21/06/2024, 00:21 Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects - UpToDate

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Beta-lactam antibiotics: Mechanisms of action and

resistance and adverse effects
AUTHOR: Alyssa R Letourneau, MD, MPH
SECTION EDITOR: David C Hooper, MD
DEPUTY EDITOR: Keri K Hall, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2024.

This topic last updated: Nov 15, 2023.

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".)
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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
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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

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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.

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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

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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

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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").
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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".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
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about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical terminology.

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.

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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.)

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Topic 479 Version 25.0

Contributor Disclosures
Alyssa R Letourneau, MD, MPH No relevant financial relationship(s) with ineligible companies to
disclose. David C Hooper, MD Consultant/Advisory Boards: Basilea [Antibiotic]; Day Zero Diagnostics
[Diagnostics]; Selux [Diagnostics]; Torus Biosystems [Diagnostics]; Venatorx [Antibiotic]. All of the
relevant financial relationships listed have been mitigated. Keri K Hall, MD, MS No relevant financial
relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
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