Penicillins and Cephalosporins

Bill Nichols bill.nichols@pharm.utah.edu 581-7564

At the end of this lecture the student will be able to describe: 1. The prototype drug in the antibiotic class and subclasses (if any exist) and the following major features: a) Mechanism of action, if known. b) Clinically useful antimicrobial spectrum. c) Key considerations of Pharmacokinetics (i.e., Absorption, distribution, metabolism, and excretion. d) Major toxicities and side effects. d) Important drug interactions possible. e) Major therapeutic indications and contraindications. f) Major clinical problems for antimicrobial family including some unique to specific drug within this family

Antibiotic Family
General Spectrum & Clinical Status Chemistry & Mechanism of Action Therapeutic Uses Spectrum Resistance Mechanisms Pharmacokinetics Adverse Effects Major Clinical Problems

What is most important to learn about antibiotics?

General Spectrum & Clinical Status
required to select appropriate antibiotic

General Features of Antibiotic Family

mechanism, pharmacokinetics, adverse rxs

Protype Drugs in Antibiotic Family

key features of spectrum, distribution, toxicity

Major Subclasses Major Clinical Problems

Penicillins
Four Subclasses (based on spectrum)
(1) Natural penicillins
(Pen G and V)

(2) Penicillinase-resistant penicillins

(Nafcillin, Methicillin, Oxacillin)

(3) Aminopenicillins
(Ampicillin and Amoxacillin)

(4) Expanded spectrum or antipsuedomonal penicillins

(Ticarcillin, Piperacillin)

General Spectrum and Clinical Status

Pen G
common streptococci (Strep. pyogenes, Strep. pneumoniae)

Nafcillin
staphylococci

Ampicillin
E. coli, Proteus, H. influenzae

Piperacillin
Psuedomonas, gram-neg. enteric bacilli

Chemistry
Beta lactam ring attached to 5membered thiazolidine ring weak acid (anionic) amino acyl side chain groups (determine spectrum, absorption, and beta lactamase susceptibility)

Mechanism of Action
Bactericidal inhibitors of cell wall synthesis
(selectively toxic to bacteria)

Target enzymes of penicillins

transpeptidases called PBP (penicillin binding proteins) that form cross-links in peptidoglycan of bacterial cell walls

Mechanism (cont.)
Penicillin binding proteins (PBPs)
accessibility of transpeptidases (PBPs ) differ in gram-pos. and gram-neg. bacteria

Differences in Gram-Pos. and Gram-Neg. bacterial cell wall

gram-pos. bacteria
no outer membrane

gram-neg. bacteria
periplasmic space between outer lipid polysaccharide membrane and cytoplasmic membrane

Other Differnces in Gram-Pos. and Gram-Neg. Bacteria

Several types of Beta Lactamases
different substrate specificity penicillinases cephalosporinases

Gram-positive Beta Lactamases

located extracellularly

Gram-negative Beta Lactamases

located in periplasmic space

Therapeutic Uses
Natural Penicillins
common upper respiratory tract infections due to streptococci prophylaxis of rheumatic fever history of valve damage

Penicillinase Resistant Penicillins

systemic infections due to stahylococci

Therapeutic Uses (cont.)

Aminopenicillins
pharyngitis and otitis media (common in children due to streptococci and H. influenzae) simple urinary tract infections serious gastroenteritis (Salmonella, Shigella)

Expanded Spectrum Penicillins

reserved for systemic gram-neg bacillary infections in hosptalized patients esp. Pseudomonas aeruginosa

Spectrum
Natural penicillins (Pen G)
most streptococci esp. Group A beta hemolytic, Strep. pneumoniae some strains of Strep. pneum. resistant

Penicillinase resistant penicillins (Nafcillin)

Staph. aureus, Staph. epidermidus

Aminopenicillins (Ampicillin, Amoxacillin)

most common streptococci many H. influenzae, Proteus, E. coli, P.mirabilis Salmonella and Shigella

Spectrum (cont.)
Expanded spectrum or antipsuedomonal penicillins
improved activity vs. many grm-neg. pathogens (esp. Pseudomonas and Klebsiella)

Combinations of expanded spectrum penicillins with beta lactamase inhibitors

penicillinase-producing staphylococci and other beta lactamase-producing pathogens)

Resistance
failure to bind to PBPs cannot penetrate porins (gram-neg.) production of beta lactamase specific for penicillins (penicillinase) lack autolytic enzymes

Pharmacokinetics (Absorption)
Differences in acid stability
Pen G is acid labile (use Pen V orally) Amoxicillin is better absorbed orally than ampicillin and not affected by food both ampicillin and amoxicillin acid stable oral forms of penicillinase resistant penicillins are available (oxacillin, cloxacillin, dicloxacillin) other penicillins should only be used parenterally

