PENICILLINSPENICILLINS

One of the most important groups of One of the most important groups of antibiotics.antibiotics.

They are still widely used .They are still widely used .

Drugs of choice for a large number of Drugs of choice for a large number of infectious diseases.infectious diseases.

B

S

C

CC

C

C

N COOHO

CH3CH3NC

OR

CH2R=

Penicillin G

A-Thiazolidine ringB-Beta-Lactam ring

A

CLASSIFICATION OF THE CLASSIFICATION OF THE PENICILLINSPENICILLINS

Natural penicillins (Pen G and V)Natural penicillins (Pen G and V) Penicillinase-resistant penicillinsPenicillinase-resistant penicillins AminopenicillinsAminopenicillins Carboxypenicillins Carboxypenicillins UreidopenicillinsUreidopenicillins Combinations with Combinations with -lactamase inhibitors-lactamase inhibitors

PENICILLIN G AND VPENICILLIN G AND V

Antimicrobial activity-Antimicrobial activity-NON-NON-PENICILLINASEPENICILLINASE producing strains of producing strains of most cocci, gram positive bacilli and most cocci, gram positive bacilli and spirochetes.spirochetes.

DISTRIBUTIONDISTRIBUTION

Widely distributed throughout body Widely distributed throughout body spaces. spaces.

NORMAL MENINGES

INFLAMED MENINGES

HOURS

CS

F C

ON

C’N

OF

PE

N G

Pen G injected

METABOLISM AND METABOLISM AND EXCRETIONEXCRETION

Only a small amount is metabolized.Only a small amount is metabolized.

Pen G is eliminated rapidly and Pen G is eliminated rapidly and primarily by active renal tubular primarily by active renal tubular secretion with a short half-life.secretion with a short half-life.

REPOSITORY PREPARATIONSREPOSITORY PREPARATIONS

Penicillin G procaine and Penicillin G Penicillin G procaine and Penicillin G benzathine (IM).benzathine (IM).

Blo

od L

evel

2 4 6 12 18 24

Time (hrs)

Pen G (IM)

Pen V (Oral)

Pen G (Oral)Procaine Pen G

Benzathine Pen G

THERAPEUTIC USESTHERAPEUTIC USES

Penicillin G is the first choice for most Penicillin G is the first choice for most infections due to bacteria sensitive to infections due to bacteria sensitive to penicillin.penicillin.

Acute pneumococcal

pneumonia

THERAPEUTIC USESTHERAPEUTIC USES

Syphilis (Benzathine Pen G)Syphilis (Benzathine Pen G)

Bacteroides fragilis

PROPHYLACTIC USESPROPHYLACTIC USES

Streptococcal infections.Streptococcal infections.

Recurrences of rheumatic fever.Recurrences of rheumatic fever.

Syphilis. Syphilis.

PENICILLIN VPENICILLIN V

Continued treatment of infections Continued treatment of infections initially treated with parenteral Pen G.initially treated with parenteral Pen G.

Prophylaxis of streptococcal infections Prophylaxis of streptococcal infections (e.g.rheumatic fever).(e.g.rheumatic fever).

SEMISYNTHETIC PENICILLINSSEMISYNTHETIC PENICILLINS

PENICILLINASE RESISTANT PENICILLINASE RESISTANT PENICILLINS-PROPERTIESPENICILLINS-PROPERTIES

Resistant to hydrolysis by staphylococcal Resistant to hydrolysis by staphylococcal penicillinase. penicillinase.

Less active vs other penicillin-sensitive Less active vs other penicillin-sensitive organisms. organisms.

THERAPEUTIC USESTHERAPEUTIC USES

Drugs of choice for infections caused by Drugs of choice for infections caused by penicillinase-producing Staph. aureus.penicillinase-producing Staph. aureus.

OCH3

OCH3

METHICILLIN

RESISTANT TO PENICILLINASE

ORAL ABSORPTION IS POOR

NARROW SPECTRUM

METHICILLIN-RESISTANT STAPH. METHICILLIN-RESISTANT STAPH. (MRSA) INFECTIONS(MRSA) INFECTIONS

Most commonly identified antibiotic-resistant Most commonly identified antibiotic-resistant pathogen in US hospitals.pathogen in US hospitals.

MRSA has spread beyond health care facilities MRSA has spread beyond health care facilities emerging in the community, where it is rapidly emerging in the community, where it is rapidly becoming a dominant pathogen. becoming a dominant pathogen.

Resistant to several antibiotics including Resistant to several antibiotics including penicillins and cephalosporins.penicillins and cephalosporins.

TREATMENT OF HA-MRSATREATMENT OF HA-MRSA

Vancomycin is the treatment of choice.Vancomycin is the treatment of choice.

CA-MRSACA-MRSA

Patients with serious CA-MRSA infections Patients with serious CA-MRSA infections should be hospitalized and treated with IV should be hospitalized and treated with IV vancomycin, linezolid vancomycin, linezolid or daptomycin.or daptomycin.

