ANTIBIOTICS
Beta-Lactam Antibiotics & Other Inhibitors of Cell
Wall Synthesis
Beta-Lactam
Compounds
Penicillins
The
penicillins are classified as -lactam drugs because of their unique four-membered
lactam ring. They share features of chemistry, mechanism of action,
pharmacologic and clinical effects, and immunologic characteristics with
cephalosporins, monobactams, carbapenems, and –lactamase inhibitors, which also
are –
lactam compounds
Chemistry
Structural
integrity of the 6-aminopenicillanic acid nucleus is essential for the biologic
activity of these compounds. If the -lactam ring is enzymatically cleaved by
bacterial -lactamases, the resulting product, penicilloic acid, lacks antibacterial
activity.
The
attachment of different substitutents to 6-aminopenicillanic acid determines
the essential pharmacologic and antibacterial properties of the resulting
molecules. Penicillins can be assigned to one of three groups (below). Within
each of these groups are compounds that are relatively stable to gastric acid
and suitable for oral administration, eg, penicillin V, dicloxacillin, and
amoxicillin.
These have the greatest activity against
gram-positive organisms, gram-negative cocci, and non- - lactamase-producing
anaerobes. However, they have little activity against gram-negative rods.
They are susceptible to hydrolysis by lactamases.
These
drugs retain the antibacterial spectrum of penicillin and have improved activity
against gramnegative organisms, but they are destroyed by lactamases.
Penicillin Units and Formulations
The activity
of penicillin G was originally defined in units. Crystalline sodium penicillin
G contains approximately 1600 units/mg (1 unit =
Semisynthetic
penicillins are prescribed by weight rather than units. The minimum
inhibitory concentration (MIC) of any penicillin (or other antimicrobial)
is usually given in g/mL.
Most
penicillins are dispensed as the sodium or potassium salt of the free acid.
Potassium penicillin G contains about 1.7 meq of K+ per million units of
penicillin (2.8 meq/g). Nafcillin contains Na+, 2.8 meq/g. Procaine salts and
benzathine salts of penicillin G provide repository forms for intramuscular
injection. In dry crystalline form, penicillin salts are stable for long
periods (eg, for years at
Mechanism of Action
Penicillins,
like all -lactam antibiotics, inhibit bacterial growth by interfering with a
specific step in bacterial cell wall synthesis. The cell wall is a rigid outer
layer that is not found in animal cells. It completely surrounds the
cytoplasmic membrane, maintaining the shape of the cell and preventing cell
lysis from high osmotic pressure. The cell wall is composed of a complex
crosslinked polymer, peptidoglycan (murein, mucopeptide), consisting of
polysaccharides and polypeptides. The polysaccharide contains alternating amino
sugars, N-acetylglucosamine and Nacetylmuramic acid. A
five-amino-acid peptide is linked to the N-acetylmuramic acid sugar.
This peptide terminates in D-alanyl-D-alanine. Penicillin-binding proteins
(PBPs) catalyze the
transpeptidase reaction that removes the terminal
alanine to form a crosslink with a nearby peptide, which gives cell wall its
structural rigidity. -Lactam antibiotics are structural analogs of the natural
D-Ala-D-Ala substrate and they are covalently bound by PBPs at the active site.
After a –lactam antibiotic has attached to the PBP, the transpeptidation
reaction is inhibited, peptidoglycan synthesis is blocked, and the cell dies.
The exact mechanism responsible for cell death is not completely understood,
but autolysins, bacterial enzymes that remodel and break down cell wall, are
involved.
Penicillins
and cephalosporins are bactericidal only if cells are actively growing and
synthesizing cell wall.
Cephalosporins & Cephamycins
Cephalosporins
and cephamycins are similar to penicillins chemically, in mechanism of action,
and in toxicity. Cephalosporins are more stable than penicillins to many
bacterial -lactamases and therefore usually have a broader spectrum of
activity. Cephalosporins are not active against enterococci and Listeria
monocytogenes.
Chemistry
The nucleus
of the cephalosporins, 7-aminocephalosporanic acid, bears a close resemblance
to 6-aminopenicillanic acid. The intrinsic antimicrobial activity of natural cephalosporins
is low, but the attachment of various R1 and R2 groups has yielded drugs of
good therapeutic activity and low toxicity. The cephalosporins have molecular
weights of 400–450. They are soluble in water and relatively stable to pH and
temperature changes. Cephalosporins can be classified into four major groups or
generations, depending mainly on the spectrum of antimicrobial activity. As a
general rule, first-generation compounds have better activity against
gram-positive organisms and the later compounds exhibit improved activity
against gram-negative aerobic organisms.
Other Beta Lactam Drugs
Monobactams
These are
drugs with a monocyclic -lactam ring.
They are relatively resistant to lactamases and active
against gram-negative rods (including pseudomonas and serratia). They have no
activity against gram-positive bacteria or anaerobes.
Aztreonam is the only monobactam available in the
USA. It resembles aminoglycosides in its spectrum of activity. Aztreonam is
given intravenously every 8 hours in a dose of 1–2 g, providing peak serum
levels of 100 g/mL. The half-life is 1–2 hours and is greatly prolonged in
renal failure.
Penicillin-allergic
patients tolerate aztreonam without reaction. Occasional skin rashes and
elevations of serum aminotransferases occur during administration of aztreonam,
but major toxicity has not yet been reported. The clinical usefulness of
aztreonam has not been fully defined.
Beta-Lactamase Inhibitors (Clavulanic Acid, Sulbactam, & Tazobactam)
These substances resemble -lactam molecules but
themselves have very weak antibacterial action. They are potent inhibitors of
many but not all bacterial lactamases and can protect hydrolyzable penicillins
from inactivation by these enzymes. -Lactamase inhibitors are most active
against Ambler class A lactamases (plasmid-encoded transposable element [TEM] -
lactamases in particular) such as those produced by staphylococci, H
influenzae, N gonorrhoeae,
salmonella,
shigella, E coli, and K pneumoniae. They are not good inhibitors
of class C - lactamases, which typically are chromosomally encoded and
inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas,
but they do inhibit chromosomal lactamases of legionella, bacteroides, and
branhamella. The three inhibitors differ slightly with respect to pharmacology,
stability, potency, and activity, but these differences are of little
therapeutic significance. -Lactamase inhibitors are available only in fixed
combinations with specific penicillins. The antibacterial spectrum of the combination
is determined by the companion penicillin, not the -lactamase inhibitor. (The
fixed combinations available in the USA are listed in the Preparations
Available section.) An inhibitor will extend the spectrum of a penicillin
provided that the inactivity of the penicillin is due to destruction by
lactamase and that the inhibitor is active against thelactamase that is
produced. Thus, ampicillinsulbactam is active against -lactamase-producing S
aureus and H influenzae but not serratia, which produces a lactamase
that is not inhibited by sulbactam. Similarly, if a strain of P aeruginosa is
resistant to piperacillin, it will also be resistant to
piperacillin-tazobactam, since tazobactam does not inhibit the chromosomal
lactamase.
The
indications for penicillin- -lactamase inhibitor combinations are empirical
therapy for infections caused by a wide range of potential pathogens in both
immunocompromised and immunocompetent patients and treatment of mixed aerobic
and anaerobic infections, such as intraabdominal infections.
Doses
are the same as those used for the single agents except that the recommended
dosage of piperacillin in the piperacillin-tazobactam combination is
Adjustments for renal insufficiency are made
based on the penicillin component.
