Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects

INTRODUCTION — Beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based upon a shared structural feature, the beta-lactam ring. Beta-lactam antibiotics include:

●Penicillins

●Cephalosporins

●Cephamycins

●Carbapenems

●Monobactams

●Beta-lactamase inhibitors

Since this category of antibiotics is so broad, it is important to subdivide these drugs into functional drug groups to facilitate understanding and prescribing practices. It is not necessary for clinicians to know every drug within each of these groups. The grouping of these agents can be based on spectrum of activity, choice of agents for an antibiotic formulary, therapeutic use, or routine susceptibility testing. Within each functional group, differences between antibiotics in pharmacokinetics, safety, duration of the clinical experience with their use, and cost allow reasonable choices to be made in selecting an individual drug as representative of that group.

The mechanisms of action and resistance and major adverse reactions to these antibiotics will be reviewed here. The penicillins, cephalosporins, and novel beta-lactam drugs are discussed separately. (See "Penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins" and "Cephalosporins" and "Combination beta-lactamase inhibitors, carbapenems, and monobactams".)

MECHANISM OF ACTION — Beta-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating enzymes located in the bacterial cell membrane, which are involved in the third stage of cell wall synthesis. It is during this stage that linear strands of peptidoglycan are cross-linked into a fishnet-like polymer that surrounds the bacterial cell and confers osmotic stability in the hypertonic milieu of the infected patient. Beta-lactams inhibit not just a single enzyme involved in cell wall synthesis, but a family of related enzymes (four to eight in different bacteria), each involved in different aspects of cell wall synthesis. These enzymes can be detected by their covalent binding of radioactively-labeled penicillin (or other beta-lactams) and hence have been called penicillin-binding proteins (PBPs).

Different PBPs appear to serve different functions for the bacterial cell. As an example, PBP2 in Escherichia coli is important in maintaining the rod-like shape of the bacillus, while PBP3 is involved in septation during cell division [1]. Different beta-lactam antibiotics may preferentially bind to and inhibit certain PBPs more than others. Thus, different agents may produce characteristic effects on bacterial morphology and have different efficacies in inhibiting bacterial growth or killing the organism.

Beta-lactam antibiotics are generally bactericidal against organisms that they inhibit. The mechanism of bacterial cell killing is an indirect consequence of the inhibition of bacterial cell wall synthesis. Enzymes that mediate autolysis of peptidoglycan are normally present in the bacterial cell wall but are strictly regulated to allow breakdown of the peptidoglycan only at growing points. Beta-lactam inhibition of cell wall synthesis leads to activation of the autolytic system through a two-component system, VncR/S, which initiates a cell death program [2].

Certain bacteria are deficient in these autolytic enzymes or have mutations in the regulatory genes; these strains show the phenomenon of "tolerance" to beta-lactam antibiotics, that is, their growth is inhibited by the antibiotic, but the bacteria are not killed.

MECHANISMS OF BACTERIAL RESISTANCE — Three general mechanisms of bacterial resistance to antibiotics, including the beta-lactams, have been well characterized: decreased penetration to or increased efflux from the target site; alteration of the target site; and inactivation of the antibiotic by a bacterial enzyme [3,4].

Decreased penetration to the target site and efflux — The outer membrane of gram-negative bacilli provides an efficient barrier to the penetration of beta-lactam antibiotics to their target penicillin-binding proteins (PBPs) in the bacterial cytoplasmic membrane. Beta-lactams usually must pass through the hydrophilic porin protein channels in the outer membrane of gram-negative bacilli to reach the periplasmic space and cytoplasmic membrane. The permeability barrier of the outer membrane is a major factor in the relative intrinsic resistance of Pseudomonas aeruginosa to many beta-lactam antibiotics. Mutations that result in decreased amounts of porin channels, those that increase the amounts of native active efflux pumps, or both can contribute to acquired resistance to beta-lactams.

