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Chapter 43: Beta­Lactam Antibiotics & Other Cell Wall­ & Membrane­Active

Antibiotics

INTRODUCTION

Penicillins and cephalosporins are the major antibiotics that inhibit bacterial cell wall synthesis. They are called beta­lactams because of the
unusual 4­member ring that is common to all their members. The beta­lactams include some of the most effective, widely used, and well­tolerated
agents available for the treatment of microbial infections. Vancomycin, fosfomycin, and bacitracin also inhibit cell wall synthesis but are not as
important as the beta­lactam drugs. Daptomycin, an alternative to vancomycin, directly disrupts the cell membrane. The selective toxicity of the
drugs discussed in this chapter is mainly due to specific actions on the synthesis of a cellular structure that is unique to the microorganism. More
than 50 antibiotics that act as cell wall synthesis inhibitors are currently available, with individual spectra of activity that afford a wide range of
clinical applications.

PENICILLINS
A. Classification

All penicillins are derivatives of 6­aminopenicillanic acid and contain a beta­lactam ring structure that is essential for antibacterial activity. Penicillin
subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and
biodisposition.

B. Pharmacokinetics

Penicillins vary in their resistance to gastric acid and therefore vary in their oral bioavailability. Parenteral formulations of ampicillin, piperacillin, and
ticarcillin are available for injection. Penicillins are polar compounds and are not metabolized extensively. They are usually excreted unchanged in the
urine via glomerular filtration and tubular secretion; the latter process is inhibited by probenecid, a treatment for gout and hyperuricemia that also
interferes with the elimination of penicillins. Exceptions are nafcillin and ampicillin, excreted mainly in the bile. The plasma half­lives of most
penicillins vary from 30 min to 1 h. Procaine and benzathine forms of penicillin G are administered intramuscularly and have long plasma half­lives
because the active drug is released very slowly into the bloodstream. Most penicillins cross the blood­brain barrier only when the meninges are
inflamed.

High­Yield Terms to Learn

Bactericidal An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms; kills bacteria

Bacteriostatic An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to eradicate the
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infection;
Chapter 43: Beta­Lactam Antibiotics & does Cell
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Wall­ & Membrane­Active Antibiotics, Page 1 / 9
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Beta­lactam antibiotics Drugs with structures containing a beta­lactam ring: includes the penicillins, cephalosporins and carbapenems. This
ring must be intact for antimicrobial action
penicillins vary from 30 min to 1 h. Procaine and benzathine forms of penicillin G are administered intramuscularly and have long plasma half­lives
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High­Yield Terms to Learn

Bactericidal An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms; kills bacteria

Bacteriostatic An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to eradicate the
infection; does not kill bacteria

Beta­lactam antibiotics Drugs with structures containing a beta­lactam ring: includes the penicillins, cephalosporins and carbapenems. This
ring must be intact for antimicrobial action

Beta­lactamases Bacterial enzymes (eg, penicillinases, cephalosporinases) that hydrolyze the beta­lactam ring of certain penicillins and
cephalosporins; confer resistance

Beta­lactam inhibitors Potent inhibitors of some bacterial beta­lactamases used in combinations to protect hydrolyzable penicillins from
inactivation

Minimal inhibitory Lowest concentration of antimicrobial drug capable of inhibiting growth of an organism in a defined growth medium
concentration (MIC)

Penicillin­binding proteins Bacterial cytoplasmic membrane proteins that act as the initial receptors for penicillins and other beta­lactam
(PBPs) antibiotics

Peptidoglycan Chains of polysaccharides and polypeptides that are cross­linked to form the bacterial cell wall

Selective toxicity More toxic to the invader than to the host; a property of useful antimicrobial drugs

Transpeptidases Bacterial enzymes involved in the cross­linking of linear peptidoglycan chains, the final step in cell wall synthesis

C. Mechanisms of Action and Resistance

Beta­lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps (Figure 43–1): (1) binding of the drug to
specific enzymes (penicillin­binding proteins [PBPs]) located in the bacterial cytoplasmic membrane; (2) inhibition of the transpeptidation
reaction that cross­links the linear peptidoglycan chain constituents of the cell wall; and (3) activation of autolytic enzymes that cause lesions in the
bacterial cell wall.

