Antibacterial Agents

PENICILLINS Back to top

The penicillins (Table 1) are a group of natural and semisynthetic antibiotics containing the

chemical nucleus 6-aminopenicillanic acid, which consists of a β-lactam ring fused to a

thiazolidine ring (Fig. 1a). The naturally occurring compounds are produced by a number

of Penicillium spp. The penicillins differ from one another in the substitution at position 6,

where changes in the side chain may modify the pharmacokinetic and antibacterial

properties of the drug.

Mechanism of Action

The major antibacterial action of penicillins is derived from their ability to inhibit a number of

bacterial enzymes, namely penicillin-binding proteins (PBPs), that are essential for

peptidoglycan synthesis (367). This ability to inhibit bacterial cell wall enzymes such as the

transpeptidases usually confers on the penicillins bactericidal activity against gram-positive

bacteria. The bactericidal activity of the penicillins is often related to their ability to trigger

membrane-associated autolytic enzymes that destroy the cell wall. Other minor mechanisms

of action include inhibition of bacterial endopeptidase and glycosidase, enzymes involved in

bacterial cell growth. There is also recent evidence suggesting that penicillins may inhibit

RNA synthesis in some bacteria, causing death without cell lysis, but the significance of these

observations remains to be determined (222).

Pharmacology

Oral absorption differs markedly among the penicillins. As a natural congener of penicillin G,

penicillin V resists gastric acid inactivation and is better absorbed from the gastrointestinal

tract than is penicillin G. Amoxicillin is a semisynthetic analog of ampicillin and has greater

gastrointestinal absorption than ampicillin (95% versus 40% absorption). Bacampicillin is an

ampicillin ester that is absorbed considerably better from the gastrointestinal tract than is

ampicillin or amoxicillin. This ester is inactive until naturally occurring esterases in the

intestinal mucosa and serum hydrolyze them to release the parent compound, ampicillin, into

the serum. The isoxazolyl penicillins, such as oxacillin, cloxacillin, and dicloxacillin, as well as

nafcillin are acid stable and are also absorbed from the gastrointestinal tract, in

contradistinction to certain other antistaphylococcal penicillins, such as methicillin, which are

not acid resistant and cannot be given via the oral route.

Repository forms of penicillin G, available in procaine or benzathine, delay absorption from

an intramuscular depot. Procaine penicillin G provides detectable levels for 12 to 24 h,

suitable for treatment of uncomplicated pneumococcal pneumonia and gonorrhea due to fully

susceptible organisms. Benzathine penicillin G achieves very low levels in blood for prolonged

periods (3 to 4 weeks) and is useful for the therapy of syphilis and for prophylaxis of

streptococcal pharyngitis and rheumatic fever.

Penicillins are well distributed to many body compartments, including lung, liver, kidney,

muscle, bone, and placenta. Penetration into the eye, brain, cerebrospinal fluid (CSF), and

prostate is poor in the absence of inflammation. These drugs are metabolized to a small

degree and are rapidly excreted, essentially unchanged, via the kidney. With average halflives

of 0.5 to 1.5 h, they are usually administered every 4 to 6 h to maintain effective blood

levels. The renal tubular excretion of penicillins can be blocked by probenecid, thus

prolonging their half-lives in serum.

Dosage reduction of most penicillins is necessary only in severe renal insufficiency

(creatinine clearance of ≤10 ml/min). Dosages of all penicillins except nafcillin and the

isoxazolyl penicillins are adjusted for hemodialysis. Peritoneal dialysis requires dosage

reduction of carbenicillin and ticarcillin.

Spectrum of Activity

The penicillins have antibacterial activity against most gram-positive and many gramnegative

and anaerobic organisms. Penicillin G is very effective against penicillinsusceptible

Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus

pyogenes, viridans group streptococci, Streptococcus bovis, Neisseria gonorrhoeae, Neisseria

meningitidis, Pasteurella multocida, anaerobic

cocci, Clostridium spp., Fusobacterium spp., Prevotellaspp., and Porphyromonas spp.

However, the occurrence of penicillin-resistant pneumococci has increased worldwide

(166, 306, 307). Penicillin G is the drug of choice for treatment of syphilis

and Actinomycesinfections. Penicillin V has a spectrum of activity similar to that of penicillin

G, except that it is less active against N. gonorrhoeae. Both drugs are drugs of choice for the

treatment of streptococcal tonsillopharyngitis and for the primary and secondary prevention

of rheumatic fever (121). Penicillinase-resistant penicillins, of which methicillin is the

prototype, are primarily effective against penicillinase-producing staphylococci. The agents

are at least 25 times more active than other penicillins against penicillinase-positive

staphylococci. Although they are also active against S. pneumoniae and S. pyogenes, their

MICs for these organisms are higher than those of penicillin G. They are not active against

enterococci, members of the familyEnterobacteriaceae, Pseudomonas spp., or members of

the Bacillus fragilis group.

Ampicillin and amoxicillin have spectra of activity similar to that of penicillin G, but they are

more active against enterococci and Listeria monocytogenes. These are the drugs of choice

for prevention of infective endocarditis in patients with high-risk cardiac conditions

undergoing invasive dental, respiratory tract, gastrointestinal, and genitourinary procedures

(376). Although they are also more active against Haemophilus influenzae andHaemophilus

parainfluenzae, up to 25% of H. influenzae isolates are resistant, usually because of β-

lactamase production. Salmonella and Shigella spp., including Salmonella enterica serovar

Typhi, and many strains ofEscherichia coli and Proteus mirabilis are susceptible to these

agents. Ampicillin is more effective against shigellae, whereas amoxicillin is more effective

against salmonellae. Both of these agents are degraded by β-lactamase and are inactive

against many Enterobacteriaceae and Pseudomonas spp.