Carbapenems
The
carbapenems are structurally related to -lactam antibiotics. Ertapenem,
imipenem, and meropenem are licensed for use in the USA. Imipenem has a wide
spectrum with good activity against many gram-negative rods, including Pseudomonas
aeruginosa, gram-positive organisms, and anaerobes. It is resistant to most
lactamases but not metallo- lactamases.
Enterococcus
faecium, methicillin-resistant strains of staphylococci, Clostridium
difficile, Burkholderia cepacia, and Stenotrophomonas maltophilia are
resistant. Imipenem is inactivated by dehydropeptidases in renal tubules,
resulting in low urinary concentrations. Consequently, it is administered
together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical
use.
Meropenem is
similar to imipenem but has slightly greater activity against gram-negative
aerobes and slightly less activity against gram-positives. It is not
significantly degraded by renal dehydropeptidase and does not require an
inhibitor. Ertapenem is less active than meropenem or imipenem against Pseudomonas
aeruginosa and acinetobacter species. It is not degraded by renal
dehydropeptidase.
Carbapenems
penetrate body tissues and fluids well, including the cerebrospinal fluid. All
are cleared renally, and the dose must be reduced in patients with renal insufficiency.
The usual dose of imipenem is 0.25–0.5 g given intravenously every 6–8 hours
(half-life 1 hour). The usual adult dose of meropenem is
Carbapenems
are active against many highly penicillin-resistant strains of pneumococci.
A
carbapenem is the - lactam antibiotic of choice for treatment of enterobacter
infections, since it is resistant to destruction by the lactamase produced by
these organisms.
Strains of Pseudomonas
aeruginosa may rapidly
develop resistance to imipenem or meropenem, so
simultaneous use of an aminoglycoside is recommended for infections caused by
those organisms. Ertapenem is insufficiently active against P
aeruginosa and
should not be used to treat infections caused by that organism. Imipenem or
meropenem with or without an aminoglycoside may be effective treatment for
febrile neutropenic patients.
The most common adverse effects of
carbapenems—which tend to be more common with imipenem—are nausea, vomiting,
diarrhea, skin rashes, and reactions at the infusion sites.
Excessive
levels of imipenem in patients with renal failure may lead to seizures.
Meropenem and ertapenem are less likely to cause seizures than imipenem.
Patients allergic to penicillins may be allergic to carbapenems as well.
Other Inhibitors of Cell Wall Synthesis
Vancomycin
Vancomycin is
an antibiotic produced by Streptococcus orientalis. With the single
exception of flavobacterium, it is active only against gram-positive bacteria,
particularly staphylococci.
Vancomycin is
a glycopeptide of molecular weight 1500. It is water-soluble and quite stable.
Mechanisms of Action & Basis of Resistance
Vancomycin
inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of
nascent peptidoglycan pentapeptide. This inhibits the transglycosylase,
preventing further elongation of peptidoglycan and cross-linking. The
peptidoglycan is thus weakened and the cell becomes susceptible to lysis. The
cell membrane is also damaged, which contributes to the antibacterial effect.
Resistance to vancomycin in enterococci is due to modification of the
D-Ala-D-Ala binding site of the peptidoglycan building block in which the
terminal D-Ala is replaced by D-lactate. This results in the loss of a critical
hydrogen bond that facilitates high-affinity binding of vancomycin to its
target and loss of activity. This mechanism is also present in
vancomycin-resistant S aureus strains (MIC 32 g/mL), which have acquired
the enterococcal resistance determinants. The mechanism for reduced vancomycin
susceptibility of vancomycin-intermediate strains (MICs = 8–16 g/mL) is not
known.
Antibacterial Activity
Vancomycin is
bactericidal for gram-positive bacteria in concentrations of 0.5–10 g/mL. Most
pathogenic staphylococci, including those producing lactamase and those
resistant to nafcillin and methicillin, are killed by 4 g/mL or less.
Vancomycin kills staphylococci relatively slowly and only if cells are actively
dividing; the rate is less than that of the penicillins both in vitro and in
vivo. Vancomycin is synergistic with gentamicin and streptomycin against E
faecium and E faecalis strains that do not exhibit high levels of
aminoglycoside resistance.
Pharmacokinetics
Vancomycin
is poorly absorbed from the intestinal tract and is administered orally only
for the treatment of antibiotic-associated enterocolitis caused by Clostridium
difficile. Parenteral doses must be administered intravenously.
A 1 hour
intravenous infusion of
Vancomycin in combination with
gentamicin• Pharyngitis, tonsillitis
is an
alternative regimen for treatment of enterococcal endocarditis in a patient
with serious penicillin allergy.
Vancomycin (in
combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for
treatment of meningitis suspected or known to be caused by a highly
penicillin-resistant strain of pneumococcus (ie, MIC > 1 g/mL). The
recommended dosage is 30 mg/kg/d in two or three divided doses. A typical
dosing regimen for most infections in adults with normal renal function is
40 mg/kg/d in three or four divided doses.
Clearance of vancomycin is directly proportionate to creatinine clearance, and
the dose is reduced accordingly in patients with renal insufficiency should
have serum concentrations checked. Recommended peak serum concentrations are
20–50 g/mL, and trough concentrations are 5–15 g/mL.
Oral
vancomycin, 0.125–0.25 g every 6 hours, is used to treat antibiotic-associated
enterocolitis caused by Clostridium difficile. However, because of the
emergence of vancomycin-resistant enterococci and the strong selective pressure
of oral vancomycin for these resistant organisms, metronidazole is strongly
preferred as initial therapy and vancomycin should be reserved for treatment of
refractory cases.
Adverse Reactions
Adverse
reactions are encountered in about 10% of cases. Most reactions are minor. Vancomycin
is irritating to tissue, resulting in phlebitis at the site of injection.
Chills and fever may occur. Ototoxicity is rare and nephrotoxicity uncommon
with current preparations. However, administration with another ototoxic or
nephrotoxic drug, such as an aminoglycoside, increases the risk of these
toxicities. Ototoxicity can be minimized by maintaining peak serum
concentrations below 60 g/mL. Among the more common reactions is the so-called
"red man" or "red neck" syndrome. This infusion-related flushing
is caused by release of histamine. It can be largely prevented by prolonging
the infusion period to 1–2 hours or increasing the dosing interval.
Teicoplanin
Teicoplanin
is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of
action and antibacterial spectrum. Unlike vancomycin, it can be given
intramuscularly as well as intravenously. Teicoplanin has a long half-life
(45–70 hours), permitting once-daily dosing. This drug is available in Europe
but has not been approved for use in the United States.
Fosfomycin
Fosfomycin
trometamol, a stable salt of fosfomycin (phosphonomycin), inhibits a
very early stage of bacterial cell wall synthesis. An analog of
phosphoenolpyruvate, it is structurally unrelated to any other antimicrobial
agent. It inhibits the cytoplasmic enzyme enolpyruvate transferase by
covalently binding to the cysteine residue of the active site and blocking the
addition of phosphoenolpyruvate to UDP-N-acetylglucosamine. This
reaction is the first step in the formation of UDP-N-acetylmuramic acid,
the precursor of N-acetylmuramic acid, which is found only in bacterial
cell walls. The drug is transported into the bacterial cell by glycerophosphate
or glucose 6-phosphate transport systems. Resistance is due to inadequate
transport of drug into the cell.
Fosfomycin is
active against both gram-positive and gram-negative organisms at concentrations
125 g/mL. Susceptibility tests should be performed in growth medium
supplemented with glucose 6-phosphate to minimize false-positive indications of
resistance. In vitro synergism occurs when fosfomycin is combined with -lactam
antibiotics, aminoglycosides, or fluoroquinolones.
