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Penicillin GSharon S.Castle VA Medical Center,Huntington,USAã2007Elsevier Inc.All rights reserved.IntroductionPenicillin G is produced by fermentation of Penicillium chrysogenum.Because of its poor oral bioavailability,it is generally given intravenously as a sodium,potassium,benzathine, or procaine salt.A beta-lactam antibiotic,penicillin G is active against gram-positive cocci,including nonpenicillin resistant streptococcal,staphylococcal,and enterococcal species.It also displays activity against some gram positive anaerobic organisms and gram negative anaerobic organisms,and has limited activity against gram negative aerobes,such as Neisseria species.However,penicillin G is rarely used to treat these infections. Penicillin G is active against certain spirochetes and is commonly used to treat syphilis. It is also employed for the treatment of skin and skin structure infections,meningitis,and endocarditis.There are a number of organisms that are resistant to penicillin G. NomenclatureName of the ClinicalFormPenicillin GRelated Names Source:EMTREE Benzylpenicillin;american penicillin;angicillin;bacinol;benzoyl penicillin;benzyl penicillin;benzylpenicillin;benzyl penicillinic acid;benzylpenicillinic acid;benzylpenicilloyl; bupenna;cilligram;cilloral;confets;conspen;depot penicillin;dis pen;dropcillin;gelacillin;g penicillin;gynocillin; iricillin;jacillin;jenets;kcillin;keracillin;liquacillin;liquapen; megapen;nebutab;novocilline;orapen;penaire;penalev; penasoid;pendex;pen eff;peneucin;penichrysin;penicillan; penicillin;penicillin9;penicillin a;penicilline;penicillineg; penioral;penisem;pentab;penzal;perolety;pharmacillin;6 phenylacetamidopenicillanate;6(phenylacetamido) penicillanic acid;6phenylacetamidopenicillanic acid; phenylmethylpenicillin;pradupen;purapeng;readcillin; retarpen;semi synthetic penicillin;sol tabs;solupen;specillin g;stanpen500;sugracillin;til pen;unicilina;vagicillin; Benzylpenicillin;(2S,5R,6R)-3,3-Dimethyl-7-oxo-6-phenylacetylamino-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid;drop cillin;k cillin;penicilline g;purapen gChemical NamesCAS Number61-33-61Basic ChemistryChemical StructureStructureCommentsPenicillin G is available as a potassium,sodium,benzathine,and procaine salt.Chemical Formula C16H18N2O4SPropertiesPhysical PropertiesPenicillin G benzathine is a white,odorless,crystalline powder,whereas penicillin G potassium is colorless or white crystals or a white,crystalline powder,and penicillin G sodium is a colorless or white crystals,or a white to slightly yellow,crystalline powder.Penicillin G sodium and potassium are odorless or practically odorless.Penicillin G procaine occurs as white crystals or a white,very fine,crystalline powder Hospital Formulary System (2001).Molecular Weight 334.394SolubilityThe solubility of penicillin G benzathine is approximately 0.2–0.3mg/ml in water and 15.4mg/ml in alcohol at 25 C.Penicillin G potassium is very soluble in water,0.9%sodium chloride,and in dextrose solutions,and is sparingly soluble in alcohol.The solubility of penicillin G sodium is approximately 25mg/ml in water at 25 C.Penicillin G procaine is soluble atapproximately 4–4.5mg/ml in water and 3.33mg/ml in alcohol American Hospital Formulary System (2001).Ionization Constant Value SaltConditionsReference Comments pka2.8Williams (2002)HAHuman PharmacokineticsPenicillin G is poorly absorbed following oral administration,and is widely distributed throughout the body.It is elimination is primarily by renal tubular secretion in urine.The various salt forms of Penicillin G have different pharmacokinetic properties.Penicillin G2Pharmacokinetic PropertiesValue Units Prep.andRoute ofAdmin.Reference CommentsAbsorptionBioavailability15–30%p.o.AmericanHospitalFormularySystem(2001)Penicillin G is poorly absorbed following oral administration.The sodium and potassium salts are rapidly