FIGURE 43–1

A highly simplified diagram of the cell envelope of a gram­negative bacterium. The outer membrane, a lipid bilayer, is present in gram­negative but not
gram­positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic access to the cytoplasmic membrane. The
peptidoglycan layer is unique to bacteria and is much thicker in gram­positive organisms than in gram­negative ones. Together, the outer membrane
and the peptidoglycan layer constitute the cell wall. Penicillin­binding proteins (PBPs) are membrane proteins that cross­link peptidoglycan. Beta­
lactamases, if present, reside in the periplasmic space or on the outer surface of the cytoplasmic membrane, where they may destroy β­lactam
antibiotics that penetrate the outer membrane. (Reproduced with permission from Katzung BG, Vanderah TW: Basic & Clinical Pharmacology, 15th ed.
New York, NY: McGraw Hill; 2021.)

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and the peptidoglycan layer constitute the cell wall. Penicillin­binding proteins (PBPs) are membrane proteins that cross­link peptidoglycan. Beta­
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lactamases, if present, reside in the periplasmic space or on the outer surface of the cytoplasmic membrane, where they may destroy β­lactam
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antibiotics that penetrate the outer membrane. (Reproduced with permission from Katzung BG, Vanderah TW: Basic & Clinical Pharmacology, 15th ed.
New York, NY: McGraw Hill; 2021.)

Enzymatic hydrolysis of the beta­lactam ring results in loss of antibacterial activity. The formation of beta­lactamases (eg, penicillinases) by most
staphylococci and many gram­negative organisms is a major mechanism of bacterial resistance. Inhibitors of these bacterial enzymes (eg, clavulanic
acid, sulbactam, tazobactam) are often used in combination with penicillins to prevent their inactivation. Structural change in target PBPs is
another mechanism of resistance and is responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumococci (eg,
PRSP, penicillin­resistant Streptococcus pneumoniae) and enterococci. In some gram­negative rods (eg, Pseudomonas aeruginosa), changes in the
porin structures in the outer cell wall membrane may contribute to resistance by impeding access of penicillins to PBPs.

D. Clinical Uses

1. Narrow­spectrum penicillinase­susceptible agents

Penicillin G is the prototype of a subclass of penicillins that have a limited spectrum of antibacterial activity and are susceptible to beta­lactamases.
Clinical uses include therapy of infections caused by common streptococci, meningococci, gram­positive bacilli, and spirochetes. Many strains of
pneumococci are now resistant to penicillins (penicillin­resistant S pneumoniae [PRSP] strains). Most strains of Staphylococcus aureus and a
significant number of strains of Neisseria gonorrhoeae are resistant via production of beta­lactamases. Although no longer suitable for treatment of
gonorrhea, penicillin G remains the drug of choice for syphilis. Activity against enterococci is enhanced by coadministration of aminoglycosides.
Penicillin V is an oral drug used mainly in oropharyngeal infections.

2. Very­narrow­spectrum penicillinase­resistant drugs

This subclass of penicillins includes methicillin (the prototype, but rarely used owing to its nephrotoxic potential), nafcillin, and oxacillin. Their
primary use is in the treatment of known or suspected staphylococcal infections. Methicillin­resistant (MR) staphylococci (S aureus [MRSA] and S
epidermidis [MRSE]) are resistant to all penicillins and are often resistant to multiple antimicrobial drugs.