Fosfomycin
trometamol is available in both oral and parenteral formulations, though only
the oral preparation is approved for use in the United States. Oral
bioavailability is approximately 40%. Peak serum concentrations are 10 g/mL and
30 g/mL following a
Fosfomycin
is approved for use as a single
The drug
appears to be safe for use in pregnancy.
Bacitracin
Bacitracin is
a cyclic peptide mixture first obtained from the Tracy strain of Bacillus
subtilis in 1943. It is active against gram-positive microorganisms.
Bacitracin inhibits cell wall formation by interfering with dephosphorylation in
cycling of the lipid carrier that transfers peptidoglycan subunits to the
growing cell wall. There is no cross-resistance between bacitracin and other
antimicrobial drugs.
Bacitracin is
markedly nephrotoxic if administered systemically, producing proteinuria,
hematuria, and nitrogen retention. Hypersensitivity reactions (eg, skin rashes)
are rare. Because of its marked toxicity when used systemically, it is limited
to topical use. Bacitracin is poorly absorbed. Topical application results in
local antibacterial activity without significant systemic toxicity. The small
amounts of bacitracin that are absorbed are excreted by glomerular filtration.
Bacitracin,
500 units/g in an ointment base (often combined with polymyxin or neomycin), is
useful for the suppression of mixed bacterial flora in surface lesions of the
skin, in wounds, or on mucous membranes. Solutions of bacitracin containing
100–200 units/mL in saline can be employed for irrigation of joints, wounds, or
the pleural cavity.
Cycloserine
Cycloserine
is an antibiotic produced by Streptomyces orchidaceus. It is
water-soluble and very unstable at acid pH. Cycloserine inhibits many
gram-positive and gram-negative organisms, but it is used almost exclusively to
treat tuberculosis caused by strains of M tuberculosis resistant to
firstline agents. Cycloserine is a structural analog of D-alanine and inhibits
the incorporation of Dalanine into peptidoglycan pentapeptide by inhibiting
alanine racemase, which converts L-alanine to D-alanine, and D-alanyl-D-alanine
ligase. After ingestion of
doses.
Cycloserine
causes serious dose-related central nervous system toxicity with headaches,
tremors, acute psychosis, and convulsions. If oral dosages are maintained below
0.75 g/d, such effects can usually be avoided.
Chloramphenicol, Tetracyclines, Macrolides,
Clindamycin, Streptogramins
Chloramphenicol
Crystalline
chloramphenicol is a neutral, stable compound with the following structure:
It is soluble in alcohol but poorly soluble in
water. Chloramphenicol succinate, which is used for parenteral administration,
is highly water-soluble. It is hydrolyzed in vivo with liberation of free
chloramphenicol.
Antimicrobial Activity
Chloramphenicol is a potent inhibitor of
microbial protein synthesis. It binds reversibly to the 50S subunit of the
bacterial ribosome. It inhibits the peptidyl transferase step of protein
synthesis. Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that
is active against both aerobic and anaerobic gram-positive and gram-negative
organisms. It is active also against rickettsiae but not chlamydiae. Most
gram-positive bacteria are inhibited at concentrations of 1–10 g/mL, and many
gram-negative bacteria are inhibited by concentrations of 0.2–5 g/mL.
Haemophilus influenzae, Neisseria
meningitidis, and some strains of bacteroides are highly
susceptible, and for them chloramphenicol may be bactericidal.
Low-level resistance may emerge from large
populations of chloramphenicol-susceptible cells by selection of mutants that
are less permeable to the drug. Clinically significant resistance is due to
production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that
inactivates the drug.
Pharmacokinetics
The usual dosage
of chloramphenicol is 50–100 mg/kg/d. After oral administration, crystalline
chloramphenicol is rapidly and completely absorbed. A
cell membranes readily. Most of the drug is
inactivated either by conjugation with glucuronic acid (principally in the
liver) or by reduction to inactive aryl amines.
Excretion of active
chloramphenicol (about 10% of the total dose
administered) and of inactive degradation products (about 90% of the total)
occurs by way of the urine. A small amount of active drug is excreted into bile
or feces. The systemic dosage of chloramphenicol need not be altered in renal
insufficiency, but it must be reduced markedly in hepatic failure. Newborns
less than a week old and premature infants also clear chloramphenicol less
well, and the dosage should be reduced to 25 mg/kg/d.
Clinical Uses
Because of
potential toxicity, bacterial resistance, and the availability of other effective
drugs (eg, cephalosporins), chloramphenicol is all but obsolete as a systemic
drug. It may be considered for treatment of serious rickettsial infections,
such as typhus or Rocky Mountain spotted fever, in children for whom
tetracyclines are contraindicated, ie, those under 8 years of age.
It
is an alternative to a -lactam antibiotic for treatment of meningococcal
meningitis occurring in patients who have major hypersensitivity reactions to penicillin
or bacterial meningitis caused by penicillinresistant strains of pneumococci.
The dosage is 50–100 mg/kg/d in four divided doses. Chloramphenicol is
occasionally used topically in the treatment of eye infections because of its
wide antibacterial spectrum and its penetration of ocular tissues and the
aqueous humor. It is ineffective for chlamydial infections.
Adverse Reactions
Gastrointestinal
Disturbances
Adults
occasionally develop nausea, vomiting, and diarrhea. This is rare in children.
Oral or vaginal candidiasis may occur as a result of alteration of normal
microbial flora. Bone Marrow Disturbances
Chloramphenicol commonly causes a dose-related
reversible suppression of red cell production at dosages exceeding 50 mg/kg/d
after 1–2 weeks. Aplastic anemia is a rare consequence of chloramphenicol
administration by any route. It is an idiosyncratic reaction unrelated to dose,
though it occurs more frequently with prolonged use. It tends to be
irreversible and can be fatal. Aplastic anemia probably develops in one of
every 24,000–40,000 patients who have taken chloramphenicol.
Toxicity for Newborn Infants
Newborn
infants lack an effective glucuronic acid conjugation mechanism for the
degradation and detoxification of chloramphenicol. Consequently, when infants
are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray
baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock,
and collapse. To avoid this toxic effect, chloramphenicol should be used with
caution in infants and the dosage limited to 50 mg/kg/d or less (during the
first week of life) in full-term infants and 25 mg/kg/d in premature infants.
Interaction with Other Drugs
Chloramphenicol
inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives
are prolonged, and the serum concentrations of phenytoin, tolbutamide,
chlorpropamide, and warfarin are increased. Like other bacteriostatic
inhibitors of microbial protein synthesis, chloramphenicol can antagonize
bactericidal drugs such as penicillins or aminoglycosides.
Tetracyclines
Free tetracyclines are crystalline amphoteric
substances of low solubility. They are available as hydrochlorides, which are
more soluble. Such solutions are acid and, with the exception of
chlortetracycline, fairly stable. Tetracyclines chelate divalent metal ions,
which can interfere with their absorption and activity.
Antimicrobial Activity
Tetracyclines
are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis.
They are active against many gram-positive and gram-negative bacteria,
including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and L forms; and
against some protozoa, eg, amebas. The antibacterial activities of most
tetracyclines are similar except that tetracycline-resistant strains may remain
susceptible to doxycycline or minocycline, drugs that are less rapidly
transported by the pump that is responsible for resistance (see Resistance).
Differences in clinical efficacy are minor and attributable largely to features
of absorption, distribution, and excretion of individual drugs.
Tetracyclines
enter microorganisms in part by passive diffusion and in part by an
energy-dependent process of active transport. Susceptible cells concentrate the
drug intracellularly. Once inside the cell, tetracyclines bind reversibly to
the 30S subunit of the bacterial ribosome, blocking the binding of
aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. This prevents
addition of amino acids to the growing peptide.