The carboxypenicillins and ureidopenicillins have increased activity against gram-negative

bacteria that are resistant to ampicillin. Although these drugs are susceptible to

staphylococcal penicillinase, they are more stable against hydrolysis by the β-lactamases

of Enterobacteriaceae and Pseudomonas aeruginosa. Carbenicillin and ticarcillin are relatively

active against streptococci as well as against Haemophilus spp., Neisseria spp., and a variety

of anaerobes. They inhibit Enterobacteriaceae but are inactive against Klebsiella spp.

Although carboxypenicillins are not particularly active against the enterococci, they may act

synergistically with aminoglycosides against these organisms.

The ureidopenicillins have greater in vitro activity against streptococci and enterococci than

do the carboxypenicillins, and they inhibit more than 75% of Klebsiella spp. (81). They have

excellent activity against many Enterobacteriaceae and anaerobic bacteria, including

members of the B. fragilis group. On a weight basis, their activities in decreasing order of

potency against P. aeruginosa are as follows: piperacillin, azlocillin > mezlocillin, ticarcillin >

carbenicillin (64). These agents also act synergistically with aminoglycosides against P.

aeruginosa.

Adverse Effects

Common reactions to penicillins include allergic skin rashes, diarrhea, and drug fever. Severe

anaphylactic reactions, which can be fatal, may occur in previously sensitized patients

rechallenged with penicillins, but fortunately, such reactions are quite rare. At high doses

(usually >30 × 106 U/day), penicillin G can cause myoclonic twitching and seizures due to

central nervous system toxicity. All of the penicillins may cause interstitial nephritis on an

allergic basis, but methicillin is more likely than the other penicillins to cause this

complication. Hepatitis has been associated with prolonged use of oxacillin. High-dose

carbenicillin can result in sodium overload and hypokalemia. Neutropenia may occur with any

of the penicillins. Thrombocytopenia and Coombs-positive hemolytic anemia are rare

complications of penicillin therapy. Bleeding tendencies due to interference with platelet

function can occur with the use of carboxypenicillins and ureidopenicillins (96). Although

pseudomembranous colitis has been associated with all the penicillins, it occurs more

frequently with ampicillin (27).

CEPHALOSPORINS Back to top

Cephalosporins are derivatives of the fermentation products of Cephalosporium

acremonium (also designatedAcremonium chrysogenum). They contain a 7-

aminocephalosporanic acid nucleus, which consists of a β-lactam ring fused to a

dihydrothiazine ring (Fig. lb). Various substitutions at positions 3 and 7 alter their

antibacterial activities and pharmacokinetic properties. Addition of a methoxy group at

position 7 of the β-lactam ring results in a new group of compounds called cephamycins,

which are highly resistant to a variety of β-lactamases.

Mechanism of Action

Similar to the penicillins, cephalosporins act by binding to PBPs of susceptible organisms,

thereby interfering with synthesis of peptidoglycan of the bacterial cell wall. In addition,

these β-lactam agents may produce bactericidal effects by triggering autolytic enzymes in

the cell envelope (367). Of note are the unique chemical structure-activity relationships for

ceftaroline and ceftobiprole, which contain a thiazole moiety and a vinylpyrrolidinone moiety,

respectively, at position 3 of the cephem ring. These chemical side chains promote binding of

the drugs to PBP 2a, thereby conferring anti-methicillin-resistant S. aureus (MRSA)

bactericidal activity (355, 392).

Pharmacology

Most cephalosporins require parenteral administration, but quite a few are available in oral

form. Cephalexin, cephradine, cefadroxil, cefaclor, cefuroxime axetil, cefprozil, loracarbef,

cefdinir, cefditoren pivoxil, cefixime, cefpodoxime proxetil, and ceftibuten are given orally

with good gastrointestinal absorption (60 to 90% of oral dose). Cefuroxime axetil is an

acetoxyethyl ester of cefuroxime, and it is de-esterified at the intestinal mucosa and

absorbed into the bloodstream as cefuroxime. Cefditoren pivoxil and cefpodoxime proxetil

are prodrugs that are absorbed and hydrolyzed by esterases in vivo to release the active

drugs cefditoren and cefpodoxime, respectively. Relatively high concentrations of these

agents are attained across the placenta and in synovial, pleural, pericardial, and peritoneal

fluids. Levels in bile are usually high, especially with cefoperazone, which is excreted mainly

in the bile. Ceftizoxime, cefotaxime, ceftriaxone, cefoperazone, moxalactam, and cefepime

penetrate well into the CSF and are useful for the treatment of meningitis. Cefuroxime

penetrates inflamed meninges, but levels in CSF are inadequate in providing bactericidal

activity against susceptible bacteria.

Cephalothin, cephapirin, and cefotaxime are converted to the desacetyl forms before

excretion. All cephalosporins except cefoperazone are excreted primarily by the kidney, and

for these drugs, dosage adjustments are necessary in patients with renal insufficiency

(creatinine clearance of <50 ml/min). Like that of the penicillins, the renal excretion of

cephalosporins, except for ceftriaxone, is impeded by probenecid. In general, these agents

are removed by hemodialysis but not by peritoneal dialysis. Of the cephalosporins, cefonicid

and ceftriaxone have the longest elimination half-lives, at 4.5 and 8 hours, respectively,

permitting once- or twice-daily drug administration in the treatment of serious infections.

Ceftaroline fosamil and ceftobiprole medocaril are developed as water-soluble prodrugs of

ceftaroline and ceftobiprole, respectively, and they undergo rapid conversion (<1 h) to the

respective active drugs after intravenous administration. With a half-life of 2.5 h, infusion of

500 mg and 1 g of ceftaroline results in maximum concentrations of 16 and 30 μg/ml in

serum, respectively (334). Following infusion of ceftobiprole medocaril at 500 mg and 1 g,

maximum concentrations achieved in serum are 35 and 72 μg/ml, respectively (355). With a

half-life of 3 to 4 h, the drug undergoes minimal hepatic metabolism and is primarily

eliminated in the urine. Dosage adjustment is necessary for both drugs in patients with renal

insufficiency.

