Beta-Lactam Antibiotics: Penicillins and Cephalosporins

• Penicillins and cephalosporins are major antibiotics inhibiting bacterial cell wall synthesis.
• Beta-lactams get their name from the unusual 4-member ring common to all members.
• Beta-lactams are effective, widely used, and well-tolerated for treating microbial infections.

CARBAPENEMS

• Includes doripenem, ertapenem, imipenem/cilastatin, and meropenem.

PENICILLINS

• Includes amoxicillin, ampicillin, dicloxacillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, and ticarcillin.

CEPHALOSPORINS

• Includes cefaclor, cefadroxil, cefazolin, cefdinir, cefepime, cefixime, cefotaxime, cefotetan, cefoxitin, cefprozil, ceftaroline, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, and cephalexin.

B-LACTAMASE INHIBITOR + ANTIBIOTIC COMBINATIONS

• Includes clavulanic acid + amoxicillin
• Includes clavulanic acid + ticarcillin
• Includes sulbactam + ampicillin
• Includes tazobactam + piperacillin

MONOBACTAMS

• Includes aztreonam.

OTHER ANTIBIOTICS

• Includes colistin, daptomycin, fosfomycin, polymyxin B, telavancin, and vancomycin.
• Penicillins are derivatives of 6-aminopenicillanic acid and contain a beta-lactam ring.
• The beta-lactam ring structure us essential for antibacterial activity.
• Substituents confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition.
• Ampicillin with sulbactam, ticarcillin with clavulanic acid, piperacillin with tazobactam, nafcillin and oxacillin are administered IV or IM.
• Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations.
• Procaine penicillin G and benzathine penicillin G are administered IM as depot forms.
• Most penicillins are incompletely absorbed after oral administration.
• Food decreases the absorption of penicillinase-resistant penicillins, so they should be taken on an empty stomach.
• Penicillins distribute well and cross the placental barrier, but are not teratogenic.
• Penetration into bone or CSF is insufficient unless these sites are inflamed.
• The primary route of excretion is by glomerular filtration.
• Adjust dosage regimens in patients with impaired renal function.
• Nafcillin and oxacillin are metabolized in the liver.
• Probenecid inhibits the secretion of penicillins and, thus, can increase blood levels.
• Beta-lactam antibiotics are bactericidal drugs inhibiting cell wall synthesis.

Mechanism of Action

• Drug binds to penicillin-binding proteins (PBPs) located in the bacterial cytoplasmic membrane.
• Inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain.
• Activation of autolytic enzymes that cause lesions in the bacterial cell wall.
• Bacterial resistance occurs through the formation of beta-lactamases (penicillinases).
• Inhibitors of bacterial enzymes clavulanic acid, sulbactam, and tazobactam are used with penicillins.
• Structural change in target PBPs results in methicillin resistance in staphylococci (MRSA).
• Structural change in target PBPs results in resistance to penicillin G in pneumococci (PRSP) and enterococci.
• Porin structure alterations in gram-negative rods may contribute to resistance.
• Penicillin G is the prototype of a subclass of penicillins.
• Clinical uses include therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes.
• Many strains of pneumococci (penicillin-resistant S. pneumoniae [PRSP] strains).
• Staphylococcus aureus and Neisseria gonorrhoeae are resistant via production of beta-lactamases.
• Penicillin G is the drug of choice for syphilis.
• Activity against enterococci is enhanced by coadministration of aminoglycosides.
• Penicillin V is an oral drug mainly used in oropharyngeal infections.
• Drugs that are very-narrow-spectrum penicillinase-resistant are methicillin, nafcillin, and oxacillin.
• Methicillin as a prototype is rarely used owing to its nephrotoxic potential.
• The primary use for drugs that are very-narrow-spectrum penicillinase-resistant is in the treatment of known or suspected staphylococcal infections.
• Methicillin-resistant (MR) staphylococci (S. aureus [MRSA] and S. epidermidis) are resistant to all penicillins.
• Ampicillin and amoxicillin have a wider spectrum of antibacterial activity than penicillin G.
• Clinical uses include indications similar to penicillin G plus infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis.
• Ampicillin is synergistic with aminoglycosides.
• Piperacillin and ticarcillin have activity against several gram-negative rods, including Pseudomonas, Enterobacter, and some cases Klebsiella species.
• Most drugs in this subgroup have synergistic actions with aminoglycosides.
• Piperacillin and ticarcillin are often used in combination with penicillinase inhibitors.
• Adverse effects includes allergic reactions - urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis.
• Methicillin causes interstitial nephritis, and nafcillin is associated with neutropenia.
• Complete cross-allergenicity between different penicillins should be assumed.
• Gastrointestinal disturbances—Nausea and diarrhea may occur with oral penicillins, especially with ampicillin, also irritation or overgrowth of organisms or yeasts.
• Cephalosporins are beta-lactam antibiotics closely related to penicillins structurally and functionally.
• Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.
• Cephalosporins have the same mode of action as penicillins and are affected by the same resistance mechanisms.
• They tend to be more resistant than the penicillins to certain beta-lactamases.
• Several cephalosporins are available for oral use, but most are administered parenterally.
• Cephalosporins with side chains may undergo hepatic metabolism, but the major elimination mechanism for drugs in this class is renal excretion via active tubular secretion.
• Cefoperazone and ceftriaxone are excreted mainly in the bile.
• Most first- and second-generation cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed.
• Cephalosporins bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis.
• Resistance results from decreases in membrane permeability to cephalosporins and from changes in PBPs.
• Cephalosporins are bactericidal against susceptible organisms.
• First-generation drugs Cefazolin, cephalexin.
• Cephalosporins are less susceptible to penicillinases produced by staphylococci.
• Methicillin-resistant staphylococci are also resistant to cephalosporins.
• They are active against gram-positive cocci, including staphylococci and common streptococci.
• Many strains of E coli and K pneumoniae are also sensitive.
• Clinical uses include treatment of infections caused by these organisms and surgical prophylaxis in selected conditions.
• Second-generation drugs have less activity against gram-positive organisms.
• Marked differences in activity occur among the drugs in this subgroup.
• Clinical uses include infections caused by the anaerobe Bacteroides fragilis (cefotetan, cefoxitin) and sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor).
• Third-generation drugs include increased activity against gram-negative organisms and ability to penetrate the blood-brain barrier (EXCEPT cefoperazone and cefixime).

