PENICILLINS  One of the most important groups of antibiotics.  They are still widely used.  Drugs of choice for a large number of infectious diseases.

B S C C C C C NCOOH O CH 3 NC O R CH 2 R= Penicillin G A-Thiazolidine ring B-Beta-Lactam ring A

CLASSIFICATION OF THE PENICILLINS  Natural penicillins (Pen G and V)  Penicillinase-resistant penicillins  Aminopenicillins  Carboxypenicillins  Ureidopenicillins  Combinations with  -lactamase inhibitors

PENICILLIN G AND V  Antimicrobial activity- NON- PENICILLINASE producing strains of most cocci, gram positive bacilli and spirochetes.

ABSORPTION  The oral absorption of penicillin G is poor. Take at least ½ hr before or 2 hrs after a meal.  Pen G is also often given parenterally (IV or IM).  Pen V is better absorbed from the GI tract.

DISTRIBUTION  Widely distributed throughout body spaces.

NORMAL MENINGES INFLAMED MENINGES HOURS CSF CONC’N OF PEN G Pen G injected

METABOLISM AND EXCRETION  Only a small amount is metabolized.  Pen G is eliminated rapidly and primarily by active renal tubular secretion with a short half-life.

REPOSITORY PREPARATIONS  Penicillin G procaine and Penicillin G benzathine (IM).

Blood Level Time (hrs) Pen G (IM) Pen V (Oral) Pen G (Oral) Procaine Pen G Benzathine Pen G

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

Acute pneumococcal pneumonia

THERAPEUTIC USES  Syphilis (Benzathine Pen G)

Bacteroides fragilis

PROPHYLACTIC USES  Streptococcal infections.  Recurrences of rheumatic fever.  Syphilis.

PENICILLIN V  Continued treatment of infections initially treated with parenteral Pen G.  Prophylaxis of streptococcal infections (e.g.rheumatic fever).

SEMISYNTHETIC PENICILLINS

PENICILLINASE RESISTANT PENICILLINS-PROPERTIES  Resistant to hydrolysis by staphylococcal penicillinase.  Less active vs other penicillin-sensitive organisms.

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

OCH 3 METHICILLIN RESISTANT TO PENICILLINASE ORAL ABSORPTION IS POOR NARROW SPECTRUM

METHICILLIN-RESISTANT STAPH. (MRSA) INFECTIONS  Most commonly identified antibiotic-resistant pathogen in US hospitals.  MRSA has spread beyond health care facilities emerging in the community, where it is rapidly becoming a dominant pathogen.  Resistant to several antibiotics including penicillins and cephalosporins.

TREATMENT OF HA-MRSA  Vancomycin is the treatment of choice.

CA-MRSA  Patients with serious CA-MRSA infections should be hospitalized and treated with IV vancomycin, linezolid or daptomycin.  For less serious CA-MRSA skin or soft tissue infections, oral TMP/SMX, minocycline, doxycycline, clindamycin or linezolid could be tried.

ISOXAZOLYL PENICILLINS  Acid stable and adequately absorbed after oral administration.  Orally for infections of moderate severity and for prolonged outpatient treatment of chronic infections (e.g. osteomyelitis).  Parenterally for serious staph infections.

OC 2 H 5 NAFCILLIN GI ABSORPTION IS VARIABLE

AMINOPENICILLINS  Increased activity against many gram - organisms.  Metabolized by  -lactamases from both gram + and – bacteria.  Not substitutes for penicillin G or V.  Includes AMOXICILLIN, AMPICILLIN and congeners.

HO CC O H NHNH AMINOPENICILLINS AMOXICILLIN Good oral absorption

AMOXICILLIN-THERAPEUTIC USES  Sinusitis and other upper respiratory infections.  Bacterial endocarditis prophylaxis-DOC for prophylaxis in patients at risk while undergoing dental, oral or upper respiratory tract procedures.

ANTIPSEUDOMONAL PENICILLINS  Extended antibacterial range compared to amoxicillin.  Hydrolyzed by penicillinases.  Carboxypenicillins and ureidopenicillins.

TICARCILLIN (Ticar)  Must be given parenterally.  Gram negative infections caused by Pseudomonas and Proteus.  For most serious systemic pseudomonal infections use an antipseudomonal penicillin plus an aminoglycoside.

UREIDOPENICILLINS- MEZLOCILLIN AND PIPERACILLIN  Given parenterally.

THERAPEUTIC USES  Serious gram negative infections, especially pseudomonas.