Spectrum of Activity

Cephalosporins are classified by a well-accepted but somewhat arbitrary scheme of grouping

by generations based on general features of their antibacterial activity (Table 2). The firstgeneration

(narrow-spectrum) drugs, exemplified by cephalothin and cefazolin, have good

gram-positive activity and relatively modest gram-negative activity. They are active against

penicillin-susceptible and -resistant S. aureus as well as S. pneumoniae, S. pyogenes, and

other aerobic and anaerobic streptococci. Methicillin-resistant staphylococci and enterococci

are resistant. Some Enterobacteriaceae, including many strains of E. coli, Klebsiella spp.,

and Proteus mirabilis, are susceptible. Pseudomonas spp., including P.

aeruginosa, many Proteus spp., and Serratia andEnterobacter spp. are resistant. These

agents are active against penicillin-susceptible anaerobes except members of the B.

fragilis group. They have only modest activity against H. influenzae.

The second-generation (expanded-spectrum) cephalosporins are stable against certain β-

lactamases found in gram-negative bacteria and, as a result, have increased activity against

gram-negative organisms. The agents are more active than narrow-spectrum drugs

against E. coli, Klebsiella spp., and Proteus spp. Their activity also extends to cover

some Enterobacter and Serratia strains, and they have good activity

against Haemophilusspp., Neisseria spp., and many anaerobes. Cefaclor, cefuroxime,

cefamandole, cefonicid, and cefprozil are active against ampicillin-resistant H.

influenzae and Moraxella catarrhalis (34, 345). However, cefamandole exhibits a significant

inoculum effect and is not suitable for treating life-threatening infections due to H.

influenzae. Ceforanide and cefonicid have spectra of antibacterial activities similar to that of

cefamandole, but they are less active than cefamandole against gram-positive cocci.

Loracarbef belongs to a new class of cephalosporin derivatives known as carbacephems, in

which the sulfur atom of the dihydrothiazine ring is replaced by a methylene group to form a

tetrahydropyridine ring (65). Since this structural modification of the cephalosporin nucleus

is minor, loracarbef is considered to be a cephalosporin. Its spectrum of antibacterial activity

is very similar to those of cefaclor, cefuroxime, and cefprozil. None of the expandedspectrum

agents is active against Pseudomonas spp.

Cefoxitin, cefotetan, and cefmetazole belong to a unique group of expanded-spectrum

cephalosporins that have marked activity against anaerobes, including members of the B.

fragilis group (168, 372). Cefotetan is two to four times less active than cefoxitin and

cefmetazole against gram-positive cocci, but it is more potent than these two drugs against

susceptible Enterobacteriaceae. The three drugs are equally active against H. influenzae, M.

catarrhalis, and N. gonorrhoeae, including penicillin-resistant strains. While these drugs are

comparable in their activities against the B. fragilis group, cefoxitin is the most active

against Prevotella spp.,Porphyromonas spp., and gram-positive anaerobic cocci. Cefotetan

and cefmetazole have the advantage of more prolonged half-lives in serum.

Third-generation (broad-spectrum) cephalosporins are generally less active than the narrowspectrum

agents against gram-positive cocci, but they are much more active against

the Enterobacteriaceae and P. aeruginosa. Their potent broad spectra of gram-negative

activity are due to their stability to β-lactamases and their ability to pass through the outer

cell envelopes of gram-negative bacilli (95, 251). There are two subgroups among these

agents: those with potent activity against P. aeruginosa (ceftazidime and cefoperazone) and

those without such activity (ceftizoxime, cefotaxime, and ceftriaxone).

Cefotaxime inhibits more than 90% of strains of Enterobacteriaceae, including those

resistant to aminoglycosides. The MIC90s for E. coli, Proteus spp., and Klebsiella spp. are

<0.5 μg/ml. Its activity against strains of S. marcescens, Enterobacter

cloacae, and Acinetobacter spp. is variable, and it is inactive against P. aeruginosa. It has

moderate activity against anaerobes but is inferior to cefoxitin and cefotetan against most of

these isolates.

Ceftizoxime and ceftriaxone have spectra of activity similar to that of cefotaxime with a few

exceptions. Ceftriaxone is the most active agent against penicillinase-positive or -negative

strains of N. gonorrhoeae, and it is effective as single-dose therapy for infections caused by

these organisms (51). However, N. gonorrhoeaestrains with reduced susceptibility to these

drugs have emerged (198). Because of its long half-life in serum (the longest of the currently

available cephalosporins), ceftriaxone is used frequently in outpatient antibiotic therapy of

serious infections, including Lyme disease (228).

Cefoperazone is less active than cefotaxime against many Enterobacteriaceae and grampositive

cocci. However, it has activity against P. aeruginosa, with an MIC50 of ≤16 μg/ml. Its

activity against anaerobes is similar to that of cefotaxime (169). Ceftazidime has potent

activity against P. aeruginosa, with an MIC90 of <8 μg/ml (251). It is more active than the

ureidopenicillins against these strains. This agent has activity similar to that of cefotaxime

against the Enterobacteriaceae but is not as active against gram-positive cocci. It has little

activity against gram-negative anaerobes.

Cefdinir (62), cefditoren (34, 165, 170), cefixime (23), cefpodoxime (108, 305), and

ceftibuten (169, 378) are extended-spectrum oral cephalosporins that are more stable than

the narrow- and expanded-spectrum oral cephalosporins against gram-negative bacterial β-

lactamases. Compared with the earlier cephalosporins, the newer drugs are equally active

against streptococci (MIC90s, ≤0.06 μg/ml) but less active against methicillin-susceptible

staphylococci (MIC90s of 2 μg/ml). With potent activities similar to that of ceftizoxime against

manyEnterobacteriaceae, H. influenzae, M. catarrhalis, and N. gonorrhoeae (including β-

lactamase-producing strains), they are inactive against Pseudomonas, Enterobacter,

Serratia, and Morganella spp. and anaerobes. None of the currently available cephalosporins

is clinically useful against enterococci.

