilis): Treatment of syphilis (congenital and neurosyphilis) caused by Treponema pallidum.
Odontogenic soft tissue infection, pyogenic: Treatment of pyogenic odontogenic infection, including severe infections of the oropharynx, caused by Fusobacterium spp. and spirochetes.
Rat bite fever: Treatment of rat bite fever (including Haverhill fever) caused by Spirillum minus or Streptobacillus moniliformis.
Tetanus: Treatment of tetanus caused by Clostridium tetani as an adjunctive agent following tetanus immune globulin and vaccine administration.
Toxic shock syndrome: Treatment of toxic shock syndrome caused by Streptococcus spp.
Bloodstream infection; Endocarditis, treatment; Leptospirosis, severe; Lyme disease (Borrelia spp. infection); Osteomyelitis and/or discitis; Prosthetic joint infection; Skin and soft tissue infection, streptococcal; Streptococcus (group B), maternal prophylaxis for prevention of neonatal disease
Penicillin may be confused with penicillamine
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Local thrombophlebitis, localized phlebitis
Central nervous system: Coma (high doses), hyperreflexia (high doses), myoclonus (high doses), seizure (high doses)
Dermatologic: Exfoliative dermatitis, maculopapular rash, skin rash
Endocrine & metabolic: Electrolyte disorder (high doses)
Gastrointestinal: Clostridioides difficile associated diarrhea, Clostridioides difficile colitis
Hematologic & oncologic: Neutropenia, positive direct Coombs test (rare, high doses)
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction (immediate and delayed), serum sickness-like reaction
Immunologic: Jarisch-Herxheimer reaction
Local: Pain at injection site
Renal: Acute interstitial nephritis (high doses), renal tubular disease (high doses)
Hypersensitivity to any penicillin or any component of the formulation
Documentation of allergenic cross-reactivity for beta-lactams (eg, penicillins and cephalosporins) is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Anaphylactic/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity (including cephalosporins) or history of sensitivity to multiple allergens. Use with caution in asthmatic patients. If a serious reaction occurs, discontinue treatment and institute supportive measures.
• Neurovascular damage: Avoid intra-arterial administration or injection into or near major peripheral nerves or blood vessels since such injections may cause severe and/or permanent neurovascular damage.
• Severe cutaneous adverse reactions: Severe cutaneous adverse reactions (SCAR) (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis) have been reported; discontinue immediately if SCAR is suspected.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended. In the presence of concomitant hepatic impairment, further dosage adjustment may be needed.
• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.
Special populations:
• Neonates: Neonates may have decreased renal clearance of penicillin and require frequent dosage adjustments depending on age.
Other warnings/precautions:
• Electrolyte imbalance: Product contains sodium and potassium; high doses of IV therapy may alter serum levels. If high doses (eg, >10 million units) are used, administer at a slower rate (eg, >30 minutes for intermittent IV infusion).
Substrate of OAT1/3
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acemetacin: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Risk C: Monitor therapy
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Dichlorphenamide: Penicillins may enhance the hypokalemic effect of Dichlorphenamide. Risk C: Monitor therapy
Immune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Sodium Benzoate: Penicillins may diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Tetracyclines: May diminish the therapeutic effect of Penicillins. Risk C: Monitor therapy
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Penicillin G crosses the placenta.
In a study of women administered IV penicillin G (parenteral/aqueous) for group B streptococcal (GBS) disease, peak fetal concentrations occurred within 1 hour (Barber 2008).
Penicillin is widely used in pregnant women. Based on available data, penicillin is generally considered compatible for use during pregnancy (Ailes 2016; Bookstaver 2015; Crider 2009; Damkier 2019; Erić 2012; Heinonen 1977; Lamont 2014; Muanda 2017a; Muanda 2017b).
Maternal penicillin G serum concentrations are not decreased in obese patients following IV administration for GBS prophylaxis; however, cord blood concentrations may be less. Based on available data, minimum inhibitory concentrations for GBS are still achieved (McCoy 2020). Penicillin G (parenteral/aqueous) is the drug of choice for intrapartum prophylaxis to prevent neonatal GBS early onset disease. Untreated asymptomatic GBS disease can result in maternal urinary tract infection, intraamniotic infection, endometritis, preterm labor, and/or stillbirth. Vertical transmission from the mother can cause sepsis, pneumonia, or meningitis in the newborn. Treatment is intended to prevent early-onset disease in newborns. Prophylaxis is reserved for pregnant patients with a positive GBS vaginal or rectal screening in late gestation, GBS bacteriuria during the current pregnancy, history of birth of an infant with early-onset GBS disease, and unknown GBS culture status with any of the following: birth <37 0/7 weeks gestation, intrapartum fever, prolonged rupture of membranes, known GBS positive in a previous pregnancy, or intrapartum nucleic acid amplification testing positive for GBS (ACOG 2020).
