β-Lactams are antibiotics that have a β-lactam ring nucleus. Subclasses include

• Cephalosporins and cephamycins (cephems)
• Carbacephems (loracarbef)
• Penicillins
• Clavams
• Carbapenems
• Monobactams

All β-lactams bind to and inactivate enzymes required for bacterial cell wall synthesis.

Cephalosporins

Cephalosporins are bactericidal (see Table 7: Bacteria and Antibacterial Drugs: Cephalosporins*). They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell synthesis.

Table 7
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Cephalosporins* Drug Route 1st Generation Cefadroxil Oral Cefazolin Parenteral Cephalexin Oral Cephradine Oral 2nd Generation Cefaclor Oral Cefotetan Parenteral Cefoxitin Parenteral Cefprozil Oral Cefuroxime Parenteral or oral Loracarbef Oral 3rd Generation Cefdinir Oral Cefditoren Oral Cefixime Oral Cefoperazone Parenteral Cefotaxime Parenteral Cefpodoxime Oral Ceftazidime Parenteral Ceftibuten Oral Ceftizoxime Parenteral Ceftriaxone Parenteral 4th Generation Cefepime Parenteral 5th Generation Ceftobiprole Parenteral *Loracarbef is technically a carbacephem, and cefoxitin and cefotetan are technically cephamycins, but they are grouped with cephalosporins because of similar antimicrobial spectra and pharmacology. Cephalosporins* Drug Route 1st Generation Cefadroxil Oral Cefazolin Parenteral Cephalexin Oral Cephradine Oral 2nd Generation Cefaclor Oral Cefotetan Parenteral Cefoxitin Parenteral Cefprozil Oral Cefuroxime Parenteral or oral Loracarbef Oral 3rd Generation Cefdinir Oral Cefditoren Oral Cefixime Oral Cefoperazone Parenteral Cefotaxime Parenteral Cefpodoxime Oral Ceftazidime Parenteral Ceftibuten Oral Ceftizoxime Parenteral Ceftriaxone Parenteral 4th Generation Cefepime Parenteral 5th Generation Ceftobiprole Parenteral *Loracarbef is technically a carbacephem, and cefoxitin and cefotetan are technically cephamycins, but they are grouped with cephalosporins because of similar antimicrobial spectra and pharmacology.

Pharmacology

Cephalosporins penetrate well into most body fluids and the ECF of most tissues, especially when inflammation (which enhances diffusion) is present. However, the only cephalosporins that reach CSF levels high enough to treat meningitis are

• Ceftriaxone
• Cefotaxime
• Ceftazidime
• Cefepime

All cephalosporins penetrate poorly into ICF and the vitreous humor.

Most cephalosporins are excreted primarily in urine, so their doses must be adjusted in patients with renal insufficiency. Cefoperazone and ceftriaxone, which have significant biliary excretion, do not require such dose adjustment.

Indications

Cephalosporins are bactericidal for most of the following:

• Gram-positive bacteria
• Gram-negative bacteria

Cephalosporins are classified in generations (see Table 8: Bacteria and Antibacterial Drugs: Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins). The 1st-generation drugs are effective mainly against gram-positive organisms. Higher generations generally have expanded spectra against aerobic gram-negative bacilli. The 5th-generation cephalosporin ceftobiprole, which is not yet available in the US, is active against methicillin-resistant Staphylococcus aureus. Cephalosporins have the following limitations:

• Lack of activity against enterococci
• Lack of activity against methicillin-resistant staphylococci (except for ceftobiprole)
• Lack of activity against anaerobic gram-negative bacilli (except for cefotetan and cefoxitin)

First-generation cephalosporins

These drugs have excellent activity against

• Gram-positive cocci

Oral 1st-generation cephalosporins are commonly used for uncomplicated skin and soft-tissue infections, which are usually due to staphylococci and streptococci. Parenteral cefazolin is frequently used for endocarditis due to methicillin-sensitive S. aureus and for prophylaxis before cardiothoracic, orthopedic, abdominal, and pelvic surgery.