Pharmacokinetics (cont.)
Distribution
all penicillins are widely distributed to most body sites not freely enter CSF unless inflammed meninges

Excretion
most are rapidly eliminated by renal secretion Probenecid can block renal tubular secretion

Repository Preparations
Procaine Pen G
IM doses may last 1-3 days depending on dose

Benzathine Pen G
deep IM for low levels lasting about 26 days

Adverse Effects
Hypersensitivity
IgE-mediated reactions due to penicilloyl moiety (open beta lactam ring) all types (rashes, contact hypersensitivity, angioedema, serum sickness, anaphylaxis)

Idiopathic skin rash (ampicillin) Diarrhea with broader spectrum penicillins (ampicillin, piperacillin) Seizures (in high doses)

Adverse Reactions (cont.)

Occasional superinfections with broad spectrum penicillins (ampicillin, piperacillin) Alterations in platelet function and bleeding problems with some expanded spectrum penicillins (rare with piperacillin) Higher sodium content with some antipseudomonal penicillins (ticarcillin) Interstitial nephritis (rare with methicillin)

Drug Interactions
Never mix a penicillin in same vial with an aminoglycoside Decreased efficacy of low-dose estrogencontaining oral contraceptives Enhanced activity of antipseudomonal penicillins combined with aminoglycosides

Cephalosporins
Classified into Four Generations based on their gram-negative spectrum and beta lactamase stability (used predominantly in hospital-acquired infections) First Generation: Cefazolin, Cephalexin Second Generation: Cefuroxime, Cefaclor Third Generation: Cefotaxime, Ceftriaxone, Cefixime Fourth Generation: Cefepime

General Spectrum and Clinical Status

First Generation: good vs. gram-pos. including staphylococci plus some gram-neg. (E. coli, Proteus mirabilis, Klebsiella) Second Generation: more active vs. gram-neg. bacteria including some H. influenzae and other enterobacteria (adequate gram-pos.) Third Generation: more active vs. gram-neg. enterobacteriae, stable to beta lactamases, less antistaphylococcal activity (some better vs. Pseud. but less active vs. other gram-neg.) Fourth Generation : expanded activity vs some gram-pos. cocci, beta lactamase stability

Chemistry
beta lactam ring attached to 6 membered cephalosprinic acid ring similiar features as penicillins
weak acid (anionic) aminoacyl side chain (spectrum, susceptibility to beta lactamases)

Mechanism
same mechanism of action as penicillins
bactericidal inhibition of cell wall synthesis

Therapeutic Uses
First Generation (Cefazolin, Cephalexin)
serious Klebsiella or staphylcoccal infections when unable to use a penicillin

Second Generation (Cefuroxime, Cefaclor)

serious gram-neg. infections due to betalactamase producing bacteria, esp. respiratory and middle ear infections due to H. influenzae

Therapeutic Uses (cont.)

Third Generation (Cefotaxime, Ceftriaxone, Cefixime)
serious hospital-acquired gram-neg. sepsis due to enteric bacilli esp. meningitis some more effective vs. Pseudomonas (Ceftazidime) others more effective vs.other gram-neg.

Fourth Generation (Cefepime)

alternative for mixed infections due to hospital-acquired gram-pos. or gram-neg.

Resistance
Same mechanism as penicillins

Pharmacokinetics
Absorption
most given parenterally some oral preps available within generations
Cephalexin (first generation) Cefaclor and Cefuroxime (second generation) Cefixime (third generation)

Pharmacokinetics (cont.)
Distribution
limited distribution into CSF for first and second generation cephalosporins only third generation cephalosporins have good csf penetration to treat meningitis

Excretion
most eliminated by renal tubular secretion like penicillins only a couple cephalosporins undergo hepatic metabolism but still active for UTI

Adverse Effects
Hypersensitivity (<2%)
idiopathic skin rash, fever, arthralgia, serum sickness-like reaction

Cross-sensitivity with penicillins (6-8%) Phlebitis, diarrhea, enterocolitis Superinfections Potential renal toxicity (in patients with decreased renal function)

Adverse Effects (cont.)

