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β-Lactams are antibiotics that have a β-lactam ring nucleus. Subclasses include the cephalosporins and cephamycins (cephems), carbacephems ( loracarbef ), penicillins, clavams, carbapenems, and monobactams. All β-lactams bind to and inactivate enzymes required for bacterial cell wall synthesis.
Cephalosporins
The cephalosporins are bactericidal with both gram-positive and gram-negative activity. Cephalosporins are classified in generations (see Table 7: Bacteria and Antibacterial Drugs: Cephalosporins* ). Higher generations generally have expanded spectra against aerobic gram-negative bacilli. Some 3rd-generation cephalosporins have relatively poor activity against gram-positive cocci, especially methicillin-sensitive Staphylococcus aureus. The 4th-generation cephalosporin, cefepime , maintains activity against gram-positive cocci and has enhanced activity against gram-negative bacilli, including Pseudomonas aeruginosa, extended-spectrum β-lactamase (ESBL)–producing Klebsiella pneumoniae and Escherichia coli, and ampC β-lactamase–producing Enterobacteriaceae, such as Enterobacter sp. Cephalosporins are not active against enterococci, methicillin-resistant staphylococci, and, except for cefotetan and cefoxitin , anaerobic gram-negative bacilli.
Pharmacology:
Cephalosporins penetrate well into most body fluids and the ECF of most tissues, especially in the presence of inflammation (which enhances diffusion). However, only ceftriaxone , cefotaxime , ceftazidime , and cefepime achieve CSF levels sufficient to treat meningitis. All cephalosporins penetrate poorly into ICF and the vitreous humor.
Most cephalosporins are excreted primarily in urine. Dose adjustment is needed for these drugs in renal insufficiency. Cefoperazone and ceftriaxone , which have significant biliary excretion, do not require dose adjustment in renal insufficiency.
Indications:
First-generation cephalosporins have excellent activity against gram-positive cocci. Among them, oral drugs 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 Staphylococcus aureus and for prophylaxis for cardiothoracic, orthopedic, abdominal, and pelvic surgery.
Second-generation cephalosporins and cephamycins ( cefoxitin and cefotetan ) are often used for polymicrobial infections involving gram-negative bacilli and gram-positive cocci. Because cephamycins are active against Bacteroides fragilis and other Bacteroides sp, they can be used when anaerobes are suspected (eg, intra-abdominal sepsis, decubitus ulcers, diabetic foot infections).
Third-generation cephalosporins are active against Haemophilus
influenzae and some Enterobacteriaceae (eg, E. coli
, K. pneumoniae
, Proteus mirabilis) that do not express ampC β-lactamase or produce ESBL. Ceftazidime and cefoperazone are active against P.
aeruginosa. Oral cefpodoxime is used for uncomplicated skin and soft-tissue infections due to staphylococci and streptococci, but oral cefixime and ceftibuten have little activity against S. aureus and should be restricted to uncomplicated infections due to streptococci.
The 4th-generation drug cefepime has good activity against gram-positive cocci (similar to cefotaxime ) and Pseudomonas (similar to ceftazidime ) and enhanced activity against many Enterobacteriaceae. Third- and 4th-generation cephalosporins are often used in polymicrobial infections involving gram-negative bacilli and gram-positive cocci (eg, intra-abdominal sepsis, decubitus ulcers, diabetic foot infections), when necessary combined with other drugs to cover anaerobes or enterococci. Ceftriaxone and some other 3rd-generation drugs are often used with a macrolide (the macrolide is used to cover “atypical” pathogens—Mycoplasma
, Chlamydophila
, Legionella) in community-acquired pneumonia. Ceftriaxone and cefotaxime are used empirically for acute meningitis due to suspected Streptococcus pneumoniae
, H. influenzae
, or Neisseria meningitides in combination with ampicillin to cover Listeria
monocytogenes. Pneumococcal strains that are resistant to ceftriaxone and cefotaxime have been reported, and guidelines suggest that strains cultured in meningitis that have MICs of ≥ 0.5 μg/mL should be considered resistant to 3rd-generation cephalosporins. Thus, in acute meningitis, ceftriaxone or cefotaxime is empirically combined with vancomycin to cover Streptococcus
pneumoniae with reduced penicillin sensitivity. Ceftazidime is part of empiric therapy for postneurosurgical meningitis to cover P. aeruginosa and combined with vancomycin to cover methicillin-resistant S. aureus, which are common pathogens in this setting.