Alteration of the target site — The target sites for the beta-lactams are the PBPs in the cytoplasmic membrane. Alterations in PBPs may influence their binding affinity for beta-lactam antibiotics and therefore the sensitivity of the altered bacterial cell to inhibition by these antibiotics. Such a mechanism is responsible for penicillin resistance in pneumococci [5], methicillin (oxacillin) resistance in staphylococci [6], and for bacteria with increasing intrinsic resistance to beta-lactams, such as gonococci, enterococci, and Haemophilus influenzae.

Inactivation by a bacterial enzyme — Production of beta-lactamases is a major mechanism of resistance to the beta-lactam antibiotics in clinical isolates. Such bacterial enzymes may cleave predominantly penicillins (penicillinases), cephalosporins (cephalosporinases), or both (beta-lactamases). Their production may be encoded within the bacterial chromosome (and hence be characteristic of an entire species) or the genes may be acquired on a plasmid or transposon (and hence be characteristic of an individual strain rather than the species). Bacteria may synthesize the beta-lactamase constitutively (as for many plasmid-mediated enzymes) or synthesis may be inducible in the presence of antibiotic (as for many chromosomal enzymes). Inducible beta-lactamases may not be reliably detected by initial susceptibility testing, particularly with the newer rapid methods.

Chromosomal beta-lactamases — Although virtually all gram-negative bacilli possess a chromosomal beta-lactamase gene, certain species express insignificant amounts of this enzyme, and their susceptibility to beta-lactams is largely determined by plasmid-mediated beta-lactamases and antibiotic permeability. These include E. coli, Proteus mirabilis, Salmonella, Shigella, and H. influenzae. Klebsiella pneumoniae produces a chromosomal beta-lactamase that is primarily a penicillinase; thus, these strains are frequently more susceptible to the cephalosporins. The last group of species within the Enterobacterales, including Enterobacter, indole-positive Proteus, Morganella, Serratia, and Citrobacter, can produce an inducible chromosomal beta-lactamase, AmpC, that may be difficult to detect on initial susceptibility testing but that can mediate resistance to all currently available beta-lactams with the exception of the carbapenems and, in some cases, cefepime [7-9]. In addition to inducible production of this chromosomal enzyme, these species may give rise to regulatory mutants that are "derepressed" and produce high levels of this broad-spectrum chromosomal enzyme constitutively. Per expert guidelines, Enterobacter cloacae complex, Klebsiella aerogenes (formerly, Enterobacter aerogenes), and Citrobacter freundii are the Enterobacterales with moderate to high risk for clinically significant AmpC production in the United States [10].

Plasmid-mediated beta-lactamases — The most common plasmid-mediated beta-lactamases of gram-negative bacteria (such as TEM-1, TEM-2, and SHV-1) mediate resistance to the penicillins and first- and some of the second-generation cephalosporins, but not cefuroxime, cephamycins, third- and fourth-generation cephalosporins, carbapenems, or aztreonam.

Extended-spectrum plasmid-mediated beta-lactamases (ESBLs; derived from the common TEM and SHV enzymes) are now common and are capable of cleaving later-generation cephalosporins and aztreonam [11]. Originally described in strains of Klebsiella from Europe, these beta-lactamases are found in a variety of gram-negative bacilli in many areas of the United States and spread between patients in intensive care units has been documented. In addition, a study from Chicago documented that nursing home patients may be an important reservoir for strains of Enterobacterales producing extended-spectrum plasmid-mediated beta-lactamases [12]. In one nursing home, for example, 18 of 39 patients were colonized with such resistant strains, and of the 55 patients in an acute care hospital colonized with resistant E. coli or K. pneumoniae, 35 had been admitted from nursing homes, and 31 of them were colonized on admission. Although the strains of resistant E. coli and K. pneumoniae differed, most harbored a common plasmid-encoded extended-spectrum beta-lactamase, suggesting intraspecies and interspecies transfer of plasmids between strains, rather than transfer of a single strain between patients. All of these strains were resistant to ceftazidime, gentamicin, and tobramycin, and 96 and 41 percent were also resistant to trimethoprim-sulfamethoxazole and ciprofloxacin, respectively.