3. Wider­spectrum penicillinase­susceptible drugs

a . Ampicillin and amoxicillin

These drugs make up a penicillin subgroup that has a wider spectrum of antibacterial activity than penicillin G but remains susceptible to
penicillinases. Their clinical uses include indications similar to penicillin G as well as infections resulting from enterococci, Listeria monocytogenes,
Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis, although resistant strains occur. When used in combination
with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced. In enterococcal and listeria infections, ampicillin is
synergistic with
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These drugs have activity against several gram­negative rods, including Pseudomonas, Enterobacter, and some Klebsiella species. Most drugs in this
a . Ampicillin and amoxicillin
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These drugs make up a penicillin subgroup that has a wider spectrum of antibacterial activity than penicillin G but remains
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penicillinases. Their clinical uses include indications similar to penicillin G as well as infections resulting from enterococci, Listeria monocytogenes,
Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis, although resistant strains occur. When used in combination
with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced. In enterococcal and listeria infections, ampicillin is
synergistic with aminoglycosides.

b. Piperacillin and ticarcillin

These drugs have activity against several gram­negative rods, including Pseudomonas, Enterobacter, and some Klebsiella species. Most drugs in this
subgroup have synergistic actions with aminoglycosides against such organisms. Piperacillin and ticarcillin are susceptible to penicillinases and are
often used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity.

E. Toxicity

1. Allergy

Allergic reactions include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis. About 5–10% of persons with a
history of penicillin reaction have an allergic response when given a penicillin again. Methicillin causes interstitial nephritis, and nafcillin is associated
with neutropenia. Antigenic determinants include degradation products of penicillins such as penicilloic acid. Complete cross­allergenicity between
different penicillins should be assumed. Ampicillin frequently causes maculopapular skin rash that does not appear to be an allergic reaction.

2. Gastrointestinal disturbances

Nausea and diarrhea may occur with oral penicillins, especially with ampicillin. Gastrointestinal upsets may be caused by direct irritation or by
overgrowth of gram­positive organisms or yeasts. Ampicillin has been implicated in pseudomembranous colitis.

CEPHALOSPORINS
A. Classification

The cephalosporins are derivatives of 7­aminocephalosporanic acid and contain the beta­lactam ring structure. Many members of this group are in
clinical use. They vary in their antibacterial activity and are designated first­, second­, third­, or fourth­generation drugs according to the order of their
introduction into clinical use; these generations also correspond loosely with extended gram­negative coverage.

B. Pharmacokinetics

Several cephalosporins are available for oral use, but most are administered parenterally. Cephalosporins with side chains may undergo hepatic
metabolism, but the major elimination mechanism for drugs in this class is renal excretion via active tubular secretion. Ceftriaxone is excreted mainly
in the bile. Most first­ and second­generation cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed.

C. Mechanisms of Action and Resistance

Cephalosporins bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to those of the penicillins.
Cephalosporins are bactericidal against susceptible organisms.

Structural differences from penicillins render cephalosporins less susceptible to penicillinases produced by staphylococci, but many bacteria are
resistant through the production of other beta­lactamases that can inactivate cephalosporins. Resistance can also result from decreases in membrane
permeability to cephalosporins and from changes in PBPs. Methicillin­resistant staphylococci are also resistant to cephalosporins.

D. Clinical Uses

1. First­generation drugs

Cefazolin (parenteral) and cephalexin (oral) are examples of this subgroup. They are active against gram­positive cocci, including staphylococci and
common streptococci. Many strains of E coli and K pneumoniae are also sensitive. Clinical uses include treatment of infections caused by these
organisms and surgical prophylaxis in selected conditions. These drugs have minimal activity against gram­negative cocci, enterococci, methicillin­
resistant
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2. Second­generation
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Cefaclor, cefuroxime, and cefprozil. Drugs in this subgroup usually have slightly less activity against gram­positive organisms than the first­
1. First­generation drugs
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Cefazolin (parenteral) and cephalexin (oral) are examples of this subgroup. They are active against gram­positive cocci,
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common streptococci. Many strains of E coli and K pneumoniae are also sensitive. Clinical uses include treatment of infections caused by these
organisms and surgical prophylaxis in selected conditions. These drugs have minimal activity against gram­negative cocci, enterococci, methicillin­
resistant staphylococci, and most gram­negative rods.