Resistance
Three
mechanisms of resistance to tetracycline have been described: (1) decreased
intracellular accumulation due to either impaired influx or increased efflux by
an active transport protein pump; (2) ribosome protection due to production of
proteins that interfere with tetracycline binding to the ribosome; and (3)
enzymatic inactivation of tetracyclines. The most important of these is
production of an efflux pump. The pump protein is encoded on a plasmid and may
be transmitted by transduction or by conjugation. Because these plasmids
commonly encode resistance genes for other drugs, eg, aminoglycosides,
sulfonamides, and chloramphenicol, tetracycline resistance is a marker for
resistance to multiple drugs.
Pharmacokinetics
Tetracyclines
mainly differ in their absorption after oral administration and their
elimination. Absorption after oral administration is approximately 30% for
chlortetracycline; 60–70% for tetracycline, oxytetracycline, demeclocycline,
and methacycline; and 95–100% for doxycycline and minocycline. A portion of an
orally administered dose of tetracycline remains in the gut lumen, modifies
intestinal flora, and is excreted in the feces. Absorption occurs mainly in the
upper small intestine and is impaired by food (except doxycycline and
minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products
and antacids, which contain multivalent cations; and by alkaline pH. Specially
buffered tetracycline solutions are formulated for intravenous administration.
Tetracyclines
are 40–80% bound by serum proteins. Oral dosages of 500 mg every 6 hours of
tetracycline hydrochloride or oxytetracycline produce peak blood levels of 4–6
g/mL. Peak levels of 2–4 g/mL are achieved with a 200 mg dose of doxycycline or
minocycline. Intravenously injected tetracyclines give somewhat higher levels
only temporarily. Tetracyclines are distributed widely to tissues and body
fluids except for cerebrospinal fluid, where concentrations are 10–25%
of those in serum. Minocycline reaches very high
concentrations in tears and saliva, which makes it useful for eradication of
the meningococcal carrier state.
Tetracyclines
cross the placenta to reach the fetus and are also excreted in milk. As a
result of chelation with calcium, tetracyclines are bound to—and damage—growing
bones and teeth.
Carbamazepine, phenytoin, barbiturates, and
chronic alcohol ingestion may shorten the half-life of doxycycline 50% by
induction of hepatic enzymes that metabolize the drug.
Tetracyclines
are excreted mainly in bile and urine. Concentrations in bile exceed those in
serum tenfold. Some of the drug excreted in bile is reabsorbed from the
intestine (enterohepatic circulation) and contributes to maintenance of serum
levels. Ten to 50 percent of various tetracyclines is excreted into the urine,
mainly by glomerular filtration. Ten to 40 percent of the drug in the body is
excreted in feces. Doxycycline, in contrast to other tetracyclines, is
eliminated by nonrenal mechanisms, does not accumulate significantly in renal failure,
and requires no dosage adjustment, making it the tetracycline of choice for use
in the setting of renal insufficiency.
Tetracyclines
are classified as short-acting (chlortetracycline, tetracycline,
oxytetracycline), intermediate-acting (demeclocycline and methacycline), or
long-acting (doxycycline and minocycline) based on serum half-lives of 6–8
hours, 12 hours, and 16–18 hours, respectively. The almost complete absorption
and slow excretion of doxycycline and minocycline allow for oncedaily dosing.
Clinical Uses
A
tetracycline is the drug of choice in infections with Mycoplasma pneumoniae,
chlamydiae, rickettsiae, and some spirochetes. They are used in combination
regimens to treat gastric and duodenal ulcer disease caused by Helicobacter
pylori. They may be employed in various grampositive and gram-negative
bacterial infections, including vibrio infections, provided the organism is not
resistant. In cholera, tetracyclines rapidly stop the shedding of vibrios, but
tetracycline resistance has appeared during epidemics. Tetracyclines remain
effective in most chlamydial infections, including sexually transmitted
diseases. Tetracyclines are no longer recommended for treatment of gonococcal
disease because of resistance. A tetracycline—usually in combination with an
aminoglycoside—is indicated for plague, tularemia, and brucellosis.
Tetracyclines are sometimes employed in the treatment of protozoal infections,
eg, those due to Entamoeba histolytica or
Plasmodium
falciparum. Other uses include treatment of acne,
exacerbations of bronchitis, community-acquired pneumonia, Lyme disease,
relapsing fever, leptospirosis, and some nontuberculous mycobacterial
infections (eg, Mycobacterium marinum). Tetracyclines formerly were used
for a variety of common infections, including bacterial gastroenteritis,
pneumonia (other than mycoplasmal or chlamydial pneumonia), and urinary tract
infections. However, many strains of bacteria causing these infections now are
resistant, and other agents have largely supplanted tetracyclines.
Minocycline,
200 mg orally daily for 5 days, can eradicate the meningococcal carrier state,
but because of side-effects and resistance of many meningococcal strains,
rifampin is preferred.
Demeclocycline inhibits the action of ADH in the
renal tubule and has been used in the treatment of inappropriate secretion of
ADH or similar peptides by certain tumors.
Oral Dosage
The oral
dosage for rapidly excreted tetracyclines, equivalent to tetracycline
hydrochloride, is 0.25–
Parenteral Dosage
Several
tetracyclines are available for intravenous injection in doses of 0.1–0.5 g
every 6–12 hours (similar to oral doses), depending on the agent. Intramuscular
injection is not recommended because of pain and inflammation at the injection
site. Doxycycline is the preferred agent, at a dosage of 100 mg every 12–24
hours.
Adverse Reactions
Hypersensitivity
reactions (drug fever, skin rashes) to tetracyclines are uncommon. Most adverse
effects are due to direct toxicity of the drug or
to alteration of microbial flora. Gastrointestinal Adverse Effects Nausea,
vomiting, and diarrhea are the most common reasons for discontinuing
tetracycline medication. These effects are attributable to direct local
irritation of the intestinal tract. Nausea, anorexia, and diarrhea can usually
be controlled by administering the drug with food or carboxymethylcellulose,
reducing drug dosage, or discontinuing the drug.
Tetracyclines
modify the normal flora, with suppression of susceptible coliform organisms and
overgrowth of pseudomonas, proteus, staphylococci, resistant coliforms,
clostridia, and candida. This can result in intestinal functional disturbances,
anal pruritus, vaginal or oral candidiasis, or enterocolitis with shock and
death. Pseudomembranous enterocolitis associated with Clostridium difficile should
be treated with metronidazole.
Bony Structures and Teeth
Tetracyclines
are readily bound to calcium deposited in newly formed bone or teeth in young
children. When the drug is given during pregnancy, it can be deposited in the
fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it
can also be deposited in bone, where it may cause deformity or growth
inhibition. If the drug is given for long periods to children under 8 years of
age, similar changes can result.
Liver Toxicity
Tetracyclines
can probably impair hepatic function, especially during pregnancy, in patients
with preexisting hepatic insufficiency and when high doses are given
intravenously. Hepatic necrosis has been reported with daily doses of
Kidney Toxicity
Renal tubular
acidosis and other renal injury resulting in nitrogen retention have been
attributed to the administration of outdated tetracycline preparations.
Tetracyclines given along with diuretics may produce nitrogen retention.
Tetracyclines other than doxycycline may accumulate to toxic levels in patients
with impaired kidney function.
Local Tissue Toxicity
Intravenous
injection can lead to venous thrombosis. Intramuscular injection produces
painful local irritation and should be avoided.