Second-generation cephalosporins and cephamycins

Second-generation cephalosporins are active against

• Gram-positive cocci
• Certain gram-negative bacilli

Cephamycins are active against

• Bacteroides sp, including B. fragilis

These drugs may be slightly less active against gram-positive cocci than 1st-generation cephalosporins. Second-generation cephalosporins and cephamycins are often used for polymicrobial infections that include gram-negative bacilli and gram-positive cocci. Because cephamycins are active against Bacteroides sp, they can be used when anaerobes are suspected (eg, in intra-abdominal sepsis, decubitus ulcers, and diabetic foot infections). However, in some medical centers, these bacilli are no longer reliably susceptible to cephamycins.

Third-generation cephalosporins

These drugs are active against

• Haemophilus influenzae and some Enterobacteriaceae (eg, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis) that do not produce ampC β-lactamase or extended-spectrum β-lactamase (ESBL)

Ceftazidime and cefoperazone are also active against

• Pseudomonas aeruginosa

Some 3rd-generation cephalosporins have relatively poor activity against gram-positive cocci. Oral cefixime and ceftibuten have little activity against S. aureus and, if used for skin and soft-tissue infections, should be restricted to uncomplicated infections due to streptococci. These cephalosporins have many clinical uses, as does the 4th-generation cephalosporin (see Table 8: Bacteria and Antibacterial Drugs: Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins).

Fourth-generation cephalosporin

The 4th-generation cephalosporin cefepime has activity against

• Gram-positive cocci (similar to cefotaxime)
• Gram-negative bacilli (enhanced activity), including P. aeruginosa (similar to ceftazidime), ESBL-producing K. pneumoniae and E. coli, and ampC β-lactamase–producing Enterobacteriaceae, such as Enterobacter sp

Table 8
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Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins Drug Indications Comments 3rd- and 4th-generation cephalosporins Polymicrobial infections involving gram-negative bacilli and gram-positive cocci (eg, intra-abdominal sepsis, decubitus ulcers, diabetic foot infections) When necessary, used with other drugs to cover anaerobes or enterococci Ceftriaxone and some other 3rd-generation drugs Community-acquired pneumonia Used with a macrolide to cover atypical pathogens (mycoplasmas, Chlamydophila sp, Legionella sp) Cefotaxime Ceftriaxone Acute meningitis suspected to be due to Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitides Used with ampicillin to cover Listeria monocytogenes and with vancomycin to cover S. pneumoniae with reduced penicillin sensitivity (pending MIC results*) Cefpodoxime (oral) Uncomplicated skin and soft-tissue infections due to staphylococci or streptococci Not used if methicillin-resistant Staphylococcus aureus is suspected Ceftazidime Empiric therapy for postneurosurgical meningitis to cover Pseudomonas aeruginosa Used with vancomycin to cover methicillin-resistant S. aureus Ceftriaxone Endocarditis caused by HACEK organisms — Endocarditis due to penicillin-sensitive streptococci — Lyme disease with neurologic complications (except isolated Bell's palsy), carditis, or arthritis — Uncomplicated gonococcal infections, chancroid, or both Single IM dose * Pneumococcal strains that are resistant to ceftriaxone and cefotaxime have been reported, and guidelines suggest that if CSF strains have MICs of ≥ 1.0 μg/mL, they should be considered nonsusceptible to 3rd-generation cephalosporins. HACEK = Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella spp; MICs = minimum inhibitory concentrations.

Fifth-generation cephalosporin

The 5th-generation cephalosporin ceftobiprole is active against

• Methicillin-resistant S. aureus

Contraindications

Cephalosporins are contraindicated in patients who are allergic to them or who have had an anaphylactic reaction to penicillins.

Use During Pregnancy and Breastfeeding

Cephalosporins are in pregnancy category B (animal studies show no risk and human evidence is incomplete, or animal studies show risk but human studies do not).

Cephalosporins enter breast milk and may alter bowel flora of the infant. Thus, use during breastfeeding is often discouraged.

Adverse Effects

Significant adverse effects include

• Hypersensitivity reactions (most common)
• Clostridium difficile–induced diarrhea (pseudomembranous colitis)
• Leukopenia
• Thrombocytopenia
• Positive Coombs' test (although hemolytic anemia is very uncommon)

Hypersensitivity reactions are the most common systemic adverse effects; rash is common, but immediate IgE-mediated urticaria and anaphylaxis are rare.

Cross-sensitivity between cephalosporins and penicillins is uncommon; cephalosporins can be given cautiously to patients with a history of delayed hypersensitivity to penicillin if necessary. However, cephalosporins should not be used in patients who have had an anaphylactic reaction to penicillin. Pain at the IM injection site and thrombophlebitis after IV use may occur.