Cefepime is a so-called fourth-generation (extended-spectrum) cephalosporin approved for

clinical use in the United States. Together with cefpirome (not licensed for clinical use in the

United States), they have the unique features of reduced affinity for and increased stability

to the Bush class I β-lactamases. Therefore, these agents are active against stably

derepressed class I β-lactamase mutants of Enterobacteriaceae and P. aeruginosa. In

addition, cefepime and cefpirome penetrate well through gram-negative bacterial outer

membrane, due to a quaternary nitrogen substitution that makes them zwitterions (net

neutral charge). They are more active in vitro than cefotaxime and ceftriaxone against

some Enterobacteriaceae (MIC90s of ≤0.1 μg/ml) (116). Cefepime has activity comparable to

that of ceftazidime against P. aeruginosa with MIC90s of ≤4 μg/ml, and it is active against

some ceftazidime-resistant strains (282). Against staphylococci (MIC90s of ≤2 μg/ml) and

streptococci (MIC90s of ≤0.12 μg/ml), the activities of this group of drugs are comparable to

those of the narrow-spectrum cephalosporins (116). However, they are not active clinically

against enterococci or anaerobes.

Ceftaroline and ceftobiprole are active against all staphylococci, including methicillinsusceptible

S. aureus(MSSA), MRSA, heterogeneous vancomycin-intermediate S.

aureus (hVISA), VISA, and vancomycin-resistant S. aureus (VRSA) at MIC90s of ≤1 μg/ml,

and against multidrug-resistant pneumococci at MIC90s of 0.5 μg/ml

(46,223, 241, 316, 334). Viridans group streptococci and beta-hemolytic streptococci are

inhibited at MIC90s of ≤1 μg/ml. While ceftaroline has minimal activity against enterococci,

ceftobiprole exhibits good activity against both vancomycin-susceptible and -resistant

enterococci, with MIC90s of 1 and 4 μg/ml, respectively (9). The gram-negative activity of

ceftaroline is limited mainly to gram-negative respiratory tract pathogens, including β-

lactamase-producing H. influenzae and M. catarrhalis (MIC90s of 0.125 and 0.25 μg/ml,

respectively), and N. gonorrhoeae (MIC90 of 0.25 μg/ml) as well as Enterobacteriaceae that

do not contain extended-spectrum β-lactamases (ESBLs). It is weakly active against P.

aeruginosa, Acinetobacter, and gram-negative bacilli with inducible AmpC β-lactamases.

Ceftobiprole is somewhat more active than ceftriaxone and ceftazidime againstP.

aeruginosa and Enterobacteriaceae with derepressed AmpC β-lactamases (MIC90s of 8 to 16

μg/ml), but it is inactive against ESBL-producing Enterobacteriaceae and multidrugresistant

Acinetobacter baumannii isolates. Both drugs display variable activity against

anaerobes, with good activity against Clostridium spp. (except C. difficile), Fusobacterium,

Lactobacillus, Peptostreptococcus, Porphyromonas, Propionibacterium

acnes, andVeillonella, but are inactive against B. fragilis, B. fragilis group,

and Prevotella (58).

Adverse Effects

Cephalosporins are generally very well tolerated. The most common side effects are diarrhea

and hypersensitivity reactions such as rash, drug fever, and serum sickness. Cross-reactions

with these drugs occur in only 3% to 7% of penicillin-allergic patients (177). Other

infrequent side effects include pseudomembranous colitis, elevated serum creatinine and

transaminase levels, leukopenia, thrombocytopenia, and Coombs-positive hemolytic anemia.

These abnormalities are usually mild and reversible. Prolonged use of ceftriaxone has been

associated with formation of gallbladder sludge, which usually resolves after the drug is

discontinued (313), and rarely cholecystitis.

Disulfiram-like reactions have been described in patients receiving cefamandole, cefotetan,

and cefoperazone. This reaction is attributed to the N-methylthiotetrazole side chains of

these antibiotics, which are similar to the chemical structure of disulfiram.

Hypoprothrombinemia and bleeding tendencies have been observed with these

cephalosporins. Causes of the coagulopathy included (i) alteration to healthy gut biota by the

antibiotics, thus inhibiting the synthesis of vitamin K and its precursors; and (ii) the Nmethylthiotetrazole

side chain, which inhibits the vitamin K-dependent carboxylase enzyme

responsible for converting clotting factors II, VII, IX, and X to their active forms and also

prevents regeneration of active vitamin K from its inactive form (310).

OTHER β-LACTAM ANTIBIOTICS Back to top

Monobactams

Aztreonam is the only monobactam antibiotic currently in clinical use. The monobactams are

β-lactams with various side chains affixed to a monocyclic nucleus (Fig. 1c).

Mechanism of Action

Aztreonam binds primarily to PBP 3 of gram-negative aerobes, including P.

aeruginosa, thereby disrupting bacterial cell wall synthesis. It is not hydrolyzed by most

commonly occurring plasmid- and chromosomally mediated β-lactamases, and it does not

induce the production of these enzymes (45).

Pharmacology

Given intravenously, aztreonam is widely distributed to body tissues and fluids. Average drug

concentrations in serum exceed the MIC90s of most Enterobacteriaceae by four to eight times

for 8 h and are inhibitory to P. aeruginosa for 4 h. It crosses inflamed meninges in sufficient

amount to be potentially therapeutic for meningitis caused by susceptible organisms. Its

half-life in serum is about 1.7 h, and it is excreted mainly unchanged by the kidney. Dosage

modification is necessary for patients with renal failure. The drug is removed by both

hemodialysis and peritoneal dialysis.

Spectrum of Activity

The antibacterial activity of aztreonam is limited to aerobic gram-negative bacilli, inhibiting

mostEnterobacteriaceae, Neisseria spp., and Haemophilus spp. with MIC90s of ≤0.5 μg/ml

(25, 342). It has significant activity against Enterobacter spp., and Serratia marcescens, with

most strains being inhibited at ≤16 μg/ml. However, many Acinetobacter spp., Burkholderia

cepacia, and S. maltophilia are resistant. It shows in vitro synergism when combined with

aminoglycosides against 30 to 60% of aztreonam-susceptible organisms, including P.

aeruginosa and aminoglycoside-resistant gram-negative bacilli (44). Bacterial tolerance and

inoculum effect are generally not seen with this agent. Aztreonam is not active against grampositive

bacteria or anaerobes.

