Beta-lactam antibiotics: Mechanisms of action and resistance

and adverse effects

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

Author
Stephen B Calderwood, MD
Section Editor
David C Hooper, MD
Deputy Editor
Allyson Bloom, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2013. | This topic last updated: Jun 27, 2012.

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.

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 "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 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 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 the 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 Enterobacteriaceae,
including Enterobacter, indole-positive Proteus, Serratia and Citrobacter, produce an
inducible chromosomal beta-lactamase 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 [ 7 ]. 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 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 [ 8 ]. Originally described in strains of Klebsiella
from Europe, these beta-lactamases have now been found in a variety of Gram negative
bacilli in several 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 [ 9 ]. 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 the extended-spectrum beta-lactamase, suggesting intragenic and intraspecies
transfer of the plasmid 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.
These enzymes mediate high-level resistance to the third- and fourth-generation
cephalosporins and aztreonam , but not to the cephamycins ( cefoxitinand 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, and tazobactam have generally
retained the ability to inhibit these newer plasmid-mediated beta-lactamases.
(See "Extended-spectrum beta-lactamases" .)

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

homologous to the chromosomal beta-lactamase of Enterobacter cloacae [ 10 ]. 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 several years, 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. In one report from New York City in
2005, 45 percent of 602 isolates of K. pneumoniae had a plasmid-encoded, extended
spectrum beta-lactamase, and of those, 3.3 percent also carried a carbapenem-hydrolyzing
beta-lactamase termed KPC-2 (Klebsiella pneumoniae carbapenemase-2) [ 11 ]. In a
subsequent report from New York City in 2007, seven strains of Escherichia coli out of 1417
tested had a similar enzyme [ 12 ]. Resistance to the carbapenems in these strains was not
always detected by currently available automated susceptibility
methods. (See "Carbapenemases", section on 'Klebsiella pneumoniae carbapenemase
(KPC)' .)

The New Delhi metallo-β-lactamase 1 (NDM-1) is another plasmid-mediated enzyme that

mediates broad resistance to all currently available antibiotics (including the carbapenems)
with the exceptions of colistin and tigecycline [ 13 ]. This enzyme has been 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.
These organisms have been referred to in the lay media as “superbugs” because of their
extensive resistance. (See "Carbapenemases", section on 'New Delhi metallo-beta-
lactamase (NDM-1)' .)

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 "Allergy to penicillins" .)

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 "Hypersensitivity vasculitis in
adults"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's 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 "Pathogenesis, clinical features, and diagnosis of erythema multiforme" and "Drug
eruptions"and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Clinical
manifestations; pathogenesis; and diagnosis" and "Hypersensitivity vasculitis in adults" .)

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) may cause seizures.
Imipenem may cause CNS toxicity and seizures, especially with high doses, renal
dysfunction, or underlying CNS disease [ 14 ]. 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 [ 15 ]. The majority of
cases occurred in patients whose dose was not appropriately adjusted for renal function and
resolved following discontinuation of cefepime or hemodialysis.

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 "Causes 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 asampicillin or amoxicillin . All
antibiotics can predispose to Clostridium difficile colitis, and ampicillin is a commonly
implicated beta-lactam [ 16 ]. (See"Clostridium difficile in adults: Epidemiology,
microbiology, and pathophysiology" .)
Hepatobiliary reactions — The semisynthetic penicillins, such as oxacillin and nafcillin ,
may cause hypersensitivity hepatitis accompanied by fever, rash, and eosinophilia [ 17 ].
This syndrome is more commonly seen at higher doses. Ceftriaxone may cause biliary
sludge and pseudocholelithiasis, particularly in children [ 18 ].

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.
• The beta-lactam antibiotics, particularly methicillin, may cause allergic interstitial
nephritis [ 19 ], 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 [ 20 ]. (See"Causes of hypokalemia" .)

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 anti-
pseudomonal penicillin, piperacillin , has less of an effect on platelet function [ 20,21 ].

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 [ 22 ]. This same side chain is associated with
intolerance to ethanol.

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SUMMARY

• Beta-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating

enzymes located in the bacterial cell membrane, known as penicillin binding
proteins, 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 penicillin binding proteins are
other mechanisms of resistance. (See 'Mechanisms of bacterial resistance' above.)
• Enterobacter, indole-positive Proteus, Serratia and Citrobacter produce an inducible
chromosomal beta-lactamase that may be difficult to detect on initial susceptibility
testing but can mediate resistance to all currently available beta-lactams other
than carbapenems. (See 'Chromosomal beta-lactamases' above.)
• The most common plasmid-mediated beta-lactamases in Gram negative bacteria
mediate resistance to penicillins and first- and 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.)