Cefamandole (no longer available in the US), cefoperazone, and cefotetan may have a disulfiram-like effect when ethanol is ingested, causing nausea and vomiting. Cefamandole, cefoperazone, and cefotetan may elevate the PT/INR and PTT, an effect that is reversible with vitamin K.

Contraindications

Ceftriaxone is contraindicated as follows:

• Ceftriaxone IV must not be coadministered with Ca-containing IV solutions (including continuous Ca-containing infusions such as parenteral nutrition) in neonates ≤ 28 days because precipitation of ceftriaxone-Ca salt is a risk. Fatal reactions with ceftriaxone-Ca precipitates in the lungs and kidneys of neonates have been reported. In some cases, different infusion lines were used, and ceftriaxone and Ca-containing solutions were given at different times. To date, no intravascular or pulmonary precipitates have been reported in patients other than neonates who are treated with ceftriaxone and Ca-containing IV solutions. However, because an interaction between ceftriaxone and IV Ca-containing solutions is theoretically possible in patients other than neonates, ceftriaxone and Ca-containing solutions should not be mixed or given within 48 h of each other (based on 5 half-lives of ceftriaxone)—even via different infusion lines at different sites—to any patient regardless of age. No data on potential interaction between ceftriaxone and oral Ca-containing products or on interaction between IM ceftriaxone and Ca-containing products (IV or oral) are available.
• Ceftriaxone should not be given to hyperbilirubinemic and preterm neonates because in vitro, ceftriaxone can displace bilirubin from serum albumin, potentially triggering kernicterus.

Penicillins

Penicillins (see Table 9: Bacteria and Antibacterial Drugs: Penicillins) are bactericidal by unknown mechanisms but perhaps by activating autolytic enzymes that destroy the cell wall in some bacteria. Some bacteria produce β-lactamase, which inactivates the drug; this effect can be blocked by adding a β-lactamase inhibitor (clavulanate, sulbactam, or tazobactam). However, available β-lactamase inhibitors do not inhibit ampC β-lactamases, commonly produced by Enterobacter, Serratia, Citrobacter, Providencia, and Morganella spp or by P. aeruginosa, and these drugs may only partially inhibit ESBL produced by some K. pneumoniae, E. coli, and other Enterobacteriaceae.

Table 9
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Penicillins Drug Route Penicillin G–like drugs Penicillin G Oral or parenteral Penicillin G benzathine Parenteral Penicillin G procaine Parenteral Penicillin V Oral Ampicillin-like drugs Ampicillin Oral or parenteral Ampicillin plus sulbactam Parenteral Amoxicillin Oral Amoxicillin plus clavulanate Oral Penicillinase-resistant penicillins Dicloxacillin Oral Nafcillin Oral or parenteral Oxacillin Oral or parenteral Broad-spectrum (antipseudomonal) penicillins Carbenicillin Oral Piperacillin Parenteral Piperacillin plus tazobactam Parenteral Ticarcillin Parenteral Ticarcillin plus clavulanate Parenteral Penicillins Drug Route Penicillin G–like drugs Penicillin G Oral or parenteral Penicillin G benzathine Parenteral Penicillin G procaine Parenteral Penicillin V Oral Ampicillin-like drugs Ampicillin Oral or parenteral Ampicillin plus sulbactam Parenteral Amoxicillin Oral Amoxicillin plus clavulanate Oral Penicillinase-resistant penicillins Dicloxacillin Oral Nafcillin Oral or parenteral Oxacillin Oral or parenteral Broad-spectrum (antipseudomonal) penicillins Carbenicillin Oral Piperacillin Parenteral Piperacillin plus tazobactam Parenteral Ticarcillin Parenteral Ticarcillin plus clavulanate Parenteral

Pharmacology

Food does not interfere with absorption of amoxicillin, but penicillin G should be given 1 h before or 2 h after a meal. Amoxicillin has generally replaced ampicillin for oral use because amoxicillin is absorbed better, has fewer GI effects, and can be given less frequently.

Penicillins are distributed rapidly in the ECF of most tissues, particularly when inflammation is present.