Adverse Effects

Aztreonam is generally a safe agent, with a toxicity profile similar to those of other β-lactam

drugs. Nausea, diarrhea, skin rash, eosinophilia, mild elevation of serum transaminase

levels, and transiently elevated serum creatinine level have occurred. It has minimal crossreactivity

with other β-lactams and can be used safely in patients allergic to penicillins or

cephalosporins (311). Hematologic abnormalities have not been reported.

Carbapenems

Carbapenems are a unique class of β-lactam agents with the widest spectrum of antibacterial

activity of the currently available antibiotics. Structurally, they differ from other β-lactams in

having a hydroxyethyl side chain in trans configuration at position 6 and lacking a sulfur or

oxygen atom in the bicyclic nucleus (Fig. 1d). The unique stereochemistry of the

hydroxyethyl side chain confers stability against β-lactamases. Doripenem, ertapenem,

imipenem, and meropenem are the carbapenems currently available for clinical use (258).

Other members of this class currently undergoing preclinical evaluation or clinical trials

include biapenem, faropenem, and panipenem (123, 124, 271).

Mechanism of Action

Carbapenems bind to PBP 1 and PBP 2 of gram-negative and gram-positive bacteria, causing

cell elongation and lysis (328). They are stable toward most plasmid- or chromosomally

mediated β-lactamases except those produced by Stenotrophomonas maltophilia and some

strains of B. fragilis (249). Bacterial resistance arises from production of carbapenemases,

such as Klebsiella pneumoniae carbapenemases, serine carbapenemases (MSE, NMC-A, IMI,

and GES), and metallo-β-lactamases (IMI and VIM), capable of hydrolyzing the carbapenem

nucleus and from alteration of the porin channels in the bacterial cell wall, thereby reducing

the permeability of the drugs.

Pharmacology

After intravenous administration, the carbapenems distribute widely in the body but undergo

no significant biliary excretion. Imipenem is metabolized and inactivated in the kidneys by a

dehydropeptidase-I (DHP-I) enzyme found in the brush border of proximal renal tubular

cells. To achieve adequate concentrations in serum and urine, a DHP inhibitor, cilastatin, was

developed; it is combined with imipenem in a 1:1 dosage ratio for clinical use. Cilastatin has

no antibacterial activity, nor does it alter the activity of imipenem. It has a renal protective

effect by preventing excessive accumulation of potentially toxic imipenem metabolites in the

renal tubular cells. Meropenem, ertapenem, faropenem, and biapenem contain a β-methyl

group substitution at position C-1 of the bicyclic nucleus, resulting in increased stability to

inactivation by human renal DHP-I. These agents do not require concomitant administration

of a DHP-I inhibitor.

The pharmacokinetics of doripenem, imipenem, and meropenem are very similar, with

elimination half-lives in serum of about 1 h. Peak concentrations of the drugs in serum are

about 25 to 35 μg/ml and 55 to 70 μg/ml following 0.5-g and 1-g doses, respectively. These

drugs penetrate inflamed meninges well, with drug levels of 0.5 to 6 μg/ml in the CSF

(67, 258). Ertapenem is highly (>95%) bound to human plasma proteins, with poor

penetration into the CSF. Its relatively long plasma half-life of 4 h allows for once-daily

dosing frequency. Peak serum concentration of 155 μg/ml is reached following a single

intravenous dose of 1 g of ertapenem (257). Dosage adjustment of these carbapenem drugs

is necessary for creatinine clearance of ≤30 ml/min. These agents, including cilastatin, are

effectively removed by hemodialysis.

Spectrum of Activity

In general, all the carbapenems have similar antibacterial potencies with minor differences.

They have excellent in vitro activity against aerobic gram-positive species: staphylococci

(penicillin-susceptible and -resistant isolates); viridans group streptococci; group A, B, C,

and G streptococci; Bacillus spp.; and L. monocytogenes. Doripenem and imipenem are two

to four times more active than meropenem and ertapenem against streptococci and

methicillin-susceptible staphylococci (MIC90s of ≤0.5 μg/ml), but methicillin-resistant

staphylococci are usually resistant to all carbapenems. Although the MICs of carbapenems

for penicillin-resistant pneumococci are elevated (MIC90s of 0.25 to 2 μg/ml), many strains

remain susceptible to these drugs, with doripenem and imipenem being most potent

(16, 175, 280). Ertapenem has poor activity againstEnterococcus faecalis, but these isolates

are inhibited by other carbapenems at ≤4 μg/ml. However,Enterococcus faecium is usually

resistant to all carbapenems.

More than 90% of Enterobacteriaceae, including those resistant to other β-lactams and

aminoglycosides, are susceptible to carbapenems, with the following decreasing order of

activity: doripenem, ertapenem, meropenem > biapenem > faropenem, imipenem

(172, 275). These agents are highly active against clinical isolates of ESBL-producing K.

pneumoniae and E. coli with MIC90s of 0.015 to 0.125 μg/ml (171, 172).

MostEnterobacter spp., Citrobacter spp., and Serratia spp. are inhibited by ≤2 μg/ml.

Although ertapenem is inactive against Acinetobacter and Pseudomonas, it is 5- to 10-fold

more active than other carbapenems against fastidious gram-negative bacteria such

as Haemophilus, Moraxella, Neisseria, and Pasteurella. Most strains of P. aeruginosa are

inhibited by other carbapenems at 4 to 8 μg/ml, with meropenem as the most potent agent,

including against imipenem-resistant strains (172, 244). While they inhibit B.

cepacia and Pseudomonas stutzeri,carbapenems are inactive against S. maltophilia (77).