ESBLs, of which there are many varieties, mediate high-level resistance to the third- and fourth-generation cephalosporins and aztreonam, but not to the cephamycins (cefoxitin and cefotetan) or the carbapenems. Use of the cephamycins against strains containing these enzymes is, however, limited by the development of permeability mutants in the porin protein, OmpF. The beta-lactamase inhibitors, clavulanate, sulbactam, tazobactam, avibactam, vaborbactam, and relebactam have generally retained the ability to inhibit ESBLs. (See "Extended-spectrum beta-lactamases".)

Another plasmid-mediated beta-lactamase, MIR-1, has been described in Klebsiella; it is homologous to the AmpC chromosomal beta-lactamase of E. cloacae [13]. This plasmid-mediated beta-lactamase is capable of cleaving all of the currently available beta-lactams (with the exception of the carbapenems) and its activity is not inhibited by clavulanate, sulbactam, or tazobactam. This plasmid-mediated beta-lactamase confers a broad resistance pattern similar to that of stably derepressed mutants of Enterobacter.

Over the past two decades, carbapenem-hydrolyzing enzymes have been described in K. pneumoniae and other members of the Enterobacterales. These are encoded on transmissible plasmids, which facilitate their spread. Resistance to the carbapenems in these strains is not always detected by currently available automated susceptibility methods. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Classifications and geographic distribution'.)

The New Delhi metallo-beta-lactamase 1 (NDM-1) is another plasmid-mediated enzyme that mediates broad resistance to all currently available beta-lactams (including the carbapenems) and is linked to other resistance genes on the plasmid that can confer resistance to all available antibiotics, with the exceptions of colistin, polymyxin B, eravacycline, and tigecycline [14-16]. This enzyme was originally found in a number of Enterobacterales in India and Pakistan as well as in individuals returning to the UK, United States, and other countries who have travelled there, particularly for medical care; they have now been found more broadly. Organisms containing metallo-beta-lactamases have been referred to in the lay media as "superbugs" because of their extensive resistance. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Classifications and geographic distribution'.)

ADVERSE EFFECTS — Several adverse reactions have been described for beta-lactam antibiotics.

IgE-mediated allergic reactions — Type I, IgE-mediated reactions present with various combinations of pruritus, flushing, urticaria, angioedema, wheezing, laryngeal edema, hypotension, and/or anaphylaxis. Symptoms usually appear within four hours of drug administration and may begin within minutes. When the allergy first develops, the initial symptoms may appear during the later days of treatment and then escalate rapidly. (See "Penicillin allergy: Immediate reactions".)

Serum sickness — Serum sickness is a late allergic reaction characterized by fever, rash (usually urticarial), adenopathy, arthritis, and occasionally glomerulonephritis. It is associated with circulating immune complexes and has been reported with all of the beta-lactam antibiotics. Each of the beta-lactam antibiotics is also capable of causing drug fever. (See "Serum sickness and serum sickness-like reactions" and "Overview of cutaneous small vessel vasculitis" and "Drug fever".)

Dermatologic reactions — A variety of rashes occur with the beta-lactam antibiotics, of which morbilliform rash is the most common. Erythema multiforme is an acute eruption characterized by distinctive target skin lesions and diagnostic histology; when the mucosal surfaces are involved as well, the reaction is termed Stevens-Johnson syndrome. Exfoliative dermatitis is a severe skin disorder with generalized erythema and scaling. Toxic epidermal necrolysis is an acute severe reaction with widespread erythema and detachment of the epidermis; there may be a positive Nikolsky sign. Hypersensitivity angiitis is a small vessel vasculitis involving mainly the venules of the skin and characterized by palpable purpura. The beta-lactam antibiotics may also cause photosensitivity reactions. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis" and "Drug eruptions" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Overview of cutaneous small vessel vasculitis".)

Neurologic reactions — Among the antibiotics, the penicillins are the most common to cause encephalopathy. Penicillin neurotoxicity is characterized by a change in the level of consciousness (somnolence, stupor, or coma) with generalized hyperreflexia, myoclonus, and seizures. This syndrome occurs with high-dose penicillin therapy (>20 million units per day), particularly if excretion is delayed by underlying renal disease or if preexisting neurologic disease is present. Penicillin neurotoxicity can potentially confuse the management of patients with bacterial meningitis.