Ceftriaxone is recommended for endocarditis caused by HACEK organisms (Haemophilus
, Actinobacillus
, Cardiobacterium
, Eikenella
, and Kingella spp) and for penicillin-sensitive streptococcal endocarditis. Ceftriaxone is used for neurologic complications of Lyme disease (except isolated Bell's palsy), carditis, and arthritis. A single IM dose of ceftriaxone is used for uncomplicated gonococcal infection and for chancroid.
Toxicity:
Hypersensitivity reactions are the most common systemic adverse effects; 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 are possible.
All cephalosporins can produce Clostridium
difficile (pseudomembranous) colitis, leukopenia, thrombocytopenia, or a positive Coombs' test (although hemolytic anemia is very uncommon).
Cefamandole, cefoperazone, and cefotetan may have a disulfiram -like effect and cause nausea and vomiting with ethanol ingestion. Cefamandole, cefoperazone, and cefotetan may elevate the PT/INR and PTT, an effect that is reversible with vitamin K.
Penicillins
Penicillins (see Table 8: Bacteria and Antibacterial Drugs: Penicillins) are bactericidal by unknown mechanisms, perhaps by activating autolytic enzymes that destroy the bacterial cell wall in some organisms. Some organisms produce β-lactamase, which inactivates the drug; this effect can be blocked by adding a β-lactamase inhibitor (clavulanic acid, sulbactam, or tazobactam). However, available β-lactamase inhibitors do not inhibit ampC β-lactamases commonly produced by Enterobacter
, Serratia
, P. aeruginosa
, Citrobacter
, Providencia
, and Morganella and may only partially inhibit extended-spectrum β-lactamases produced by some K. pneumoniae
, E. coli, and other Enterobacteriaceae.
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, causes fewer GI effects, and can be given less frequently.
Penicillins are distributed rapidly in ECF of most tissues, particularly with inflammation.
Urinary excretion of all penicillins except nafcillin is high, necessitating dose reduction in patients with severe renal insufficiency. Probenecid inhibits renal tubular secretion of many penicillins, increasing blood levels. Parenteral penicillin G is rapidly excreted (serum half-life 0.5 h) except for repository forms (the benzathine or procaine salt of penicillin G ), which 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 more slowly and is generally longer acting than procaine penicillin. Three benzathine penicillin G –containing products are available: Bicillin L-A (benzathine penicillin alone), Bicillin C-R (a mixture of equal amounts of benzathine and procaine penicillin G ), and Bicillin® C-R 900/300 (a mixture of 0.9 MU benzathine and 0.3 MU procaine penicillin G ). Only
Bicillin L-A is recommended for treating syphilis and preventing rheumatic
fever. Both Bicillin L-A and Bicillin C-R are indicated for treatment of URIs and skin and soft-tissue infections caused by susceptible streptococci. The efficacy of Bicillin C-R to treat syphilis is unknown.
Indications:
Penicillin G –like drugs (including penicillin V) are primarily used for gram-positive organisms and some gram-negative cocci (eg, meningococcus); a minority of gram-negative bacilli also are 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, in combination with gentamicin , for endocarditis due to susceptible enterococci.
Amoxicillin and ampicillin are more active against enterococci and certain gram-negative bacilli, such as non-β-lactamase–producing H. influenzae
, E. coli, and P. mirabilis; Salmonella; and Shigella. The addition of a β-lactamase inhibitor allows use against methicillin-sensitive staphylococci, H. influenzae
, N. gonorrhoeae
, Moraxella catarrhalis
, Bacteroides
, E. coli
, and K. pneumoniae. Ampicillin is indicated primarily for infections typically caused by sensitive gram-negative organisms (eg, UTI, meningococcal meningitis, biliary sepsis, respiratory infections, Listeria meningitis, enterococcal infections, some typhoid fever and typhoid carriers).