All penicillins except nafcillin are excreted in urine and reach high levels in urine. Parenteral penicillin G is rapidly excreted (serum half-life 0.5 h), except for repository forms (the benzathine or procaine salt of penicillin G); these forms are intended for deep IM injection only and provide a tissue depot from which absorption takes place over several hours to several days. Benzathine penicillin reaches its peak level more slowly and is generally longer-acting than procaine penicillin.

Indications

Penicillin G–like drugs (including penicillin V) are primarily used against

• Gram-positive bacteria
• Some gram-negative cocci (eg, meningococci)

A minority of gram-negative bacilli are also susceptible to large parenteral doses of penicillin G. Most staphylococci, most Neisseria gonorrhoeae, many anaerobic gram-negative bacilli, and about 30% of H. influenzae are resistant. Penicillin G is the drug of choice for syphilis and, with gentamicin, for endocarditis due to susceptible enterococci.

Benzathine penicillin G is available as pure benzathine penicillin, a mixture of equal amounts of benzathine and procaine penicillin G, and a mixture of 0.9 million units benzathine and 0.3 million units procaine penicillin G. Of the 3 products, only pure benzathine penicillin is recommended for treating syphilis and preventing rheumatic fever. Whether the mixture of equal amounts is effective in treating syphilis is unknown. Pure benzathine penicillin and the mixture of equal amounts are indicated for treating URIs and skin and soft-tissue infections caused by susceptible streptococci.

Amoxicillin and ampicillin

These drugs are more active against

• Enterococci
• Certain gram-negative bacilli, such as non-β-lactamase–producing H. influenzae, E. coli, and P. mirabilis; Salmonella sp; and Shigella sp

The addition of a β-lactamase inhibitor allows use against methicillin-sensitive staphylococci, H. influenzae, N. gonorrhoeae, Moraxella catarrhalis, Bacteroides sp, E. coli, and K. pneumoniae. Ampicillin is indicated primarily for infections typically caused by susceptible gram-negative bacteria:

• UTIs
• Meningococcal meningitis
• Biliary sepsis
• Respiratory infections
• Listeria meningitis
• Enterococcal infections
• Some typhoid fever and typhoid carriers

Penicillinase-resistant penicillins

These drugs are used primarily for

• Penicillinase-producing methicillin-sensitive S. aureus

These drugs are also used to treat some S. pneumoniae, group A streptococcal, and methicillin-sensitive coagulase-negative staphylococcal infections.

Broad-spectrum (antipseudomonal) penicillin

These drugs have activity against

• Bacteria susceptible to ampicillin
• Some strains of Enterobacter and Serratia spp
• Many strains of P. aeruginosa

Ticarcillin is less active against enterococci than piperacillin. The addition of a β-lactamase inhibitor enhances activity against β-lactamase–producing methicillin-sensitive S. aureus, E. coli, K. pneumoniae, H. influenzae, and gram-negative anaerobic bacilli, but not against gram-negative bacilli that produce ampC β-lactamase, and may only partially inhibit ESBL produced by some K. pneumoniae, E. coli, and other Enterobacteriaceae. Broad-spectrum penicillins exhibit synergy with aminoglycosides and are usually used with this class to treat P. aeruginosa infections.

Contraindications

Penicillins are contraindicated in patients who have had serious allergic reactions to them.

Use During Pregnancy and Breastfeeding

Penicillins are in pregnancy category B (animal studies show no risk and human evidence is incomplete, or animal studies show risk but human studies do not).

Penicillins enter breast milk in small amounts. Their use is usually considered compatible with breastfeeding.

Adverse Effects

Adverse effects include

• Hypersensitivity reactions, including rashes (most common)

Other adverse effects occur less commonly.

Hypersensitivity

Most adverse effects are hypersensitivity reactions:

• Immediate reactions: Anaphylaxis (which can cause death within minutes), urticaria and angioneurotic edema (in 1 to 5/10,000 injections), and death (in about 0.3/10,000 injections)
• Delayed reactions (in up to 8% of patients): Serum sickness, rashes (eg, macular, papular, morbilliform), and exfoliative dermatitis (which usually appears after 7 to 10 days of therapy)

Most patients who report an allergic reaction to penicillin do not react to subsequent exposure to penicillin. Although small, risk of an allergic reaction is about 10 times higher for patients who have had a previous allergic reaction. Many patients report adverse reactions to penicillin that are not truly allergic (eg, GI adverse effects, nonspecific symptoms). If patients have a vague or inconsistent history of penicillin allergy and taking alternative antibiotics is not effective or convenient, skin testing may be done (see Allergic, Autoimmune, and Other Hypersensitivity Disorders: Skin testing). Desensitization may be attempted in patients with a positive skin test if there is no alternative to a penicillin-type drug. However, patients with a history of anaphylaxis to penicillin should not be given any β-lactam again (including for skin testing), except in very rare circumstances when no substitute can be found. In such cases, special precautions and desensitization regimens are required (see Allergic, Autoimmune, and Other Hypersensitivity Disorders: Desensitization).

