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

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©2023 UpToDate®

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

Contributor Disclosures

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

Literature review current through: Feb 2023. | This topic last updated: Aug 04, 2021.

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 upon spectrum of activity, for choice of agents for an antibiotic
formulary, for therapeutic use, or for 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.

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

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

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

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 — 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 plasma 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 plasma membrane. The
permeability barrier of the outer membrane is a major factor in the resistance of
Pseudomonas aeruginosa to many beta-lactam antibiotics.

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-lactamase 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.

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

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 Enterobacteriaceae,
including Enterobacter, indole-positive Proteus, Morganella, Serratia, and Citrobacter,
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 perhaps 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.

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, or the
novel beta-lactam compounds such as the carbapenems or aztreonam.

More recently, extended-spectrum plasmid-mediated beta-lactamases (derived from the

common TEM and SHV enzymes) have arisen, which are capable of cleaving later-
generation cephalosporins and aztreonam [10]. Originally described in strains of Klebsiella
from Europe, these beta-lactamases have now been 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 Enterobacteriaceae producing
extended-spectrum plasmid-mediated beta-lactamases [11]. 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 encoding an extended-spectrum beta-lactamase, suggesting
intraspecies and interspecies transfer of the plasmid between strains, rather than transfer

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

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.

These enzymes, 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. However, use of the cephamycins against
strains containing these new enzymes is limited by the development of permeability
mutants in the porin protein, OmpF. The beta-lactamase inhibitors, clavulanate, sulbactam,
tazobactam, and avibactam, have generally retained the ability to inhibit these newer
plasmid-mediated beta-lactamases. (See "Extended-spectrum beta-lactamases".)

Another plasmid-mediated beta-lactamase, MIR-1, has been described in Klebsiella, which

is homologous to the AmpC chromosomal beta-lactamase of Enterobacter cloacae [12].
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 stably derepressed mutants of Enterobacter.

Over the past two decades, carbapenem-hydrolyzing enzymes have been described in
Klebsiella pneumoniae and other members of the Enterobacteriaceae. 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)".)

The New Delhi metallo-β-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 confer
resistance to all available antibiotics, with the exceptions of colistin and tigecycline [13].
This enzyme was originally found in a number of Enterobacteriaceae in India and Pakistan,
as well as in individuals returning to the UK, US, and other countries who have travelled
there, particularly for medical care; they have now been described more broadly. These
organisms 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)".)

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

ADVERSE EFFECTS

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

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 [14]. Central nervous system (CNS)
toxicity of imipenem correlates with high doses, renal dysfunction, or underlying CNS
disease [14,15]. 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) [16]. The majority of 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
[17,18].

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 [19]. 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 [20].
This syndrome is more commonly seen at higher doses. Ceftriaxone may cause biliary
sludge and pseudocholelithiasis, particularly in children [21].

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

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

● Concomitant use of piperacillin-tazobactam and vancomycin has been associated

with acute kidney injury [22-24]. (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 [25], 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 [26]. (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 [26,27].

Broad spectrum antibiotic therapy suppresses gut flora and may contribute to vitamin K
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Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects

deficiency. Hypoprothrombinemia has been a particular problem with antibiotics

containing the N-methylthiotetrazole side chain [28]. 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
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 jargon.

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

● 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 plasma
membrane target site and alterations in the PBPs are other mechanisms of
resistance. (See 'Mechanisms of bacterial resistance' above.)

● Enterobacter, indole-positive Proteus, Serratia, Morganella, and Citrobacter produce

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 perhaps cefepime. (See 'Chromosomal beta-
lactamases' above.)

● 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".)

● 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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