Photosensitization
Systemic
tetracycline administration, especially of demeclocycline, can induce
sensitivity to sunlight or ultraviolet light, particularly in fair-skinned
persons.
Vestibular Reactions
Dizziness,
vertigo, nausea, and vomiting have been particularly noted with doxycycline at
doses above 100 mg. With dosages of 200–400 mg/d of minocycline, 35–70% of
patients will have these reactions.
Medical & Social Implications of Overuse
Tetracyclines have been extensively used in
animal feeds to enhance growth. This practice has contributed to the spread of
tetracycline resistance among enteric bacteria and of plasmids that encode
tetracycline resistance genes.
Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins
Macrolides
The
macrolides are a group of closely related compounds characterized by a
macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy
sugars are attached. The prototype drug, erythromycin, which consists of two
sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces
erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of
erythromycin.
Erythromycin
Chemistry
The
general structure of erythromycin is shown above with the macrolide ring and
the sugars desosamine and cladinose.
It is poorly soluble in water (0.1%) but
dissolves readily in organic solvents. Solutions are fairly stable at
Antimicrobial Activity
Erythromycin
is effective against gram-positive organisms, especially pneumococci,
streptococci, staphylococci, and corynebacteria, in plasma concentrations of
0.02–2 g/mL. Mycoplasma, legionella, Chlamydia trachomatis, C psittaci, C
pneumoniae, helicobacter, listeria, and certain mycobacteria (Mycobacterium
kansasii, Mycobacterium scrofulaceum) are also susceptible. Gramnegative
organisms such as neisseria species, Bordetella pertussis, Bartonella
henselae, and B quintana (etiologic agents of cat-scratch disease
and bacillary angiomatosis), some rickettsia species, Treponema pallidum, and
campylobacter species are susceptible. Haemophilus influenzae is
somewhat less susceptible.
The antibacterial action of erythromycin may be
inhibitory or bactericidal, particularly at higher concentrations, for
susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of
protein synthesis occurs via binding to the 50S ribosomal RNA. Protein
synthesis is inhibited because aminoacyl translocation reactions and the
formation of initiation complexes are blocked
Resistance
Resistance to
erythromycin is usually plasmid-encoded. Three mechanisms have been identified:
(1) reduced permeability of the cell membrane or active efflux; (2) production
(by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3)
modification of the ribosomal binding site (so-called ribosomal protection) by
chromosomal mutation or by a macrolide-inducible or constitutive
methylase. Efflux and methylase production
account for the vast majority of cases of resistance in gram-positive
organisms. Cross-resistance is complete between erythromycin and the other
macrolides. Constitutive methylase production also confers resistance to
structurally unrelated but mechanistically similar compounds such as
clindamycin and streptogramin B (so-called macrolidelincosamide
streptogramin, or MLS-type B, resistance), which
share the same ribosomal binding site. Because nonmacrolides are poor inducers
of the methylase, strains expressing an inducible methylase will appear
susceptible in vitro. However, constitutive mutants that are resistant can be
selected out and emerge during therapy with clindamycin.
Pharmacokinetics
Erythromycin
base is destroyed by stomach acid and must be administered with enteric
coating. Food interferes with absorption. Stearates and esters are fairly acid-resistant
and somewhat better absorbed. The lauryl salt of the propionyl ester of
erythromycin (erythromycin estolate) is the bestabsorbed oral preparation. Oral
dosage of 2 g/d results in serum erythromycin base and ester concentrations of
approximately 2 g/mL. However, only the base is microbiologically active, and
its concentration tends to be similar regardless
of the formulation. A 500 mg intravenous dose of erythromycin lactobionate
produces serum concentrations of 10 g/mL 1 hour after dosing. The serum
half-life is approximately 1.5 h normally and 5 hours in patients with anuria.
Adjustment for renal failure is not necessary. Erythromycin is not removed by
dialysis. Large amounts of an administered dose are excreted in the bile and
lost in feces, and only 5% is excreted in the urine. Absorbed drug is
distributed widely except to the brain and cerebrospinal fluid. Erythromycin is
taken up by polymorphonuclear leukocytes and macrophages. It traverses the
placenta and reaches the fetus.
Clinical Uses
An
erythromycin is the drug of choice in corynebacterial infections (diphtheria,
corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or
genital chlamydial infections; and in treatment of community-acquired pneumonia
because its spectrum of activity includes the pneumococcus, mycoplasma, and
legionella. Erythromycin is also useful as a penicillin substitute in
penicillin-allergic individuals with infections caused by staphylococci
(assuming that the isolate is susceptible), streptococci, or pneumococci.
Emergence of erythromycin resistance in strains of group A streptococci and
pneumococci (penicillin-resistant pneumococci in particular) has made
macrolides less attractive as first-line agents for treatment of pharyngitis,
skin and soft tissue infections, and pneumonia. Erythromycin has been
recommended as prophylaxis against endocarditis during dental procedures in
individuals with valvular heart disease, though clindamycin, which is better
tolerated, has largely replaced it. Although erythromycin estolate is the
best-absorbed salt, it imposes the greatest risk of adverse reactions.
Therefore, the stearate or succinate salt may be preferred.
The oral
dosage of erythromycin base, stearate, or estolate is 0.25–0.5 g every 6 hours
(for children, 40 mg/kg/d). The dosage of erythromycin ethylsuccinate is
0.4–0.6 g every 6 hours. Oral erythromycin base (
Adverse Reactions
Gastrointestinal Effects
Anorexia, nausea, vomiting, and diarrhea
occasionally accompany oral administration. Gastrointestinal intolerance, which
is due to a direct stimulation of gut motility, is the most frequent reason for
discontinuing erythromycin and substituting another antibiotic.
Liver Toxicity
Erythromycins, particularly the estolate, can
produce acute cholestatic hepatitis (fever, jaundice, impaired liver function),
probably as a hypersensitivity reaction. Most patients recover from this, but
hepatitis recurs if the drug is readministered. Other allergic reactions
include fever, eosinophilia, and rashes.
Drug Interactions
Erythromycin metabolites can inhibit cytochrome
P450 enzymes and thus increase the serum concentrations of numerous drugs,
including theophylline, oral anticoagulants, cyclosporine, and
methylprednisolone. Erythromycin increases serum concentrations of oral digoxin
by increasing its bioavailability.
Clarithromycin
Clarithromycin
is derived from erythromycin by addition of a methyl group and has improved
acid stability and oral absorption compared with erythromycin. Its mechanism of
action is the same as that of erythromycin. Clarithromycin and erythromycin are
virtually identical with respect to antibacterial activity except that
clarithromycin is more active against Mycobacterium avium Complex leprae
and Toxoplasma gondii. Erythromycin-resistant streptococci and
staphylococci are also
resistant to clarithromycin. A 500 mg dose
produces serum concentrations of 2–3 g/mL. The longer half-life of
clarithromycin (6 hours) compared with erythromycin permits twice-daily dosing.
The recommended dosage is
250–500 mg twice daily. Clarithromycin penetrates
most tissues well, with concentrations equal to or exceeding serum
concentrations.
Clarithromycin
is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin,
which also has antibacterial activity. A portion of active drug and this major
metabolite is eliminated in the urine, and dosage reduction (eg, a 500 mg
loading dose, then 250 mg once or twice daily) is recommended for patients with
creatinine clearances less than 30 mL/min.
Clarithromycin
has drug interactions similar to those described for erythromycin. The
advantages of clarithromycin compared with erythromycin are lower frequency of
gastrointestinal intolerance and less frequent dosing. Except for the specific
organisms noted above, the two drugs are otherwise therapeutically very
similar, and the choice of one over the other usually turns on issues of cost
(clarithromycin being much more expensive) and tolerability.