For less serious CA-MRSA skin or soft tissue For less serious CA-MRSA skin or soft tissue infections, oral TMP/SMX, minocycline, infections, oral TMP/SMX, minocycline, doxycycline, clindamycin or linezolid could be doxycycline, clindamycin or linezolid could be tried.tried.

ISOXAZOLYL PENICILLINSISOXAZOLYL PENICILLINS

Acid stable and adequately absorbed Acid stable and adequately absorbed after oral administration.after oral administration.

Orally for infections of moderate severity Orally for infections of moderate severity and for prolonged outpatient treatment and for prolonged outpatient treatment of chronic infections (e.g. osteomyelitis).of chronic infections (e.g. osteomyelitis).

Parenterally for serious staph infections.Parenterally for serious staph infections.

OC2H5

NAFCILLIN

GI ABSORPTION IS VARIABLE

AMINOPENICILLINSAMINOPENICILLINS

Increased activity against many gram Increased activity against many gram - - organisms.organisms.

Metabolized by Metabolized by -lactamases from both gram + -lactamases from both gram + and – bacteria. and – bacteria.

Not substitutes for penicillin G or V.Not substitutes for penicillin G or V.

Includes Includes AMOXICILLIN, AMPICILLINAMOXICILLIN, AMPICILLIN and congeners.and congeners.

HO C C

OH

NH

AMINOPENICILLINS

AMOXICILLIN

Good oral absorption

AMOXICILLIN-THERAPEUTIC AMOXICILLIN-THERAPEUTIC USESUSES

Sinusitis and other upper respiratory Sinusitis and other upper respiratory infections.infections.

Bacterial endocarditis prophylaxis-DOC Bacterial endocarditis prophylaxis-DOC for prophylaxis in patients at risk while for prophylaxis in patients at risk while undergoing dental, oral or upper undergoing dental, oral or upper respiratory tract procedures.respiratory tract procedures.

ANTIPSEUDOMONAL ANTIPSEUDOMONAL PENICILLINSPENICILLINS

Extended antibacterial range compared Extended antibacterial range compared to amoxicillin.to amoxicillin.

Hydrolyzed by penicillinases.Hydrolyzed by penicillinases.

Carboxypenicillins and ureidopenicillins.Carboxypenicillins and ureidopenicillins.

TICARCILLIN (Ticar)TICARCILLIN (Ticar)

Must be given parenterally.Must be given parenterally.

Gram negative infections caused byGram negative infections caused by PseudomonasPseudomonas and and Proteus.Proteus.

For most serious systemic pseudomonal For most serious systemic pseudomonal infections use an antipseudomonal infections use an antipseudomonal penicillin plus an aminoglycoside.penicillin plus an aminoglycoside.

UREIDOPENICILLINS- UREIDOPENICILLINS- MEZLOCILLIN AND MEZLOCILLIN AND

PIPERACILLINPIPERACILLIN Given parenterally. Given parenterally.

THERAPEUTIC USESTHERAPEUTIC USES

Serious gram negative infections, Serious gram negative infections, especially pseudomonas.especially pseudomonas.

COMBINATIONS WITH BETA COMBINATIONS WITH BETA LACTAMASE INHIBITORSLACTAMASE INHIBITORS

Penicillin plus a beta lactamase Penicillin plus a beta lactamase inhibitor.inhibitor.

BETA-LACTAMASE BETA-LACTAMASE INHIBITOR COMBINATIONSINHIBITOR COMBINATIONS

Inhibitor has only weak intrinsic activity.Inhibitor has only weak intrinsic activity.

Combination has a broader spectrum Combination has a broader spectrum than penicillin alone.than penicillin alone.

THERAPEUTIC USESTHERAPEUTIC USES

Useful in infections caused by Useful in infections caused by - - lactamase producing bacteria, certain lactamase producing bacteria, certain anaerobic infections and other infectionsanaerobic infections and other infections usually not sensitive to penicillin.usually not sensitive to penicillin.

Penicillin GPenicillin G Streptococci, Streptococci, syphilis, anaerobic syphilis, anaerobic infections, infections, Prophylactic useProphylactic use

Penicillin VPenicillin V Similar to Similar to penicillin G but penicillin G but for oral usefor oral use

Isoxazolyl Isoxazolyl penicillinspenicillins

Staph infectionsStaph infections

AminopenicillinsAminopenicillins Gram- infectionsGram- infections

SUMMARY OF THE USES OF THE DIFFERENT PENICILLINS

CarboxypenicillinsCarboxypenicillins Pseudomonal Pseudomonal infectionsinfections

UreidopenicillinsUreidopenicillins Pseudomonal Pseudomonal infectionsinfections

Penicillins +beta Penicillins +beta lactamase lactamase inhibitorsinhibitors

Extended Extended spectrumspectrum

SUMMARY OF THE USES OF THE DIFFERENT PENICILLINS

ADVERSE REACTIONS TO THE ADVERSE REACTIONS TO THE PENICILLINSPENICILLINS

HYPERSENSITIVITY HYPERSENSITIVITY REACTIONSREACTIONS

Cross allergenicity among all the Cross allergenicity among all the penicillins.penicillins.