Penicillin G is the drug of choice for treatment of syphilis during pregnancy (CDC [Workowski 2021]). Untreated maternal syphilis can cause congenital syphilis which is associated with bone deformities, neurologic impairment, stillbirth, or neonatal death (USPSTF 2018). Symptoms of congenital syphilis may include hepatosplenomegaly, jaundice, nonimmune hydrops, pseudoparalysis of an extremity, rhinitis, or skin rash. The CDC Sexually Transmitted Diseases Treatment Guidelines provide recommendations for the treatment of syphilis in pregnant patients. The penicillin regimen (dose, duration, and preparation) for the treatment of pregnant patients is the same as for a nonpregnant patient and depends on the stage of syphilis. Parenteral penicillin G is the only agent with documented efficacy in pregnancy. Patients who are allergic to penicillin should be desensitized and treated with penicillin. Pregnant patients being treated for latent syphilis must repeat the full course of therapy if any doses are missed. A Jarisch-Herxheimer reaction may occur in any patient within the first 24 hours of therapy, including pregnant patients. This reaction may induce early labor, fetal distress, or stillbirth (rare); however, it is not a reason to prevent or delay maternal therapy (CDC [Workowski 2021]).
Maternal infection with Bacillus anthracis may cause preterm labor, fetal infection, fetal distress, or fetal loss. Maternal death may also occur. When IV therapy is required for anthrax infection in pregnant and postpartum patients, penicillin G may be used as an alternative agent. The dose and duration of antibiotic therapy in pregnant and postpartum patients is the same as in nonpregnant adults. Adjustments in dose for pregnancy are not recommended until additional pharmacokinetic data becomes available (Meaney-Delman 2014).
Penicillin G is present in breast milk.
Concentrations of penicillin class antibiotics in breast milk are limited (Nau 1987). Following a single dose of penicillin G 360 mg IM to 2 or 3 women 5 to 7 days postpartum, peak breast milk concentrations (0.32 mcg/mL) occurred 1 hour after the dose and decreased to trace amounts 6 hours after the dose. The highest maternal serum concentration (0.92 mcg/mL) was found 1 hour after the dose, also decreasing to trace amounts 6 hours after the dose (Matsuda 1984). Higher breast milk concentrations occurred following multiple IM doses, however, exposure remained minimal (Greene 1946).
In general, antibiotics that are present in breast milk may cause nondose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea (WHO 2002).
Although the manufacturer recommends that caution be exercised when administering penicillin to breastfeeding patients, penicillin is considered compatible with breastfeeding when used in usual recommended doses (WHO 2002).
Some products may contain potassium and/or sodium.
Periodic electrolyte, hepatic, renal, cardiac and hematologic function tests during prolonged/high-dose therapy; observe for signs and symptoms of anaphylaxis during first dose. In older adults, especially those with decreased renal function, monitor for seizure activity.
Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria
Distribution: Poor penetration across blood-brain barrier, despite inflamed meninges
Relative diffusion from blood into CSF: Poor unless meninges inflamed (exceeds usual MICs)
CSF:blood level ratio: Inflamed meninges: 2% to 6%
Half-life elimination:
Neonates: <6 days of age: 3.1 hours; ≥14 days of age: 1.4 hours
Adults: Normal renal function: 31 to 50 minutes
End-stage renal disease (ESRD): 6 to 20 hours (Aronoff 2007)
Time to peak, serum: IV: Immediately after infusion
Excretion: Urine (58% to 85% as unchanged drug)
Altered kidney function: Excretion is delayed.
Hepatic function impairment: When combined with impaired renal function, elimination is further delayed.
Older adult: Renal clearance may be delayed (caused by decreased renal function).
Anti-infective considerations:
Parameters associated with efficacy:
Time dependent, associated with time free drug concentration (fT) > minimum inhibitory concentration (MIC), goal: ≥50% fT > MIC (bactericidal) (Craig 1996; Craig 1998).
Expected drug exposure in adults with normal renal function:
5 million units over 3 to 5 minutes (single dose): 400 mg/L (5 to 6 minutes postinfusion); 273 mg/L (10 minutes postinfusion); 3 mg/L (4 hours postinfusion).
Postantibiotic effect: Minimal bacterial killing continues after penicillin concentration falls below the MIC of targeted pathogen and varies based on the organism:
Gram-positive cocci: 1.5 to 3.5 hours (Craig 1991; Garcia 1995; Zhanel 1991).
Gram-negative bacilli: 0 to 1.5 hours (Craig 1991; Zhanel 1991).
Solution (reconstituted) (Penicillin G Potassium Injection)
5000000 unit (per each): $5.23 - $42.18
20000000 unit (per each): $59.99 - $160.26
Solution (reconstituted) (Penicillin G Sodium Injection)
5000000 unit (per each): $57.60
Solution (reconstituted) (Pfizerpen Injection)
5000000 unit (per each): $15.26
20000000 unit (per each): $61.06
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