Emergence of resistant Pseudomonas spp. has been observed during therapy with

carbapenems. Imipenem may show in vitro antagonism with broad-spectrum cephalosporins

or extended-spectrum penicillins as a result of its ability to induce class I β-lactamase

production (249).

Carbapenems are the most potent β-lactams against anaerobes, with activities comparable

to those of clindamycin and metronidazole. The MIC90s for anaerobic gram-positive

cocci, Clostridium, the B. fragilis group,Fusobacterium, Porphyromonas, and Prevotella are

≤4 μg/ml (323, 324, 371). This class of drugs is also active in vitro against Actinomyces,

Nocardia, and atypical mycobacteria (86, 130).

Adverse Effects

The side effects of carbapenems are similar to those of other β-lactam antibiotics. Nausea,

vomiting, and diarrhea occur in up to 5% of patients, usually associated with parenteral

administration of ertapenem and imipenem. Pseudomembranous colitis can occur with

carbapenems. Allergic reactions such as drug fever, skin rashes, and urticaria are seen in

about 3% of patients. Cross-reactivity with other β-lactam agents is possible but has not

been fully studied. Seizures of unclear etiology have occurred in up to 5% of patients

receiving imipenem, particularly in the elderly age group and in patients with renal

insufficiency or underlying neurologic disorders, while other carbapenems have low seizureinducing

potential (<1%) (391). Reversible elevation of serum transaminases, leukopenia,

and thrombocytopenia have been described for carbapenems, but coagulopathy has not been

reported.

β-LACTAMASE INHIBITORS Back to top

Clavulanic Acid

Clavulanic acid is a naturally occurring weak antimicrobial agent found initially in cultures

of Streptomyces clavuligerus (253). It inhibits β-lactamases from staphylococci and many

gram-negative bacteria. This agent acts primarily as a “suicide inhibitor” by forming an

irreversible acyl enzyme complex with the β-lactamase, leading to loss of activity of the

enzyme.

Clavulanic acid acts synergistically with various penicillins and cephalosporins against β-

lactamase-producing staphylococci, klebsiellae, H. influenzae, M. catarrhalis, N. gonorrhoeae,

E. coli, Proteus spp., the B. fragilis group,Prevotella spp., and Porphyromonas spp.

(20, 105). Plasmid-mediated TEM β-lactamases present in ceftazidime-resistant strains of K.

pneumoniae and E. coli are inactivated by this drug (161). However, the inducible β-

lactamases (chromosomal class I) of Enterobacter, Citrobacter, Proteus, Acinetobacter,

Serratia, andPseudomonas spp. are not inhibited by clavulanic acid (181). The combination

of clavulanic acid with ampicillin, amoxicillin, or ticarcillin is active in vitro

against Mycobacterium tuberculosis, which is known to produce β-lactamases (69, 383).

In the United States, clavulanic acid is available for clinical use in combination with oral

amoxicillin at dosage ratios of 1:2, 1:4, 1:7, and 1:16 and in a 1:15 or 1:30 parenteral

combination with ticarcillin. Intravenous combinations of clavulanic acid and amoxicillin at

ratios of 1:5 and 1:10 are also used outside North America. The pharmacologic parameters

of amoxicillin and ticarcillin are not significantly altered when either drug is combined with

clavulanic acid. Amoxicillin-clavulanate is moderately well absorbed from the gastrointestinal

tract, with a half-life in serum of about 1 h for each component. One-third of a dose is

metabolized, while the remainder is excreted unchanged in the urine. The drug is widely

distributed to various body tissues and fluids, but it penetrates uninflamed meninges very

poorly.

Adverse reactions are similar to those reported for amoxicillin or ticarcillin used alone.

Nausea, vomiting, abdominal cramps, and diarrhea occur in 5 to 10% of patients taking

amoxicillin-clavulanate. The incidence of allergic skin reactions is similar to that of ampicillin

alone.

Sulbactam

Sulbactam is a semisynthetic 6-desaminopenicillin sulfone with weak antibacterial activity

(10). It functions as an effective inhibitor of certain plasmid- and chromosomally mediated β-

lactamases of S. aureus, manyEnterobacteriaceae, H. influenzae, M. catarrhalis,

Neisseria spp., Legionella spp., the B. fragilis group, Prevotellaspp., Porphyromonas spp.,

and Mycobacterium spp. (236). Sulbactam alone is active against N. gonorrhoeae, N.

meningitidis, some Acinetobacter spp., and B. cepacia (162, 238). It acts synergistically with

penicillins and cephalosporins against organisms that are otherwise resistant to the β-lactam

drugs because of the production of β-lactamases. A combination of sulbactam (8 μg/ml) and

ampicillin (16 μg/ml) inhibits most strains of staphylococci, Klebsiella spp., E. coli, H.

influenzae, M. catarrhalis, Neisseria spp., the B. fragilis group,Prevotella spp.,

and Porphyromonas spp. that are ampicillin resistant (288, 373). Like clavulanic acid,

sulbactam does not inhibit the β-lactamases of Enterobacter, Citrobacter, Providencia,

indole-positive Proteus, Pseudomonasspp., or S. maltophilia.

For clinical use, sulbactam is combined with ampicillin as a parenteral preparation in a 1:2

ratio. The pharmacologic properties of the drugs are not affected by each other in this

combination. Ampicillin-sulbactam penetrates well into body tissues and fluids, including

peritoneal and blister fluids. It enters the CSF in the presence of inflamed meninges. Like

ampicillin, sulbactam has a half-life in serum of 1 h, and 85% of the drug is excreted

unchanged via the kidneys. Since clearances of both sulbactam and ampicillin are affected

similarly in patients with impaired renal function, dosage adjustments are similar for the two

drugs.

The most common side effects of the ampicillin-sulbactam combination have been nausea,

diarrhea, and skin rash. Transient eosinophilia and transaminasemia have been reported.

Adverse reactions attributed to ampicillin may also occur with the use of ampicillinsulbactam.