2. Second­generation drugs

Cefaclor, cefuroxime, and cefprozil. Drugs in this subgroup usually have slightly less activity against gram­positive organisms than the first­
generation drugs but have an extended gram­negative coverage. Marked differences in activity occur among the drugs in this subgroup. Examples of
clinical uses include infections caused by the anaerobe Bacteroides fragilis (cefotetan, cefoxitin) and sinus, ear, and respiratory infections caused
by H influenzae or M catarrhalis (cefuroxime, cefaclor).

3. Third­generation drugs

Characteristic features of third­generation drugs (eg, ceftazidime, cefotaxime) include increased activity against gram­negative organisms resistant
to other beta­lactam drugs and ability to penetrate the blood­brain barrier (except cefixime). Most are active against Providencia, Serratia marcescens,
and beta­lactamase­producing strains of H influenzae and Neisseria; they are less active against Enterobacter strains that produce extended­spectrum
beta­lactamases. Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin­resistant pneumococci (PRSP strains), but
resistance is reported. Individual drugs also have activity against Pseudomonas (ceftazidime) and B fragilis (ceftizoxime). Drugs in this subclass
should usually be reserved for treatment of serious infections. Ceftriaxone (parenteral) and cefixime (oral), currently drugs of choice in gonorrhea,
are exceptions. Likewise, in acute otitis media, a single injection of ceftriaxone is usually as effective as a 10­day course of treatment with amoxicillin.

4. Fourth­generation drugs

Cefepime is more resistant to beta­lactamases produced by gram­negative organisms, including Enterobacter, Haemophilus, Neisseria, and some
penicillin­resistant pneumococci. Cefepime combines the gram­positive activity of first­generation agents with the wider gram­negative spectrum of
third­generation cephalosporins. Ceftaroline has activity in infections caused by methicillin­resistant staphylococci.

E. Toxicity

1. Allergy

Cephalosporins cause a range of allergic reactions from skin rashes to anaphylactic shock. These reactions occur less frequently with cephalosporins
than with penicillins. Complete cross­hypersensitivity between different cephalosporins should be assumed. Cross­reactivity between penicillins and
cephalosporins is incomplete (5–10%), so penicillin­allergic patients are sometimes treated successfully with a cephalosporin. However, patients with
a history of anaphylaxis to penicillins should not be treated with a cephalosporin.

2. Other adverse effects

Cephalosporins may cause pain at intramuscular injection sites and phlebitis after intravenous administration. They may increase the nephrotoxicity
of aminoglycosides when the two are administered together. Drugs containing a methylthiotetrazole group (eg, cefoperazone, cefotetan) may cause
hypoprothrombinemia and disulfiram­like reactions with ethanol.

OTHER BETA­LACTAM DRUGS

A. Aztreonam

Aztreonam is a monobactam that is resistant to beta­lactamases produced by certain gram­negative rods, including Klebsiella, Pseudomonas, and
Serratia. The drug has no activity against gram­positive bacteria or anaerobes. It is an inhibitor of cell wall synthesis, preferentially binding to a specific
penicillin­binding protein (PBP3), and is synergistic with aminoglycosides.

Aztreonam is administered intravenously and is eliminated via renal tubular secretion. Its half­life is prolonged in renal failure. Adverse effects include
gastrointestinal upset with possible superinfection, vertigo and headache, and rarely hepatotoxicity. Although skin rash may occur, there is no cross­
allergenicity with penicillins.