COMBINATIONS WITH BETA LACTAMASE INHIBITORS  Penicillin plus a beta lactamase inhibitor.

BETA-LACTAMASE INHIBITOR COMBINATIONS  Inhibitor has only weak intrinsic activity.  Combination has a broader spectrum than penicillin alone.

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

Penicillin G Streptococci, syphilis, anaerobic infections, Prophylactic use Penicillin V Similar to penicillin G but for oral use Isoxazolyl penicillins Staph infections Aminopenicillins Gram- infections SUMMARY OF THE USES OF THE DIFFERENT PENICILLINS

Carboxypenicillins Pseudomonal infections Ureidopenicillins Penicillins +beta lactamase inhibitors Extended spectrum SUMMARY OF THE USES OF THE DIFFERENT PENICILLINS

ADVERSE REACTIONS TO THE PENICILLINS  Hypersensitivity reactions are the most common adverse reactions of the penicillins.  Penicillins are probably the most common cause of drug allergy.

ADVERSE REACTIONS TO THE PENICILLINS

HYPERSENSITIVITY REACTIONS  Cross allergenicity among all the penicillins.  Result from a previous treatment.  A breakdown product of the penicillin molecule combines with a protein carrier to form an antigen.

HYPERSENSITIVITY REACTIONS  Cross allergenicity among all the penicillins.  Result from a previous treatment.

HYPERSENSITIVITY REACTIONS  Occur with almost any dosage form of penicillin. Oral penicillins have a lower risk than parenterals.  Usually clear with elimination of the penicillin.

HYPERSENSITIVITY REACTIONS  Skin rashes.  Fever.  Bronchospasm.  Vasculitis, serum sickness, exfoliative dermatitis, contact sensitivity, local swelling and redness,oral lesions, eosinophilia.  ANGIOEDEMA AND ANAPHYLAXIS.

ANAPHYLAXIS  Most important immediate danger.  Incidence is low ( %).  Sudden, severe hypotension and rapid death.

ANAPHYLAXIS  Careful observation of the patient is important.

ANAPHYLAXIS-TREATMENT  Epinephrine (IV or IM)  IV steroids  Supportive measures

MGMT. OF THE PATIENT POTENTIALLY ALLERGIC  Evaluation and history.

DESENSITIZATION.

DIRECT PENICILLIN TOXICITY  Pain and inflammation at the site of IM injection.  Phlebitis when given IV.  GI Irritation when given orally.

DIRECT TOXICITY  Neurological effects - CNS and PNS.  Renal/electrolyte toxicity -cation intoxication, interstitial nephritis and renal failure.  Hematological toxicity- bone marrow depression and impairment of platelet aggregation.

SUPERINFECTIONS

PENICILLINS  SAFEST OF ALL ANTIBIOTICS IN PREGNANCY

MECHANISM OF ACTION  They inhibit the formation of the bacterial cell wall.

Plus penicillin Spheroplast Emerging Spheroplast Dividing Bacteria Division Growth site Growth

MECHANISM OF ACTION  Inhibit cross-linking of peptidoglycan strands of the cell wall.  Inhibit a transpeptidase enzyme.

Penicillin Binding Proteins Transpeptidases Carboxypeptidases Endopeptidases Penicillin

AUTOLYSINS

CELL LYSIS AND DEATH  Requires autolytic enzyme activity  Murein (peptidoglycan) hydrolases are autolysins  Autolysins degrade the cell wall  Penicillins decrease the availability of inhibitors of autolysins

MECHANISM OF ACTION  All beta-lactam antibiotics act by the same mechanism.

RESISTANCE  Structural differences in the penicillin binding proteins.  Inability to penetrate to its site of action.

RESISTANCE  Increased production of beta-lactamase (penicillinase) enzymes.

GI Upset Headache, Dizziness

Penicillins: Pen G and Pen V Gram-negative Anaerobic 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 Anaerobic P. aeruginosa H. influenzaeNeissseria spp E. Coli (coliforms) S. aureus Streptococcus spp Bacteroides spp Clostridium spp Enterococcus spp Penicillins: Penicillinase-resistant

S C C C C C NCOOH O CH 3 NC O R Penicillinase S C C C CNCOOH CH 3 N C O R OH O Penicilloic Acid

S C C C C C NCOOH O CH 3 NC O R Amidase S C C C C C NCOOH CH 3 N C O R 2H2H H 6-Aminopenicillanic Acid O

Mur NAc X Glycopeptide Polymer X Mur NAc Glycopeptide Polymer X Glycopeptide Polymer D-Alanine Transpeptidase