Tazobactam

Tazobactam is a penicillanic acid sulfone derivative structurally related to sulbactam. Like

clavulanic acid and sulbactam, tazobactam acts as a suicidal β-lactamase inhibitor and binds

to bacterial PBP 1 or PBP 2 (238). Despite having very poor intrinsic antibacterial activity by

itself, it is comparable to clavulanate and sulbactam in lowering the MICs up to 20-fold for

many organisms when combined with various β-lactams against β-lactamase-producing

organisms. Tazobactam actively inhibits the β-lactamases of staphylococci, H. influenzae, N.

gonorrhoeae, E. coli, the B. fragilis group, Prevotella spp., and Porphyromonas spp.

(6, 139, 186). It also has activity against the class I β-lactamases of Acinetobacter,

Citrobacter, Proteus, Providencia, and Morganella spp., but it remains inactive against those

of Enterobacter spp., Pseudomonas spp., S. maltophilia, and someKlebsiella spp.

(181, 186, 238). Of the penicillin-β-lactamase inhibitor combinations, piperacillintazobactam

is the one most active (two- to eightfold-lower MICs) against β-lactamaseproducing

aerobic and anaerobic gram-negative bacilli (88, 186).

Available as a 1:8 ratio dosage combination with piperacillin, tazobactam is administered

parenterally. The two drugs do not affect each other ’s metabolism or pharmacokinetics. High

concentrations of both agents are achieved in the intestinal mucosa, lung, and skin, with

relatively poor distribution to muscle, fat, prostate, and CSF (in the absence of inflamed

meninges). With a half-life in serum of about 1 h, elimination of tazobactam is mainly via the

renal route and is not affected by hepatic failure (327). Major adverse effects of the

piperacillin-tazobactam combination are similar to those of piperacillin alone, such as

diarrhea, skin rash, and allergic reactions. Mild elevation in serum transaminase levels may

be encountered in about 10% of patients.

NXL104

NXL104 is a novel non-β-lactam inhibitor of class A and C β-lactamases through the

formation of stable covalent carbamoyl linkages (28, 79). It is currently undergoing

preclinical and clinical studies in combination with ceftazidime and ceftaroline for the

treatment of nosocomial gram-negative infections. When tested at a concentration of 4

μg/ml in combination with ceftazidime and cefotaxime against Enterobacteriaceae, this drug

potentiated the activity of the cephalosporins 4- to 8,000-fold with MICs of ≤1.0 μg/ml for all

organisms, including those producing AmpC β-lactamases, ESBLs of TEM, SHV, or CTX-M

types, and K. pneumoniaecarbapenemases (202). Although it effectively restores the activity

of imipenem against isolates producing class A carbapenemases, NXL104 does not potentiate

the activity of ceftazidime and cefotaxime againstEnterobacteriaceae containing IMP or VIM

metallo-β-lactamases.

AMINOGLYCOSIDES AND AMINOCYCLITOLS Back to top

Since the first aminoglycoside (aminoglycosidic aminocyclitol), streptomycin, was introduced

in 1944, this class of antibiotic has played a vital role in the treatment of serious gramnegative

infections. Among the unique features of the aminoglycosides are the bactericidal

activity against aerobic gram-negative bacilli (includingPseudomonas spp.), activity

against M. tuberculosis, and a relatively low incidence of bacterial resistance. The currently

available aminoglycosides are derived from Micromonospora spp. (gentamicin, netilmicin,

and sisomicin) or from Streptomyces spp. (kanamycin, neomycin, paromomycin,

streptomycin, and tobramycin). The difference in origin of these compounds accounts for the

differences of their suffixes, “micin” versus “mycin.” Streptomycin, neomycin, kanamycin,

tobramycin, and gentamicin are naturally occurring aminoglycosides, whereas amikacin and

netilmicin are semisynthetic derivatives of kanamycin and sisomicin, respectively.

Structurally, each of these aminoglycosides contains two or more amino sugars linked by

glycosidic bonds to an aminocyclitol ring nucleus.

Spectinomycin is an aminocyclitol antibiotic isolated from Streptomyces spectabilis. Although

it contains an aminocyclitol nucleus, it is not strictly an aminoglycoside because it does not

contain an amino sugar or a glycosidic bond.

Mechanism of Action

Aminoglycosides are bactericidal agents that inhibit bacterial protein synthesis by binding

irreversibly to the bacterial 30S ribosomal subunit. The aminoglycoside-bound bacterial

ribosomes then become unavailable for translation of mRNA during protein synthesis,

thereby leading to cell death (75). The aminoglycosides also cause misreading of the genetic

code, with resultant production of nonsense proteins. To reach the intracellular ribosomal

binding targets, an aerobic energy-dependent process is necessary to enable successful

penetration of the bacterial inner cell membrane by the aminoglycosides. Bacterial uptake of

these agents is facilitated by inhibitors of bacterial cell wall synthesis such as β-lactams and

vancomycin. This interaction forms the basis of antibacterial synergism between

aminoglycosides and β-lactam antibiotics. There are three known mechanisms of bacterial

resistance to aminoglycosides: (i) decreased intracellular accumulation of the antibiotic by

altering the outer membrane permeability, decreasing inner membrane transport, or active

efflux; (ii) modification of the target site by mutation in the ribosomal proteins or 16S RNA

or posttranscriptional methylation of 16S RNA (117); and (iii) enzymatic modification of the

drug (the most common resistance mechanism) (318).

Spectinomycin acts similarly to the aminoglycosides by binding to the 30S ribosomal

subunits and inhibiting protein synthesis. However, it does not cause misreading of the

mRNA and is not bactericidal.

Pharmacology

All aminoglycosides have similar pharmacologic properties. Gastrointestinal absorption of

these agents is unpredictable and always low. Because of its severe toxicity with systemic

administration, neomycin is available only for oral and topical use. After intravenous

administration, aminoglycosides are freely distributed in the extracellular space but

penetrate poorly into the CSF, vitreous fluid of the eye, biliary tract, prostate, and

tracheobronchial secretions, even in the presence of inflammation.