Result from a previous treatment.Result from a previous treatment.

HYPERSENSITIVITY HYPERSENSITIVITY REACTIONSREACTIONS

Occur with almost any dosage form of Occur with almost any dosage form of penicillin. Oral penicillins have a lower penicillin. Oral penicillins have a lower risk than parenterals.risk than parenterals.

Usually clear with elimination of the Usually clear with elimination of the penicillin.penicillin.

HYPERSENSITIVITY HYPERSENSITIVITY REACTIONSREACTIONS

Skin rashes.Skin rashes. Fever.Fever. Bronchospasm.Bronchospasm. Vasculitis, serum sickness, exfoliative Vasculitis, serum sickness, exfoliative

dermatitis, contact sensitivity, local swelling dermatitis, contact sensitivity, local swelling and redness,oral lesions, eosinophilia.and redness,oral lesions, eosinophilia.

ANGIOEDEMA AND ANGIOEDEMA AND ANAPHYLAXIS.ANAPHYLAXIS.

ANAPHYLAXISANAPHYLAXIS

Most important immediate danger.Most important immediate danger.

Incidence is low (0.04 -0.2%).Incidence is low (0.04 -0.2%).

Sudden, severe hypotension and rapid Sudden, severe hypotension and rapid death.death.

ANAPHYLAXISANAPHYLAXIS

Careful observation of the Careful observation of the patient is important.patient is important.

ANAPHYLAXIS-TREATMENTANAPHYLAXIS-TREATMENT

Epinephrine (IV or IM)Epinephrine (IV or IM)

IV steroidsIV steroids

Supportive measuresSupportive measures

MGMT. OF THE PATIENT MGMT. OF THE PATIENT POTENTIALLY ALLERGIC POTENTIALLY ALLERGIC

Evaluation and history.Evaluation and history.

DESENSITIZATION.DESENSITIZATION.

DIRECT PENICILLIN TOXICITYDIRECT PENICILLIN TOXICITY

Pain and inflammation at the site of IM Pain and inflammation at the site of IM injection.injection.

Phlebitis when given IV.Phlebitis when given IV.

GI Irritation when given orally.GI Irritation when given orally.

DIRECT TOXICITYDIRECT TOXICITY

Neurological effects - CNS and PNS.Neurological effects - CNS and PNS.

Renal/electrolyte toxicity -cation Renal/electrolyte toxicity -cation intoxication, interstitial nephritis and intoxication, interstitial nephritis and renal failure.renal failure.

Hematological toxicity- bone marrow Hematological toxicity- bone marrow depression and impairment of platelet depression and impairment of platelet aggregation.aggregation.

SUPERINFECTIONSSUPERINFECTIONS

PENICILLINSPENICILLINS

SAFEST OF ALL SAFEST OF ALL ANTIBIOTICS IN ANTIBIOTICS IN PREGNANCYPREGNANCY

MECHANISM OF ACTIONMECHANISM OF ACTION

They inhibit the formation of the They inhibit the formation of the bacterial cell wall.bacterial cell wall.

Plus penicillin

Spheroplast

Emerging Spheroplast

Dividing Bacteria

Division

Growth site

Growth

Penicillin Binding Proteins

Transpeptidases

Carboxypeptidases

Endopeptidases

Penicillin

AUTOLYSINS

MECHANISM OF ACTIONMECHANISM OF ACTION

All beta-lactam antibiotics act by the All beta-lactam antibiotics act by the same mechanism.same mechanism.

RESISTANCE RESISTANCE

Structural differences in the penicillin Structural differences in the penicillin binding proteins.binding proteins.

Inability to penetrate to its site of action.Inability to penetrate to its site of action.

GI Upset

Headache, Dizziness

Penicillins: Pen G and Pen VPenicillins: Pen G and Pen VGram-negative

Ana

erob

ic

P. aeruginosa

H. influenzaeNeissseria spp

E. Coli(coliforms)

S. aureus

Streptococcus spp

Bacteroides spp

Enterococcus spp

Clostridium spp

Gram-positive

AND: Spirochetes

Gram-negative

Gram-positive

Ana

erob

ic

P. aeruginosa

H. influenzaeNeissseria spp

E. Coli(coliforms)

S. aureus

Streptococcus spp

Bacteroides spp

Clostridium spp

Enterococcus spp

Penicillins: Penicillinase-resistantPenicillins: Penicillinase-resistant

S

C

CC

C

C

N COOHO

CH3

CH3NCO

R

Penicillinase

S

C

CC

C N COOH

CH3

CH3NCO

R

OHO

Penicilloic Acid

S

C

CC

C

C

N COOHO

CH3

CH3NCO

R

Amidase

S

C

CC

C

C

N COOH

CH3

CH3NCO

R 2HH

6-Aminopenicillanic Acid

O

Mur NAc

X

Glycopeptide Polymer

X

Mur NAc

Glycopeptide Polymer

X

Glycopeptide Polymer

D-Alanine

Transpeptidase