Azithromycin
Azithromycin,
a 15-atom lactone macrolide ring compound, is derived from erythromycin by
addition of a methylated nitrogen into the lactone ring of erythromycin. Its
spectrum of activity and clinical uses are virtually identical to those of
clarithromycin. Azithromycin is active against M avium complex and T
gondii. Azithromycin is slightly less active than erythromycin and
clarithromycin against staphylococci and streptococci and slightly more active
against H influenzae. Azithromycin is highly active against chlamydia.
Azithromycin differs from erythromycin and clarithromycin mainly in
pharmacokinetic properties.
A 500 mg dose of azithromycin produces relatively
low serum concentrations of approximately 0.4 g/mL. However, azithromycin
penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells
extremely well, with tissue concentrations exceeding serum concentrations by
10- to 100-fold. The drug is slowly released from tissues (tissue half-life of
2–4 days) to produce an elimination half-life approaching 3 days. These unique
properties permit once-daily dosing and
shortening of the duration of treatment in many
cases. For example, a single
Azithromycin
is rapidly absorbed and well tolerated orally. It should be administered 1 hour
before or 2 hours after meals. Aluminum and magnesium antacids do not alter
bioavailability but delay absorption and reduce peak serum concentrations.
Because it has a 15-member (not 14-member) lactone ring, azithromycin does not
inactivate cytochrome P450 enzymes and therefore is free of the drug
interactions that occur with erythromycin and clarithromycin.
Clindamycin
penetrates well into most tissues, with brain and cerebrospinal fluid being
important exceptions. It penetrates well into abscesses and is actively taken
up and concentrated by phagocytic cells. Clindamycin is metabolized by the
liver, and both active drug and active metabolites are excreted in bile. The
half-life is about 2.5 hours in normal individuals, increasing to 6 hours in
patients with anuria. No dosage adjustment is required for renal failure.
Clinical Uses
Clindamycin
is indicated for treatment of severe anaerobic infection caused by bacteroides
and other anaerobes that often participate in mixed infections. Clindamycin,
sometimes in combination with an aminoglycoside or cephalosporin, is used to
treat penetrating wounds of the abdomen and the gut; infections originating in
the female genital tract, eg, septic abortion and pelvic abscesses; or
aspiration pneumonia.
Clindamycin is now recommended instead of erythromycin for prophylaxis of
endocarditis in patients with valvular heart disease who are undergoing certain
dental procedures.
Clindamycin
plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole
for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS
patients. It is also used in combination with pyrimethamine for AIDS-related
toxoplasmosis of the brain.
Adverse Effects
Common
adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function
(with or without jaundice) and neutropenia sometimes occur. Severe diarrhea and
enterocolitis have followed clindamycin administration. Antibiotic-associated
colitis that has followed administration of clindamycin and other drugs is
caused by toxigenic C difficile. This potentially fatal complication
must be recognized promptly and treated with metronidazole, 500 mg orally or
intravenously three times a day (the preferred therapy), or vancomycin, 125 mg
orally four times a day (less desirable given the increasing prevalence of
vancomycin-resistant enterococci). Relapse may occur. Variations in the local
prevalence of C difficile may account for the great differences in
incidence of antibiotic-associated colitis. For unknown reasons, neonates given
clindamycin may become colonized with toxigenic C difficile but do not
develop colitis.
Aminoglycosides Spectinomycin
Aminoglycosides
Aminoglycosides are
a group of bactericidal antibiotics originally obtained from various streptomyces
species and sharing chemical, antimicrobial, pharmacologic, and toxic
characteristics.
The
group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin,
tobramycin, sisomicin, netilmicin, and others.
Aminoglycosides are used most widely against
gram-negative enteric bacteria, especially in bacteremia and sepsis, in
combination with vancomycin or a penicillin for endocarditis, and for treatment
of tuberculosis. Streptomycin is the oldest and best-studied of the
aminoglycosides. Gentamicin, tobramycin, and amikacin are the most widely
employed aminoglycosides at present. Neomycin and kanamycin are now largely
limited to topical or oral use.
General Properties of Aminoglycosides
Physical and Chemical Properties
Aminoglycosides have a hexose ring, either
streptidine (in streptomycin) or 2-deoxystreptamine (other aminoglycosides), to
which various amino sugars are attached by glycosidic linkages. They are
water-soluble, stable in solution, and more active at alkaline than at acid pH.
Aminoglycosides frequently exhibit synergism with -lactams or vancomycin in
vitro.
In combination they eradicate organisms more
rapidly than would be predicted from the activity of either single agent.
However, at high concentrations aminoglycosides may complex with –lactam drugs,
resulting in loss of activity, and they should not be mixed together for
administration.
Spectinomycin
Spectinomycin
is an aminocyclitol antibiotic that is structurally related to aminoglycosides.
It lacks amino sugars and glycosidic bonds.
While active in vitro against
many gram-positive and gram-negative organisms, spectinomycin is used almost
solely as an alternative treatment for gonorrhea in patients who are allergic
to penicillin or whose gonococci are resistant to other drugs. The vast
majority of gonococcal isolates are inhibited by 6 g/mL of spectinomycin.
Strains of gonococci may be resistant to
spectinomycin, but there is no cross-resistance with other drugs used in
gonorrhea. Spectinomycin is rapidly absorbed after intramuscular injection. A
single dose of 40 mg/kg up to a maximum of
Preparations Available
Antibacterial Drugs
Drugs for
Treating Bacterial Infections
When
bacteria overcome the cutaneous or mucosal barriers and penetrate body tissues,
a bacterial infection is present. Frequently the body succeeds in
removing the invaders, without outward signs of disease, by mounting an immune response.
If bacteria multiply faster than the body’s defenses can destroy them, infectious
disease develops with inflammatory signs, e.g., purulent wound
infection or urinary tract infection. Appropriate treatment employs substances
that injure bacteria and thereby prevent their further multiplication, without
harming cells of the host organism (1).
Apropos
nomenclature: antibiotics are
produced by microorganisms (fungi, bacteria) and are directed “against life” at
any phylogenetic level (prokaryotes, eukaryotes). Chemotherapeutic agents originate from chemical synthesis. This
distinction has been lost in current usage.
Specific
damage to bacteria is particularly
practicable when a substance interferes with a metabolic process that occurs in
bacterial but not in host cells.
Clearly this applies to inhibitors
of cell wall synthesis, because human and animal cells lack a cell wall. The points of attack of antibacterial agents are
schematically illustrated in a grossly simplified bacterial cell, as depicted
in (2).
In the following sections,
polymyxins and tyrothricin are not considered further. These polypeptide
antibiotics enhance cell membrane permeability. Due to their poor tolerability,
they are prescribed in humans only for topical use.
The effect of antibacterial drugs can be
observed in vitro (3). Bacteria
multiply in a growth medium under control conditions. If the medium contains an
antibacterial drug, two results can be discerned: 1. bacteria are killed—bactericidal effect; 2. bacteria
survive, but do not multiply—bacteriostatic
effect. Although variations may occur under therapeutic conditions,
different drugs can be classified according to their respective primary mode of
action (color tone in 2 and 3). When bacterial growth remains
unaffected by an antibacterial drug, bacterial resistance is present. This may occur
because of certain metabolic characteristics that confer a natural
insensitivity to the drug on a particular strain of bacteria (natural
resistance).Depending on whether a drug affects only a few or
numerous types of bacteria, the terms narrow-spectrum
(e.g., penicillin G) or broad-spectrum
(e.g., tetracyclines) antibiotic
are applied. Naturally susceptible bacterial strains can be transformed
under the influence of antibacterial drugs into resistant ones (acquired
resistance), when a random genetic alteration (mutation)
gives rise to a resistant bacterium. Under the influence of the drug, the
susceptible bacteria die off, whereas the mutant multiplies unimpeded. The more
frequently a given drug is applied, the more probable the emergence of
resistant strains (e.g., hospital strains with multiple resistance)!