High doses of the beta-lactam antibiotics (particularly penicillins, fourth-generation cephalosporins, and imipenem) may cause seizures [17]. Central nervous system (CNS) toxicity of imipenem correlates with high doses, renal dysfunction, or underlying CNS disease [17,18]. Cefepime has also been associated with seizures, particularly in the setting of renal impairment. Between 1996 and 2012, 59 cases of nonconvulsive status epilepticus during cefepime use in patients with renal dysfunction were reported to the United States Food and Drug Administration (FDA) [19]. Most cases occurred in patients whose dose was not appropriately adjusted for renal function and resolved following hemodialysis or discontinuation of cefepime.

Cefepime neurotoxicity can also manifest as changes in level of consciousness, disorientation or agitation, and myoclonus as described in two systematic reviews; older patients with renal dysfunction are at increased risk [20,21]. An observational study of 503 patients receiving cefepime reported that 4 percent (22 patients) experienced cefepime-related neurotoxicity, with a greater risk in those with higher drug levels and those with renal dysfunction [22]. In a randomized trial comparing cefepime to piperacillin-tazobactam in over 2500 hospitalized patients, 21 percent of patients on cefepime experienced delirium or coma compared with 17 percent on piperacillin-tazobactam; patients on cefepime experienced fewer days alive and were free of delirium (11.9 days) than patients on piperacillin-tazobactam (12.2 days; OR 0.79; 95% CI, 0.65 to 0.95) [23].

Pulmonary reactions — Beta-lactam antibiotics occasionally cause the pulmonary infiltrate with eosinophilia (PIE) syndrome, which has an abrupt onset with fever, chills, dyspnea, pulmonary infiltrates, and peripheral eosinophilia (see "Overview of pulmonary eosinophilia"). Beta-lactam antibiotics may also cause drug-induced lupus, with manifestations including serositis (pleural effusions or pericarditis), fever, and pneumonia. (See "Drug-induced lupus".)

Gastrointestinal reactions — Diarrhea is a frequent nonspecific complication of antibiotic therapy, especially with certain oral antibiotics such as ampicillin or amoxicillin [24]. All antibiotics can predispose to Clostridioides (formerly Clostridium) difficile colitis, including penicillins and cephalosporins. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Antibiotic use'.)

Hepatobiliary reactions — The semisynthetic penicillins, such as oxacillin and nafcillin, may cause hypersensitivity hepatitis accompanied by fever, rash, and eosinophilia [25]. This syndrome is more commonly seen at higher doses. Ceftriaxone may cause biliary sludge and pseudocholelithiasis, particularly in children [26].

Renal reactions — Several types of reactions can occur in the kidneys.

●Glomerulonephritis may be seen in association with hypersensitivity angiitis or serum sickness following administration of beta-lactam antibiotics.

●The cephalosporin antibiotics may potentiate the renal toxicity of aminoglycosides.

●In observational studies, concomitant use of piperacillin-tazobactam and vancomycin has been associated with acute kidney injury [27-29]. However, a randomized trial comparing cefepime to piperacillin-tazobactam in over 1900 hospitalized patients who were also on vancomycin found that the incidence of major kidney events at day 14 was comparable between groups (10 percent in the cefepime group compared with 9 percent in the piperacillin-tazobactam group; absolute difference, 1.4 percent; 95% CI -1.0 to 3.8 percent) [23]. The median duration of antibiotic treatment was three days, and there was substantial crossover of study drugs (approximately 18 percent in both groups). Based on these data, we believe the risk of nephrotoxicity from coadministration of vancomycin and piperacillin-tazobactam is less than that suggested by observational data. For patients who warrant prolonged coadministration of vancomycin with an antipseudomonal agent, we weigh the potential risk of nephrotoxicity against possible drawbacks of other beta-lactams, such as risk of neurotoxicity with cefepime or overly broad coverage with carbapenems. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Acute kidney injury'.)