The penicillinase-resistant penicillins are used primarily for penicillinase-producing S. aureus. These drugs also treat some S. pneumoniae, group A streptococci, and coagulase-negative staphylococcal infections.
The broad-spectrum (antipseudomonal) penicillins have activity similar to ampicillin but are also active against some strains of Enterobacter and Serratia and 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. The broad-spectrum penicillins exhibit synergy with aminoglycosides, with which they are usually combined for P. aeruginosa infections.
Toxicity:
Most adverse effects are hypersensitivity reactions. Immediate reactions, including anaphylaxis (which can cause death within minutes), urticaria, and angioneurotic edema, occur in 1 to 5/10,000 injections, and fatalities occur in about 0.3/10,000 injections. Delayed reactions (occurring in up to 8% of patients) include 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, the risk of an allergic reaction is about 10-fold higher for those 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). Patients with mild or vague reactions may undergo skin tests (see Allergic and Other Hypersensitivity Disorders: Skin testing). However, patients with serious reactions should not be given any β
-lactam
again (including skin testing), except with special precautions and desensitization regimens in rare circumstances when no substitute can be found.
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.
CNS toxicity (eg, seizures) may occur with high penicillin doses, especially with renal insufficiency. All penicillins can cause nephritis, C. difficile colitis (pseudomembranous), Coombs'-positive hemolytic anemia, leukopenia, and thrombocytopenia. Leukopenia seems to occur most often with nafcillin . Although any penicillin used in very high IV doses can interfere with platelet function and cause bleeding, ticarcillin is the most common cause, especially in patients with renal insufficiency.
Other reactions include pain at the IM injection site, thrombophlebitis when the same site is used repeatedly for IV injection, and GI disturbances with oral preparations. Black tongue, due to irritation of the glossal surface and keratinization of the superficial layers, may occur more often with oral preparations. Ticarcillin may cause Na overload when used in large doses, owing to ticarcillin being a disodium salt. Ticarcillin also can cause hypokalemic metabolic alkalosis, owing to the large amount of nonabsorbable anion presented to the distal tubules, which alter H+ ion excretion and secondarily results in K+ loss.
Other β-Lactams
The carbapenems (imipenem, meropenem , ertapenem ) are parenteral bactericidal drugs that have an extremely broad spectrum. H. influenzae, anaerobes, and most Enterobacteriaceae (including those that produce ampC β-lactamase and ESBL) are susceptible, although P.
mirabilis tends to have higher imipenem MICs. Enterococcus faecalis and many P. aeruginosa strains, including those resistant to broad-spectrum penicillins and cephalosporins, are susceptible to imipenem and meropenem but are resistant to ertapenem . Carbapenems are active against methicillin-sensitive staphylococci and streptococci, including S.
pneumoniae (except possibly strains with reduced penicillin sensitivity). Carbapenems are active synergistically with aminoglycosides against P. aeruginosa. Penicillin-resistant Enterococcus faecium and methicillin-resistant staphylococci are resistant.
Many multidrug-resistant hospital-acquired pathogens are sensitive only to carbapenems. However, expanded use of carbapenems has resulted in some carbapenem resistance.
Imipenem and meropenem penetrate into CSF with inflamed meninges. Meropenem is used for gram-negative bacillary meningitis; imipenem is not used in meningitis because it may cause seizures. Most seizures occur in patients with CNS pathology or renal insufficiency who have received inappropriately high doses.
Aztreonam is a parenteral bactericidal antibiotic as active as ceftazidime against Enterobacteriaceae that do not express ampC β-lactamase or produce an ESBL, and against P. aeruginosa. Aztreonam is not active against anaerobes. Unlike cephalosporins, gram-positive organisms are resistant. Aztreonam acts synergistically with aminoglycosides. Because the metabolic products of aztreonam differ from those of other β-lactams, cross-hypersensitivity is unlikely. Thus the main use of aztreonam is severe aerobic gram-negative bacillary infections, including meningitis, in patients with serious β-lactam allergy who nevertheless require β-lactam therapy. Additional antibiotics are added to cover any suspected gram-positive cocci and anaerobes. The dose is reduced in renal failure.
Last full review/revision November 2005
Content last modified November 2005
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