Coagulation abnormalities due to hypoprothrombinemia
due to cephalosporins with Nmethylthiotetrazole (NMTT) substituent cefamandole, cefmetazole, cefaperazone, cefotetan, ceftriaxone

Disulfiram (Antabuse)-like reaction with alcohol

same above drugs

Cephalosporins
First-Gen.: Cefazolin (Ancef), Cephalexin (Keflex) Second-Gen.: Cefuroxime (Zinacef, Kefurox), Cefoxitin (Mefoxin), Cefaclor (Ceclor), Loracarbef (Lorabid), Third-Gen.: Cefotaxime (Claforan), Ceftriaxone (Rocephin), Ceftazidime (Fortaz), Cefixime (Suprax) Fourth-Gen.: Cefepime (Maxipime)

Beta Lactamase Inhibitors

Clavulanic Acid, Sulbactam, Tazobactam General Features
inactivate beta lactamases of Staphylococci and many gram-neg. bacteria Suicide substrates that bind at active site of beta lactamase (irreversible) not inhibit all beta lactamases such as some produced by Pseudomonas, Enterobacter, and Serratia poor intrinsic antimicrobial activity

Combinations with Beta Lactamase Inhibitors

Clavulanate plus Amoxacillin (Augmentin) Clavulanate plus Ticarcillin (Timentin) Sulbactam plus Ampicillin (Unasyn) Tazobactam plus Piperacillin (Zosyn)

Carbapenems
Imipenem (Primaxin) Meropenem (Merrem) Entrapenem (Invanz)

General Spectrum and Clinical Status

Inhibit most gram-positive bacteria (both streptococci and staphylococci) Inhibit most enteric gram-negative bacilli plus H. influenzae and Pseudomonas Inhibit anaerobes such as Bacteroides fragilis Resistant to most beta lactamases used for serious hospital-acquired infections and mixed infections

Chemistry
beta lactam ring linked to 5-membered ring without sulfur resistant to most beta lactamases

Mechanism
Mechanism is same as other beta lactams
high affinity for critical PBPs in wide variety of bacterial pathogens bactericidal inhibitor of cell wall synthesis like other beta lactams

Spectrum (very broad)

Most gram-positive
Group A beta hemolytic streptococci, Strep. pneumoniae, viridans strep., enterococci, staphylococci

Most common gram-negative

Enteriobacteriae, H. influenzae, Neisseria, Moraxella, Pseudomonas aeruginosa

Anaerobes
Bacteroides fragilis

Resistance
Different PBPs in methicillin-resistant Staph. aureus and Enterococcus Absence of outer membrane porins in resistant Pseudomonas aeruginosa

Therapeutic Uses
Reserved for serious nosocomial infections resistant to other beta lactams Bacteremias, respiratory tract infections, intra-abdominal infections, and UTIs caused by resistant pathogens Effective vs most beta lactamase producing bacteria Resistance can develope during therapy, esp. some strains of Pseudomonas and Enterococcus

Comparison of Carbapenems
Impenem and Meropenem have similar spectrum and half-life (~ 1 hr) Ertapenem has good activity vs. gram-neg. enteric bacteria and anaerobes but less active vs Pseudomonas aeruginosa and Acinetobacter

Pharmacokinetics
Parenteral only Similiar to other beta lactams Imipenem available only in combination with cilistatin Cilistatin inhibits renal tubular metabolism by dehydropeptidases Meropenem used alone (not metabolized by renal enzymes) Ertapenem has longer half-life (~4 hrs)

Adverse Effects
Painful injections and Thrombophlebitis Allergic reactions Superinfections (diarrhea) Seizures (rare unless other CNS disorders)

Monobactam (Aztreonam)
General Spectrum and Clinical Status
limited spectrum (only aerobic gram-neg.) alternative for gram-neg. UTI

Mechanism
same as other beta lactams

Unique Features
no cross sensitivity with penicillins, parenteral

Adverse Effects
gram-pos. superinfections

Cephalosporin vs Penicillin
Cephalosporin advantages
cover staphylococci better vs. Klebsiella, enteric gram-neg. bacilli, gonococci

Cephalsporin disadvantages
cost poor distribution to CSF (1st & 2nd gen) not cover enterococcus

Problems of Penicillins
Pen G (all penicillins)
IgE mediated hypersensitivity Seizures in high doses

Ampicillin
Idiopathic skin rash and fever diarrhea, enterocolitis

Methicillin
interstitial nephritis

Problems with Cephalosporins

Idiopathic skin rash and fever Phlebitis Diarrhea and enterocolitis

Problems with Imipenem

Diarrhea Superinfections

Summary of Penicillins
Pen G has narrowest spectrum that covers common streptococcal infections Ampicillin and Amoxicillin cover the common upper resp. tract pathogens in children plus simple UTIs Piperacillin covers more gram-neg. hospitalacquired infections (esp. Pseudomonas and Klebsiella)

Penicillin Summary (cont.)

Beta lactamase inhibitors expand penicillin spectrum to cover staphylococci

Summary of Cephalosporins
First Generation Cephalosporins are important drugs for hospitalized patients and surgical patients More serious hospital acquired infections require 2nd or 3rd generation cephalosporins that involve beta lactamase producing gram negative infections

Cephalosporin Summary (cont.)

Only 3rd generation cephalosporins useful for treatment of meninigitis but have reduced activity vs. gram-pos. (esp. Staph.)