absorbed following i.m. injection.The benzathine and procaine salts are relatively insoluble and are slowly absorbed and hydrolyzed to penicillin G.The benzathine and procaine forms have a more prolonged action.DistributionVolume of Distribution0.53–0.67l/kg AmericanHospitalFormularySystem(2001)Penetration of penicillin into the cerebrospinal fluid is best with inflamed meninges or when it is administered concomitantly with probenecid.Plasma Protein Binding45–68%AmericanHospitalFormularySystem(2001)MetabolismPlasma Half-Life0.4–0.9hrs AmericanHospitalFormularySystem(2001)Bio Half-LifeClearanceRoutes of Elimination Elimination of penicillin is primarily by way of renal tubular secretion.Up to30%of an i.m.dose of penicillin G sodium is metabolized.Intramuscularbenzathine penicillin G remains in serum for up to4weeks and in urine forup to12weeks.Procaine penicillin G remains in the serum for1–2daysfollowing i.m.administration.Targets-PharmacodynamicsPenicillin G is a bactericidal beta-lactam antibiotic.It inhibits bacterial cell wall synthesisby binding to one or more of the penicillin-binding proteins(e.g.,carboxypeptidases, endopeptidases,transpeptidases)in the bacterial cytoplasmic membrane.PenicillinG inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cellwalls,thus inhibiting cell wall biosynthesis.Bacterial cell death occurs through the actionof the autolytic enzymes,autolysins,hydrolases,and murein hydrolases.Penicillins aremost effective against actively dividing cells.Those in the lag phase of growth may be unaffected by penicillins.Penicillin G3Target Name(s):Penicillin-binding proteinsTherapeuticsPenicillin G is active against gram-positive cocci,including Streptococcus pyogenes(group A),Streptococcus pneumoniae,and certain strains of Streptococcus viridans.However,resis-tant Streptococcus pneumoniae has appeared and is common in some geographic areas.In some instances,this resistance can be overcome with high doses of penicillin.Nonpeni-cillinase-producing Staphylococcus aureus can be treated with penicillin G.Treatment of enterococcus species generally requires higher doses of penicillin G.Gram-positive anaerobic bacteria,such as Peptostreptococcus,Peptococcus,and some Clostridium strains,are also usually sensitive to penicillin G.Penicillin G is effective against some nonpenicillinase-producing gram-negative organisms including Neisseria meningitidis,Hae-mophilus influenzae,and Neisseria gonorrhoeae.The Enterobacteriaceae are resistant to penicillin G therapy.Gram negative anaerobic activity varies for penicillin G.It is active against spirochetes including Treponema pallidum,Borrelia bugdorferi,and Leptospira. IndicationsValue Units Prep.and Routeof Admin.Reference CommentsInfections,adultsDosage5–30millionunits i.v.divided in6doses or as acontinuousinfusionAmerican HospitalFormularySystem(2001)Dose chosen will be dependent onthe indication and causativeorganism.Higher doses should beemployed for more severeinfections,and a dosageadjustment is required with renalinsufficiency.Penicillin G procainedoses are600,000to1.2millionunits daily for approximately10–14days.Penicillin G procaineshould be administeredintramuscularly.It cannot be givenintravenously.The penicillinG benzathine dose is1.2millionunits/day as a deep intramuscularinjection.It cannot be givenintravenously.Infections,children>1monthDosage25,000–400,000units/kg i.v.divided in4doses or as acontinuousinfusion American HospitalFormularySystem(2001)Higher doses should be used formore severe infections.Neonatedosing differs based on age.Dosage adjustment required withrenal insufficiency.MeningitisDosage20–30millionunits i.v.divided in6doses or as acontinuousinfusionAmerican HospitalFormularySystem(2001)Dosage adjustment required withrenal insufficiency.EndocarditisDosage12–30millionunits i.v.divided in6doses or as acontinuousinfusionAmerican HospitalFormularySystem(2001)The dose