B. Imipenem, Doripenem, Meropenem, and Ertapenem

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These drugs Beta­Lactam
carbapenems Antibiotics &different
(chemically Other Cell Wall­
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penicillins Membrane­Active Antibiotics,
retaining the beta­lactam Page 5 / 9
ring structure) with low susceptibility to beta­
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lactamases. They have wide activity against gram­positive cocci (including some penicillin­resistant pneumococci), gram­negative rods, and
anaerobes. With the exception of ertapenem, the carbapenems are active against P aeruginosa and Acinetobacter species. For pseudomonal
infections, they are often used in combination with an aminoglycoside. The carbapenems are administered parenterally and are useful for infections
penicillin­binding protein (PBP3), and is synergistic with aminoglycosides.
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Aztreonam is administered intravenously and is eliminated via renal tubular secretion. Its half­life is prolonged in renal failure. Adverse effects include
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gastrointestinal upset with possible superinfection, vertigo and headache, and rarely hepatotoxicity. Although skin rash may occur, there is no cross­
allergenicity with penicillins.

B. Imipenem, Doripenem, Meropenem, and Ertapenem

These drugs are carbapenems (chemically different from penicillins but retaining the beta­lactam ring structure) with low susceptibility to beta­
lactamases. They have wide activity against gram­positive cocci (including some penicillin­resistant pneumococci), gram­negative rods, and
anaerobes. With the exception of ertapenem, the carbapenems are active against P aeruginosa and Acinetobacter species. For pseudomonal
infections, they are often used in combination with an aminoglycoside. The carbapenems are administered parenterally and are useful for infections
caused by organisms resistant to other antibiotics. However, MRSA strains of staphylococci are resistant. Carbapenems are currently co­drugs of
choice for infections caused by Enterobacter, Citrobacter, and Serratia species. Imipenem is rapidly inactivated by renal dehydropeptidase I and is
administered in fixed combination with cilastatin, an inhibitor of this enzyme. Cilastatin increases the plasma half­life of imipenem and inhibits the
formation of a potentially nephrotoxic metabolite. The other carbapenems are not significantly degraded by the kidney.

Adverse effects of imipenem­cilastatin include gastrointestinal distress, skin rash, and, at very high plasma levels, CNS toxicity (confusion,
encephalopathy, seizures). There is partial cross­allergenicity with the penicillins. Meropenem is similar to imipenem except that it is not metabolized
by renal dehydropeptidases and is less likely to cause seizures. Ertapenem has a long half­life but is less active against enterococci and
Pseudomonas, and its intramuscular injection causes pain and irritation.

C. Beta­Lactamase Inhibitors

Clavulanic acid, sulbactam, and tazobactam are used in fixed combinations with certain hydrolyzable penicillins. They are most active against
plasmid­encoded beta­lactamases such as those produced by gonococci, streptococci, E coli, and H influenzae. They are not good inhibitors of
inducible chromosomal beta­lactamases formed by Enterobacter, Pseudomonas, and Serratia.

OTHER CELL WALL OR MEMBRANE­ACTIVE AGENTS

A. Vancomycin

Vancomycin is a bactericidal glycoprotein that binds to the D­Ala­D­Ala terminal of the nascent peptidoglycan pentapeptide side chain and inhibits
transglycosylation. This action prevents elongation of the peptidoglycan chain and interferes with cross­linking. Resistance in strains of enterococci
(vancomycin­resistant enterococci [VRE]) and staphylococci (vancomycin­resistant S aureus [VRSA]) involves a decreased affinity of vancomycin for the
binding site because of the replacement of the terminal D­Ala by D­lactate. Vancomycin has a narrow spectrum of activity and is used for serious
infections caused by drug­resistant gram­positive organisms, including methicillin­resistant staphylococci (MRSA), and in combination with a third­
generation cephalosporin such as ceftriaxone for treatment of infections due to penicillin­resistant pneumococci (PRSP). Vancomycin is also used in
the treatment of infections caused by Clostridioides (formerly Clostridium) difficile. Teicoplanin and telavancin, other glycopeptide derivatives,
have similar characteristics.

Vancomycin­resistant enterococci are increasing and pose a potentially serious clinical problem because such organisms usually exhibit multiple­drug
resistance. Vancomycin­intermediate strains of S aureus resulting in treatment failures have also been reported. Vancomycin is not absorbed from the
gastrointestinal tract and may be given orally for bacterial enterocolitis. When given parenterally, vancomycin penetrates most tissues and is
eliminated unchanged in the urine. Dosage modification is mandatory in patients with renal impairment. Toxic effects of vancomycin include chills,
fever, phlebitis, ototoxicity, and nephrotoxicity. Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”) from histamine release.