Resistance
can also be acquired when DNA responsible for nonsusceptibility (so-called resistance
plasmid) is passed on from other resistant bacteria
by conjugation or transduction.
Inhibitors of Cell Wall
Synthesis
In
most bacteria, a cell wall surrounds the cell like a rigid shell that protects against
noxious outside influences and prevents rupture of the plasma membrane from a
high internal osmotic pressure. The structural stability of the cell wall is
due mainly to the murein (peptidoglycan) lattice. This consists of basic
building blocks linked together to form a large macromolecule. Each basic unit
contains the two linked aminosugars N-acetylglucosamine and N-acetylmuramyl
acid; the latter bears a peptide chain. The building blocks are synthesized in
the bacterium, transported outward through the cell membrane, and assembled as
illustrated schematically. The enzyme transpeptidase cross-links the peptide
chains of adjacent aminosugar chains.
Inhibitors
of cell wall synthesis are suitable
antibacterial agents, because animal and human cells lack a cell wall. They
exert a bactericidal action on growing or multiplying germs. Members of
this class include -lactam antibiotics such as the penicillins
and cephalosporins, in addition to bacitracin and vancomycin.
Penicillins (A). The parent substance of this group is penicillin G
(benzylpenicillin). It is obtained from cultures of mold fungi, originally
from Penicillium notatum. Penicillin G contains the basic structure
common to all penicillins, 6-amino-penicillanic acid (p. 271, 6-APA),
comprised of a thiazolidine and a 4-membered -lactam
ring. 6- APA itself lacks antibacterial activity.
Penicillins disrupt cell wall synthesis by inhibiting transpeptidase.
When bacteria are in their growth and replication phase, penicillins are
bactericidal; due to cell wall defects, the bacteria swell and burst.
Penicillins
are generally well tolerated; with penicillin G, the daily dose can
range from approx.
up to 5%), with manifestations ranging from skin eruptions to
anaphylactic shock (in less than 0.05% of patients). Known penicillin allergy
is a contraindication for these drugs. Because of an increased risk of sensitization,
penicillins must not be used locally.
Neurotoxic
effects, mostly convulsions due to GABA
antagonism, may occur if the brain is exposed to extremely high concentrations,
e.g., after rapid i.v. injection of a large dose or intrathecal injection.
Penicillin G undergoes rapid renal elimination mainly in unchanged form
(plasma t1/2 ~ 0.5 h). The duration of the effect can be prolonged by:
1.
Use of higher doses, enabling plasma levels to remain above the
minimally effective antibacterial concentration;
2.
Combination with probenecid. Renal elimination of penicillin occurs
chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of
6-APA). The acid probenecid (p. 316) competes for this route and thus retards
penicillin elimination;
3.
Intramuscular administration in depot form. In its anionic form (-COO-)
penicillin G forms poorly water-soluble salts with substances containing a
positively charged amino group. Depending on the substance, release of
penicillin from the depot occurs over a variable interval.
Although
very well tolerated, penicillin G has disadvantages (A) that
limit its therapeutic usefulness: (1) It is inactivated by gastric acid, which
cleaves the β -lactam ring, necessitating parenteral administration. (2)
The β-lactam ring can also be opened by bacterial enzymes (β
-lactamases); in particular, penicillinase, which can be produced by
staphylococcal strains, renders them resistant to penicillin G. (3) The
antibacterial spectrum is narrow; although it encompasses many gram-positive
bacteria, gram-negative cocci, and spirochetes, many gram-negative pathogens
are unaffected.
Derivatives
with a different substituent on 6-APA
possess advantages (B): (1) Acid resistance permits oral administration,
provided that enteral absorption is possible. All derivatives shown in (B) can
be given orally. Penicillin V (phenoxymethylpenicillin) exhibits
antibacterial properties similar to those of penicillin G. (2) Due to their penicillinase
resistance, isoxazolylpenicillins caused penicillinaseproducing
staphylococci. (3) Activity spectrum: The
aminopenicillin
amoxicillin is active against many gramnegative organisms, e.g., coli bacteria or Salmonella
typhi. It can be protected from destruction by penicillinase by combination
with inhibitors of penicillinase (clavulanic acid, sulbactam, tazobactam).
The
structurally close congener ampicillin (no 4-hydroxy group) has a
similar activity spectrum. However, because it is poorly absorbed (<50%) and
therefore causes more extensive damage to the gut microbial flora (side effect:
diarrhea), it should be given only by injection. A still broader spectrum
(including Pseudomonas bacteria) is shown by carboxypenicillins (carbenicillin,
ticarcillin) and acylaminopenicillins (mezclocillin, azlocillin, piperacillin).
These substances are neither acid stable nor penicillinase resistant.
Cephalosporins (C). These β-lactam
antibiotics are also fungal products and have bactericidal activity due to inhibition
of transpeptidase.
Their
shared basic structure is 7-aminocephalosporanic acid, as exemplified by cephalexin
(gray rectangle). Cephalosporins are acid stable, but many are poorly
absorbed. Because they must be given parenterally, most—including those with
high activity—are used only in clinical settings. A few, e.g., cephalexin, are
suitable for oral use.
Cephalosporins
are penicillinase-resistant, but cephalosporinase-forming organisms do exist.
Some derivatives are, however, also resistant to this -lactamase.
Cephalosporins
are broad-spectrum antibacterials. Newer derivatives (e.g., cefotaxime,
cefmenoxin, cefoperazone, ceftriaxone, ceftazidime, moxalactam) are also
effective against pathogens resistant to various other antibacterials.
Cephalosporins are mostly well tolerated. All can cause allergic reactions,
some also renal injury, alcohol intolerance, and bleeding (vitamin K
antagonism).
Other inhibitors of cell
wall synthesis.
Bacitracin
and vancomycin interfere with the transport of peptidoglycans through the
cytoplasmic membrane and are active only against gram-positive bacteria.
Bacitracin
is a polypeptide mixture, markedly
nephrotoxic and used only topically.
Vancomycin is a glycopeptide and the drug of choice for the (oral) treatment of
bowel inflammations occurring as a complication of antibiotic therapy
(pseudomembranous enterocolitis caused by Clostridium difficile). It is
not absorbed.
Inhibitors of
Tetrahydrofolate Synthesis
Tetrahydrofolic acid (THF) is a
co-enzyme in the synthesis of purine bases and thymidine. These are
constituents of DNA and RNA and required for cell growth and replication. Lack
of THF leads to inhibition of cell proliferation. Formation of THF from
dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is
made from folic acid, a vitamin that cannot be synthesized in the body, but
must be taken up from exogenous sources. Most bacteria do not have a
requirement for folate, because they are capable of synthesizing folate, more
precisely DHF, from precursors. Selective interference with bacterial
biosynthesis of THF can be achieved with sulfonamides and trimethoprim.
Sulfonamides structurally resemble
p-aminobenzoic acid (PABA), a precursor in bacterial DHF synthesis. As false
substrates, sulfonamides competitively inhibit utilization of PABA,
hence DHF synthesis. Because most bacteria cannot take up exogenous
folate, they are depleted of DHF. Sulfonamides thus possess bacteriostatic
activity against a broad spectrum of pathogens. Sulfonamides are
produced by chemical synthesis. The basic structure is shown in (A). Residue
R determines the pharmacokinetic properties of a given sulfonamide.