selected is dependent onthe organism.Entococcusendocarditis requires18–30million units,whereas Viridansstreptococci and Streptococcusbovis dosing ranges from12–18Penicillin G 4million units and is dependent onMICs to e incombination with gentamicin.Dosage adjustment required withrenal insufficiency. NeurosyphillisDosage18–24millionunits i.v.divided in6doses or as acontinuousinfusionAmerican HospitalFormularySystem(2001)Treat for10–14days.Considerfollowing treatment withintramuscular penicillinG benzathine2.4million units.Dosage adjustment required withrenal insufficiency.ContraindicationsPenicillin G is contraindicated in those who are hypersensitive to penicillins,cephalos-porins,and carbapenems and in those known to be hypersensitive to procaine or ben-zathine if these salt forms are to be administered.Some commercially available penicillin procaine preparations contain sulfites that can cause allergic reactions.Also,some commercially available preparations of penicillin G contain tartrazine that may causeallergic reactions in susceptible individuals.Adverse EffectsThe most common adverse effects reported with penicillin G are gastrointestinal dis-turbances,rash,and hypersensitivity reactions.Gastrointestinal effects include nausea, vomiting,anorexia,diarrhea,and gastritis.Clostridium difficile colitis has rarely been reported with penicillin G therapy.Hypersensitivity reactions include rash,angioedema,toxic epidermal necrolysis,erythema multiforme,Stevens-Johnson syndrome,and serum sickness-like reactions.Anaphylaxis can also occur with penicillin G therapy.Hemato-logic reactions include eosinophilia,hemolytic anemia,leukopenia,neutropenia,agranu-locytosis,and thrombocytopenia.Rare cases of acute interstitial nephritis have been reported.Neurotoxic reactions to penicillin G include hallucinations,confusion,lethargy, dysphasia,seizures,and coma.These neurotoxic effects occur more commonly with dosesof more than20million units/day in those with renal insufficiency.Benzathine or procaine penicillin can cause Hoigne’s syndrome,which is characterized by bizarre behavior and neurologic reactions.Jarisch-Herxheimer reaction occurs when penicillinG is used to treat syphilis.Occurring2–12hours after initiation of penicillin G therapy,this reaction consists of headache,fever,chills,sweating,sore throat,and changes in vitalsigns.It occurs most commonly in those with primary and secondary syphilis American Hospital Formulary System(2001).Agent-Agent InteractionsAgent Name Mode of InteractionProbenecid Probenecid increases the serum concentration of penicillin G by inhibiting itssecretion into urine.Oral contraceptives Penicillin G may reduce the effectiveness of oral contraceptives by alteringintestinal flora.Methotrexate Penicillins may increase the risk of methotrexate toxicity by inhibiting the renalsecretion of the antimetabolite.Aminoglycosides Penicillins and aminoglycosides may inactivate one another when used incombination.However,synergistic effects under certain circumstances aredocumented.These agents are incompatible when mixed together in vitro.Penicillin G5Pre-Clinical ResearchPharmacokineticsPotencyValueUnits Organ/TissuePrep.and Route of Admin.Cell Line/TypeEffects Exp.End PointReference Comments Mouse LD50 2.3g/kgs.c.O’Neil et al (2001)Procaine saltBook CitationsWilliams,D.,2002.pKa Values for Some Drugs and Miscellaneous Organic Acids and Bases.Williams,D.A.,Lemke,T.L.(Ed.),Foye’s Principles of Medicinal Chemistry ,pp.1071,Lippincott Williams and Wilkins,Philadelphia,PA.American Hospital Formulary System 2001Drug Monographs.McEvoy,G.(Ed.),American HospitalFormulary System ,pp.315–346,American Society of Health-System Pharmacists,Inc.,Bethesda,MD.O’Neil,M.J.,et al.2001.Monographs.O’Neil,M.J.,Smith,A.,Heckelman,P.E.(Ed.),The Merck Index ,Edition 13,p.1273,Merck Research Laboratories,Division of Merck and Company,Inc.,Whitehouse Station,NJ.Penicillin G6。