B. Daptomycin

Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin­resistant strains of enterococci and
staphylococci. The drug inserts into the cytoplasmic membrane, causing potassium leak and cell death. Daptomycin is eliminated via the kidney.
Creatine phosphokinase should be monitored because daptomycin may cause myopathy.

C. Fosfomycin

Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyruvate transferase. This action prevents the formation of N­acetylmuramic acid, an
essential precursor molecule for peptidoglycan chain formation. Resistance to fosfomycin occurs via decreased intracellular accumulation of the drug.

Fosfomycin is2022­8­8
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Chapter 43:the
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drug is lessAntibiotics &
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a 7­day Cell Wall­
course & with
of treatment Membrane­Active Antibiotics,
fluoroquinolones. Page 6 / 9
However, with multiple dosing, resistance emerges
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rapidly and diarrhea is common. Fosfomycin may be synergistic with beta­lactam and quinolone antibiotics in specific infections.

D. Bacitracin
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Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyruvate transferase. This action prevents the formation of N­acetylmuramic acid, an
essential precursor molecule for peptidoglycan chain formation. Resistance to fosfomycin occurs via decreased intracellular accumulation of the drug.

Fosfomycin is excreted by the kidney, with urinary levels exceeding the minimal inhibitory concentrations (MICs) for many urinary tract pathogens. In a
single dose, the drug is less effective than a 7­day course of treatment with fluoroquinolones. However, with multiple dosing, resistance emerges
rapidly and diarrhea is common. Fosfomycin may be synergistic with beta­lactam and quinolone antibiotics in specific infections.

D. Bacitracin

Bacitracin is a peptide antibiotic that interferes with a late stage in cell wall synthesis in gram­positive organisms. Because of its marked nephrotoxicity,
the drug is limited to topical use.

E. Cycloserine

Cycloserine is an antimetabolite that blocks the incorporation of D­Ala into the pentapeptide side chain of the peptidoglycan. Because of its potential
neurotoxicity (tremors, seizures, psychosis), cycloserine is only used to treat tuberculosis caused by organisms resistant to first­line antituberculosis
drugs.

CHECKLIST

CHECKLIST

When you complete this chapter, you should be able to:

Describe the mechanism of antibacterial action of beta­lactam antibiotics.

Describe 3 mechanisms underlying the resistance of bacteria to beta­lactam antibiotics.

Identify the prototype drugs in each subclass of penicillins, and describe their antibacterial activity and clinical uses.

Identify the 4 subclasses of cephalosporins, and describe their antibacterial activities and clinical uses.

List the major adverse effects of the penicillins and the cephalosporins.

Identify the important features of aztreonam, imipenem, and meropenem.

Describe the clinical uses and toxicities of vancomycin.

DRUG SUMMARY TABLE

DRUG SUMMARY TABLE: Beta­Lactam & Other Cell Wall­ & Membrane­Active Antibioticsa

Mechanism of Activity Spectrum & Pharmacokinetics &

Subclass Toxicities
Action Clinical Uses Interactions

Penicillins Bind to and inhibit

cell wall
transpeptidation

Narrow
spectrum

Penicillinase­ Streptococcal and Rapid renal elimination; short Hypersensitivity reactions (∼5–6%
susceptible meningococcal infections • half­lives necessitate frequent incidence) • assume complete cross­
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DOC for syphilis dosing • some biliary clearance reactivity; GI distress and
Chapter 43: Beta­Lactam
Penicillin V Antibiotics & Other Cell Wall­ & Membrane­Active
of nafcillin andAntibiotics,
oxacillin maculopapular rash (ampicillin) Page 7 / 9
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Penicillinase­ Staphylococcal infections
resistant
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spectrum