●The beta-lactam antibiotics, particularly methicillin and nafcillin, may cause allergic interstitial nephritis [30], characterized by acute, often severe, renal failure, with an active urinary sediment with hematuria, proteinuria, and pyuria, but generally no red cell casts (see "Clinical manifestations and diagnosis of acute interstitial nephritis"). Signs of hypersensitivity are generally present, including fever, peripheral eosinophilia, and rash; eosinophiluria is characteristic but not always found.

There are several case reports of cross-sensitivity between beta-lactam antibiotics eliciting acute allergic interstitial nephritis, so the occurrence of this syndrome with one beta-lactam antibiotic generally cautions against the use of other agents in this class.

The antipseudomonal penicillins, particularly ticarcillin (which is a disodium salt), may cause sodium overload and hypokalemic alkalosis [31]. (See "Causes of hypokalemia in adults".)

Hematologic reactions — Beta-lactam antibiotics may be associated with immune-mediated destruction of polymorphonuclear leukocytes, which is characterized by an abrupt onset of neutropenia with fever, rash, and eosinophilia. Similarly, beta-lactam antibiotics may cause immune-mediated hemolytic anemia, characterized by a positive non-gamma Coombs' test or by subacute extravascular hemolysis with a positive gamma Coombs' test. This latter reaction generally requires prolonged, high-dose therapy and signs of hypersensitivity are usually absent.

Acute immune thrombocytopenia has been associated with beta-lactam antibiotic administration. The platelet count generally normalizes within two weeks after the drug is stopped. Platelet dysfunction may be caused by high doses of ticarcillin; the newer antipseudomonal penicillin, piperacillin, has less of an effect on platelet function [31,32].

Broad spectrum antibiotic therapy suppresses gut flora and may contribute to vitamin K deficiency. Hypoprothrombinemia has been a particular problem with antibiotics containing the N-methylthiotetrazole side chain [33]. This same side chain is associated with intolerance to ethanol.

USE OF BETA-LACTAM ANTIBIOTICS IN THE PENICILLIN OR CEPHALOSPORIN-ALLERGIC PATIENT — Penicillins and cephalosporins may be safe to use in the allergic patient. (See "Choice of antibiotics in penicillin-allergic hospitalized patients" and "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Carbapenem-resistant enterobacterales (The Basics)")

●Beyond the Basics topic (see "Patient education: Allergy to penicillin and related antibiotics (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Beta-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating enzymes located in the bacterial cell membrane, known as penicillin-binding proteins (PBPs), which are involved in cell wall synthesis. These antibiotics are generally bactericidal against susceptible organisms. (See 'Mechanism of action' above.)

●Mechanisms of resistance – The major mechanism of resistance to the beta-lactam antibiotics in clinical isolates is production of enzymes that cleave penicillins (penicillinases), cephalosporins (cephalosporinases), or both (beta-lactamases). Decreased penetration to the cytoplasmic membrane target site and alterations in the PBPs are other mechanisms of resistance. (See 'Mechanisms of bacterial resistance' above.)

●Chromosomal beta-lactamases – Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii are at moderate to high risk for producing an inducible chromosomal beta-lactamase, AmpC, that may be difficult to detect on initial susceptibility testing but can mediate resistance to all currently available beta-lactams other than carbapenems and, in some cases, cefepime. (See 'Chromosomal beta-lactamases' above.)

●Plasmid-mediated beta-lactamases – The most common plasmid-mediated beta-lactamases in gram-negative bacteria mediate resistance to penicillins and first- and some second-generation cephalosporins. Extended spectrum plasmid-mediated beta-lactamases can additionally cleave later-generation cephalosporins and aztreonam. These plasmids can transfer to other species and genera. (See 'Plasmid-mediated beta-lactamases' above and "Extended-spectrum beta-lactamases".)

●Adverse effects – Use of beta-lactams is associated with various adverse effects, including IgE-mediated allergic reactions, rash, diarrhea, renal toxicity, and other hypersensitivity and immune-mediated reactions. The penicillins are the most common antibiotics to cause encephalopathy and high doses of beta-lactams can cause seizures. (See 'Adverse effects' above.)