Rashes

Rashes occur more often with ampicillin and amoxicillin than with other penicillins. Patients with infectious mononucleosis often develop a nonallergic rash, typically maculopapular, usually beginning between days 4 and 7 of treatment.

Other adverse effects

Penicillins can also cause

• CNS toxicity (eg, seizures) if doses are high, especially in patients with renal insufficiency
• Nephritis
• C. difficile–induced diarrhea (pseudomembranous colitis)
• Coombs'-positive hemolytic anemia
• Leukopenia
• Thrombocytopenia

Leukopenia seems to occur most often with nafcillin. Any penicillin used in very high IV doses can interfere with platelet function and cause bleeding, but ticarcillin is the most common cause, especially in patients with renal insufficiency.

Other adverse effects include pain at the IM injection site, thrombophlebitis when the same site is used repeatedly for IV injection, and, with oral formulations, GI disturbances. Rarely, black tongue, due to irritation of the glossal surface and keratinization of the superficial layers, occurs, usually when oral formulations are used. Ticarcillin in high doses may cause Na overload because ticarcillin is a disodium salt. Ticarcillin can also cause hypokalemic metabolic alkalosis because the large amount of nonabsorbable anion presented to the distal tubules alters H⁺ ion excretion and secondarily results in K⁺ loss.

Dosing Considerations

Because penicillins, except nafcillin, reach high levels in urine, doses must be reduced in patients with severe renal insufficiency. Probenecid inhibits renal tubular secretion of many penicillins, increasing blood levels. It is sometimes given to maintain high blood levels.

Other β-Lactams

Carbapenems (imipenem, meropenem, doripenem, and ertapenem) are parenteral bactericidal antibiotics that have an extremely broad spectrum. They are active against

• H. influenzae
• Anaerobes
• Most Enterobacteriaceae (including those that produce ampC β-lactamase and ESBL, although P. mirabilis tends to have higher imipenem MICs)
• Methicillin-sensitive staphylococci and streptococci, including S. pneumoniae (except possibly strains with reduced penicillin sensitivity)

Most Enterococcus faecalis and many P. aeruginosa strains, including those resistant to broad-spectrum penicillins and cephalosporins, are susceptible to imipenem, meropenem, and doripenem but are resistant to ertapenem. Carbapenems are active synergistically with aminoglycosides against P. aeruginosa. E. faecium and methicillin-resistant staphylococci are resistant.

Many multidrug-resistant hospital-acquired bacteria are sensitive only to carbapenems. However, expanded use of carbapenems has resulted in some carbapenem resistance.

Imipenem and meropenem penetrate into CSF when meninges are inflamed. Meropenem is used for gram-negative bacillary meningitis; imipenem is not used in meningitis because it may cause seizures. Most seizures occur in patients who have CNS abnormalities or renal insufficiency and who are given inappropriately high doses.

Aztreonam is a parenteral bactericidal antibiotic; it is as active as ceftazidime against

• Enterobacteriaceae that do not produce ampC β-lactamase or ESBL
• P. aeruginosa

Aztreonam is not active against anaerobes. Gram-positive bacteria are resistant to aztreonam (in contrast to cephalosporins). Aztreonam acts synergistically with aminoglycosides. Because the metabolic products of aztreonam differ from those of other β-lactams, cross-hypersensitivity is unlikely. Thus, aztreonam is used mainly for

• Severe aerobic gram-negative bacillary infections, including meningitis, in patients who have a serious β-lactam allergy but who nevertheless require β-lactam therapy

Other antibiotics are added to cover any suspected gram-positive cocci and anaerobes. The dose is reduced in renal failure.

Last full review/revision July 2009 by Matthew E. Levison, MD