Penicillinase­ Streptococcal and Rapid renal elimination; short Hypersensitivity reactions (∼5–6%
susceptible meningococcal infections • half­lives necessitate frequent incidence) • assume complete cross­
Penicillin G DOC for syphilis dosing • some biliary clearance reactivity; GI distress and
Penicillin V of nafcillin and oxacillin maculopapular rash (ampicillin)

Penicillinase­ Staphylococcal infections

resistant

Nafcillin

Oxacillin

Wider Greater activity vs gram­

spectrum+/– negative bacteria
penicillinase
inhibitor

Ampicillin All penicillins (and Use with clavulanic

Amoxicillin cephalosporins) are acid/tazobactam
Piperacillin bactericidal
Ticarcillin

Cephalosporins Bind to and inhibit

cell wall
transpeptidation

First Skin, soft tissue UT Oral use for older drugs; Hypersensitivity reactions (∼2%
generation infections mostly IV for newer drugs • renal incidence) • assume complete cross­
Cephalexin, elimination reactivity between cephalosporins •
others partial with penicillins • GI distress

Second More active vs S Short half­lives

generation pneumoniae and H
Cefaclor influenzae; B fragilis
Cefotetan (cefotetan)
Cefprozil
Cefoxitin
Cefuroxime

Third Many uses including Third­generation drugs enter

generation pneumonia, meningitis, and CNS
Ceftriaxone gonorrhea
Cefotaxime
Ceftazidime
Cefixime
Cefpodoxime
proxetil
Cefdinir
Cefditoren
pivoxil
Ceftibuten

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Broad activity, beta­
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generationBeta­Lactam Antibiotics & Other Cell Wall­ & Membrane­Active Antibiotics,
lactamase­stable Page 8 / 9
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Cefepime

Carbapenems
 Cefdinir
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Cefditoren
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pivoxil
Ceftibuten

Fourth Broad activity, beta­

generation lactamase­stable
Cefepime

Carbapenems

Imipenem­ Bind to and inhibit Broad spectrum includes Parenteral; cilastatin inhibits Partial cross­reactivity with penicillins •
cilastatin cell wall some PRSP strains (not renal metabolism of imipenem • CNS effects include confusion and
Doripenem transpeptidation MRSA), gram­negative rods, renal elimination seizures
Meropenem and Pseudomonas spp
Ertapenem

Monobactams

Aztreonam Binds to and inhibits Active only vs gram­ Parenteral use • renal GI upsets, headache, vertigo • no cross­
cell wall negative bacteria: elimination allergenicity with beta­lactams
transpeptidation Klebsiella, Pseudomonas,
and Serratia spp

Glycopeptides

Vancomycin Bind to d­Ala­d­Ala Gram­positive activity Parenteral (oral for C difficile “Red man” syndrome, rare
Teicoplanin terminus to inhibit includes colitis) • renal elimination IV nephrotoxicity
Dalbavancin transglycosylation MRSA and PRSP strains only, long half­life
Oritavancin and cell wall Teicoplanin: long half­life (45–70
Telavancin synthesis h) permits once­daily dosing
Dalbavancin: IV, very long half­
life (>10 days) permits once­
weekly dosing
Oritavancin: IV, very long half­life
(>10 days) permits once­weekly
dosing
Telavancin: IV, once­daily dosing

Lipopeptide

Daptomycin Binds to and Gram­positive activity; used Renal elimination Myopathy • monitor CPK weekly
destabilizes in endocarditis and sepsis
membrane

aAll the drugs listed are bactericidal cell wall synthesis inhibitors except daptomycin, which destabilizes bacterial cell membranes.

CPK, creatine phosphokinase; MRSA, methicillin­resistant Staphylococcus aureus; PRSP, penicillin­resistant Streptococcus pneumoniae; UT, urinary tract.

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Chapter 43: Beta­Lactam Antibiotics & Other Cell Wall­ & Membrane­Active Antibiotics, Page 9 / 9
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