Third-generation drugs

• Includes ceftazidime, cefoperazone, cefotaxime

• Most are active against Providencia, Serratia marcescens, and beta-lactamase producing strains of H influenzae and Neisseria.

• Ceftriaxone and cefotaxime are the most active cephalosporins against penicillin-resistant pneumococci (PRSP strains)

• They also have activity against Pseudomonas (cefoperazone, ceftazidime) and B fragilis (ceftizoxime).

• Ceftriaxone (parenteral) and cefixime (oral), drugs of choice in gonorrhea.

Fourth-generation drugs

• Cefepime
• Cefepime is more resistant to beta-lactamases produced by gram-negative organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillin resistant pneumococci.
• Cefepime combines the gram-positive activity of first-generation agents with the wider gram-negative spectrum of third-generation cephalosporins.
• Ceftaroline has activity in infections caused by methicillin-resistant staphylococci.

Adverse effects of Cephalosporins

• Allergy-Cephalosporins cause a range of allergic reactions from skin rashes to anaphylactic shock.
• These reactions occur less frequently with cephalosporins than with penicillins.
• Cephalosporins may cause pain at intramuscular injection sites and phlebitis after I.V administration.
• They may increase the nephrotoxicity of aminoglycosides when the two are administered together.

OTHER BETA-LACTAM DRUGS

Aztreonam

• A monobactam resistant to beta-lactamases produced by certain gram-negative rods, including Klebsiella, Pseudomonas, and Serratia.
• The drug has no activity against gram positive bacteria or anaerobes.
• Administered intravenously and is eliminated via renal tubular secretion.
• A prolonged half-life is a common sign of renal failure.
• Adverse effects include gastrointestinal upset with possible superinfection, vertigo and headache, and rarely hepatotoxicity, skin rash.
• No cross allergenicity with penicillins.

Imipenem, Doripenem, Meropenem, and Ertapenem (parenterally)

• These drugs are carbapenems and are chemically different from penicillins but retain the beta-lactam ring structure.
• They have wide activity against gram-positive cocci, including some penicillin-resistant pneumococci, gram-negative rods, and anaerobes.
• For pseudomonal infections, they are often used in combination with an aminoglycoside.
• MRSA strains of staphylococci are resistant.
• Imipenem is rapidly inactivated by renal dehydropeptidase-I and is administered in fixed combination with cilastatin, an inhibitor of this enzyme.
• Cilastatin increases the plasma half life of imipenem and inhibits the formation of potentially nephrotoxic metabolite.
• Adverse effects of imipenem-cilastatin include gastrointestinal distress, skin rash, and, at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures).
• There is partial cross allergenicity with the penicillins.

Beta-Lactamase Inhibitors

• Clavulanic acid, sulbactam, and tazobactam are used in fixed combinations with certain hydrolyzable penicillins.
• They are most active against plasmid-encoded beta-lactamases.
• They are NOT good inhibitors of inducible chromosomal beta-lactamases.

OTHER CELL WALL OR MEMBRANE-ACTIVE AGENTS

Vancomycin

• A bactericidal glycoprotein that binds to the d-Ala-d-Ala terminal of the nascent peptidoglycan pentapeptide side chain and inhibits transglycosylation.
• Resistance in strains of enterococci and staphylococci involves a decreased affinity of vancomycin for the binding site.
• Vancomycin has a narrow spectrum of activity and is used for serious infections caused by drug-resistant gram-positive organisms.
• Toxic effects of vancomycin include chills, fever, phlebitis, ototoxicity, and nephrotoxicity.
• Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”) from histamine release.

Fosfomycin

• Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyruvate transferase.
• Prevents the formation of N-acetylmuramic acid, an essential precursor molecule for peptidoglycan chain formation.
• Excreted by the kidney, with urinary levels exceeding the minimal inhibitory concentrations (MICs).
• Indicated for urinary tract infections caused by E. coli or E. faecalis.
• Maintains high concentrations in the urine over several days, allowing for a one-time dose.
• Adverse effects include diarrhea, vaginitis, nausea, and headache.

Daptomycin

• A bactericidal, a novel cyclic lipopeptide; spectrum similar to vancomycin; active against vancomycin-resistant strains of enterococci and staphylococci.
• Indicated for the treatment of complicated skin and skin structure infections and bacteremia caused by S. aureus.
• Inactivated by pulmonary surfactants; thus, it should never be used in the treatment of pneumonia.
• Creatine phosphokinase should be monitored since daptomycin may cause myopathy.

POLYMYXINS

• Cation polypeptides that bind to phospholipids on the bacterial cell membrane of gram-negative bacteria.
• Polymyxins are concentration-dependent bactericidal agents.
• Only two forms of polymyxin are in clinical use today, polymyxin B and colistin.
• Colistin is only available as a prodrug, colistimethate sodium.
• The use of these drugs has been limited for a long time, due to the increased risk of nephrotoxicity and neurotoxicity.