In adults with normal renal function, the aminoglycosides have half-lives in serum of about 2

to 3 h. They are primarily excreted, essentially unchanged, via the kidneys. There is

considerable variation in the elimination of aminoglycosides among individuals, especially in

patients with impaired renal function. Monitoring of serum aminoglycoside levels in these

patients is essential for providing adequate therapy and reducing toxicity. With their features

of concentration-dependent killing and prolonged postantibiotic effect, aminoglycosides may

be administered once daily to achieve maximum bactericidal activity at high concentrations

in serum without increased risk of toxicities (29). In renal failure, the drugs accumulate and

dosage reductions are necessary. Aminoglycosides are substantially removed by

hemodialysis and to a lesser extent by peritoneal dialysis.

Spectrum of Activity

Aminoglycoside antibiotics are active primarily against aerobic gram-negative bacilli and S.

aureus. As a group, they are particularly potent against the Enterobacteriaceae, P.

aeruginosa, and Acinetobacter spp. Certain differences in antimicrobial spectra among the

various aminoglycosides do exist. Kanamycin is limited in its spectrum because of the

common resistance of P. aeruginosa and frequent occurrence of plasmid-mediated

inactivating enzymes among other gram-negative bacilli (75). It is now used occasionally as

a “second-line” drug in combination with other antibiotics for the therapy of mycobacterial

infections (361). Similarly, widespread resistance among Enterobacteriaceae has limited the

usefulness of streptomycin. As a single agent, streptomycin is used in the therapy of

infections due to Francisella tularensis (tularemia) and Yersinia pestis (plague) (219). It is

often used in conjunction with tetracycline for the treatment of brucellosis. It has the

greatest in vitro activity of the aminoglycosides against M. tuberculosis. It may also be used

in combination with penicillin or vancomycin for the treatment of infective endocarditis due to

viridans group streptococci or enterococci, provided that the organisms do not possess highlevel

ribosomal or enzymatic resistance to streptomycin (14, 377).

Although gentamicin and tobramycin have very similar antibacterial activity profiles,

gentamicin is more active in vitro against Serratia spp., whereas tobramycin is more active

against P. aeruginosa (252). However, these minor differences have not been correlated with

greater efficacy of one agent over the other. For the most part, gentamicin and tobramycin

are susceptible to inactivation by the same modifying enzymes produced by resistant

bacteria, except that in contrast to gentamicin, tobramycin can be inactivated by 6-

acetyltransferase and 4′-adenyltransferase and has variable susceptibility to 3-

acetyltransferase. Netilmicin and amikacin are resistant to many of these aminoglycosidemodifying

enzymes and therefore are active against mostEnterobacteriaceae that are

resistant to gentamicin and tobramycin (243). Netilmicin is intrinsically less active than

gentamicin or tobramycin against P. aeruginosa, and most gentamicin-resistant Serratia,

Proteus, Providencia, and Pseudomonas isolates are also usually resistant to netilmicin (114).

Amikacin is often used as the aminoglycoside of choice when gentamicin and tobramycin

resistances are prevalent. In addition, amikacin is active against many Mycobacterium spp.

(361). Aminoglycosides are only moderately active againstHaemophilus and Neisseria spp. Of

the agents active against Bartonella spp., aminoglycosides are the only drugs consistently

bactericidal toward this group of organisms (219).

Although active against staphylococci, aminoglycosides are not recommended as single

agents for the treatment of staphylococcal infections. Gentamicin is often combined with a

penicillin or vancomycin for synergy in the treatment of serious infections due to

staphylococci, enterococci, or viridans group streptococci (14,366, 377). The

aminoglycosides are not active against anaerobes.

Paromomycin is an aminoglycoside notable for its amebicidal and antihelminthic effects, and

it is used clinically for the treatment of intestinal amebiasis and tapeworm infections (229). It

has modest antibacterial activity against gram-positive cocci and Enterobacteriaceae, but P.

aeruginosa isolates are generally resistant (74).

Spectinomycin is used primarily for uncomplicated anogenital infections due to N.

gonorrhoeae in patients with penicillin or cephalosporin allergy and contraindications to

fluoroquinolone therapy (51). It is effective against β-lactamase-producing and

fluoroquinolone-resistant strains, and gonococci are rarely resistant to this drug (98).

However, spectinomycin is ineffective for pharyngeal gonococcal infections, syphilis, or

chlamydial infections.

Adverse Effects

Considerable intrinsic toxicity, mainly in the form of nephrotoxicity and auditory or vestibular

toxicity, is characteristic of all of the aminoglycosides. The nephrotoxic potential varies

among the aminoglycosides, with neomycin being the most toxic and streptomycin the least.

This effect is usually reversible when the drug is discontinued. The presence of hypotension,

prolonged duration of therapy, preexisting renal insufficiency, and possibly excessive trough

serum aminoglycoside concentrations increase the risk of nephrotoxicity.

All aminoglycosides are capable of causing damage to the eighth cranial nerve in humans.

Vestibular toxicity is more frequently associated with streptomycin, gentamicin, and

tobramycin, whereas auditory toxicity is more typical of kanamycin and amikacin. This

frequently irreversible side effect may occur even after discontinuation of the drug and is

cumulative with repeated courses of the agent. The ototoxicity is a result of selective

destruction of the hair cells in the cochlea. Clinically detectable auditory and vestibular

dysfunction has been reported to occur in 3 to 5% of patients receiving gentamicin,

tobramycin, or amikacin who underwent audiometric testing (97).

Neuromuscular paralysis, which is usually reversible, can occur after rapid intravenous

infusion of aminoglycosides. This phenomenon occurs particularly in the setting of

myasthenia gravis or concurrent use of succinylcholine during anesthesia. Other minor

adverse reactions include local pain and allergic skin rashes. Serious adverse reactions have

not been reported for spectinomycin.