Most
sulfonamides are well absorbed via the enteral route. They are metabolized to
varying degrees and eliminated through the kidney. Rates of elimination, hence
duration of effect, may vary widely. Some members are poorly absorbed from the
gut and are thus suitable for the treatment of bacterial bowel infections.
Adverse effects may include, among others, allergic reactions, sometimes with
severe skin
damage,
displacement of other plasma protein-bound drugs or bilirubin in neonates
(danger of kernicterus, hence contraindication for the last weeks of gestation
and in the neonate). Because of the frequent emergence of resistant bacteria,
sulfonamides are now rarely used.
Introduced
in 1935, they were the first broad-spectrum chemotherapeutics. Trimethoprim inhibits
bacterial DHF reductase, the human enzyme being significantly less sensitive
than the bacterial one (rarely bone marrow depression). A
2,4-diaminopyrimidine, trimethoprim, has bacteriostatic activity against a
broad spectrum of pathogens. It is used mostly as a component of cotrimoxazole.
Co-trimoxazole is a combination of trimethoprim and the
sulfonamide sulfamethoxazole. Since THF synthesis is inhibited at two
successive steps, the antibacterial effect of co-trimoxazole is better than
that of the individual components. Resistant pathogens are infrequent; a
bactericidal effect may occur.
Adverse
effects correspond to those of the components. Although initially developed as
anantirheumatic agent, sulfasalazine (salazosulfapyridine) is used
mainly in the treatment of inflammatory bowel disease (ulcerative colitis and
terminal ileitis or Crohn’s disease). Gut bacteria split this compound into the
sulfonamide sulfapyridine and mesalamine (5-aminosalicylic acid). The
latter is probably the anti-inflammatory agent (inhibition of synthesis of
chemotactic signals for granulocytes, and of H2O2 formation in mucosa), but
must be present on the gut mucosa in high concentrations. Coupling to the
sulfonamide prevents premature absorption in upper small bowel segments. The
cleaved-off sulfonamide can be absorbed and may produce typical adverse effects
(see above).
Dapsone
(p. 280) has several therapeutic uses:
besides treatment of leprosy, it is used for prevention/prophylaxis of malaria,
toxoplasmosis, and actinomycosis.
Inhibitors of DNA Function
Deoxyribonucleic acid (DNA) serves
as a template for the synthesis of nucleic acids. Ribonucleic acid (RNA)
executes protein synthesis and thus permits cell growth. Synthesis of new DNA
is a prerequisite for cell division. Substances that inhibit reading of genetic
information at the DNA template damage the regulatory center of cell
metabolism. The substances listed below are useful as antibacterial drugs
because they do not affect human cells.
Gyrase inhibitors. The enzyme gyrase (topoisomerase II) permits the orderly accommodation of
a ~1000 µmlong bacterial chromosome in a bacterial cell of ~1 µm. Within the
chromosomal strand, double-stranded DNA has a double helical configuration. The
former, in turn, is arranged in loops that are shortened by supercoiling. The
gyrase catalyzes this operation, as illustrated, by opening, underwinding, and
closing the DNA double strand such that the full loop need not be rotated.
Derivatives
of 4-quinolone-3-carboxylic acid (green portion of ofloxacin formula) are
inhibitors of bacterial gyrases.
They
appear to prevent specifically the resealing of opened strands and thereby act
bactericidally. These agents are absorbed after oral ingestion. The older drug,
nalidixic acid, affects exclusively gram-negative bacteria and attains
effective concentrations only in urine; it is used as a urinary tract
antiseptic.
Norfloxacin
has a broader spectrum. Ofloxacin,
ciprofloxacin, and enoxacin, and others, also yield systemically effective
concentrations and are used for infections of internal organs. Besides gastrointestinal
problems and allergy, adverse effects particularly involve the CNS (confusion,
hallucinations, seizures). Since they can damage epiphyseal chondrocytes and
joint cartilages in laboratory animals, gyrase inhibitors should not be used
during pregnancy, lactation, and periods of growth.
Azomycin (nitroimidazole) derivatives, such
as metronidazole, damage DNA by complex formation or strand breakage.
This occurs in obligate anaerobes, i.e., bacteria growing under O2 exclusion. Under
these conditions, conversion to reactive metabolites that attack DNA takes
place (e.g., the hydroxylamine shown). The effect is bactericidal. A similar
mechanism is involved in the antiprotozoal action on Trichomonas vaginalis (causative
agent of vaginitis and urethritis) and Entamoeba histolytica (causative
agent of large bowel inflammation, amebic dysentery, and hepatic abscesses).
Metronidazole is well absorbed via the enteral route; it is also given i.v. or
topically (vaginal insert). Because metronidazole is
considered potentially mutagenic, carcinogenic, and teratogenic in the
human, it should not be used longer than 10 d, if possible, and be avoided
during pregnancy and lactation. Timidazole may be considered equivalent
to metronidazole.
Rifampin
inhibits the bacterial enzyme that
catalyzes DNA template-directed RNA transcription, i.e., DNA-dependent RNA
polymerase. Rifampin acts bactericidally against mycobacteria (M. tuberculosis,
M. leprae), as well as many gram-positive and gram-negative bacteria. It is
well absorbed after oral ingestion. Because resistance may develop with
frequent usage, it is restricted to the treatment of tuberculosis and leprosy
(p. 280). Rifampin is contraindicated in the first trimester of gestation and
during lactation. Rifabutin resembles rifampin but may be effective in
infections resistant to the latter.
Inhibitors of Protein Synthesis
Protein
synthesis means translation into a peptide chain
of a genetic message first copied (transcribed) into m- RNA (p. 274). Amino
acid (AA) assembly occurs at the ribosome. Delivery of amino acids to m-RNA
involves different transfer RNA molecules (t-RNA), each of which binds a
specific AA. Each t-RNA bears an “anticodon” nucleobase triplet that is
complementary to a particular m-RNA coding unit (codon, consisting of 3
nucleobases. Incorporation of an AA normally involves the following steps (A):
1. The ribosome “focuses” two codons on m-RNA; one (at the left) has bound
its t-RNA-AA complex, the AA having already been added to the peptide chain;
the other (at the right) is ready to receive the next t-RNA-AA complex.
2. After the latter attaches, the
AAs of the two adjacent complexes are linked by the action of the enzyme
peptide synthetase (peptidyltransferase). Concurrently, AA and t-RNA of the
left complex disengage.
3. The left t-RNA dissociates from
m-RNA. The ribosome can advance along the m-RNA strand and focus on the next
codon.
4. Consequently, the right t-RNAAA
complex shifts to the left, allowing the next complex to be bound at the right.
These individual steps are susceptible to inhibition by antibiotics of
different groups. The examples shown originate
primarily from Streptomyces bacteria, some of
the aminoglycosides also being derived from Micromonospora bacteria.
1a. Tetracyclines inhibit
the binding of t-RNA-AA complexes. Their action is bacteriostatic and affects a
broad spectrum of pathogens.
1b. Aminoglycosides induce
the binding of “wrong” t-RNA-AA complexes, resulting in synthesis of false
proteins.
Aminoglycosides
are bactericidal. Their activity spectrum encompasses mainly gram-negative
organisms. Streptomycin and kanamycin are used predominantly in the treatment
of tuberculosis. Note on spelling: -mycin designates origin from
Streptomyces species; -micin (e.g., gentamicin) from Micromonospora
species.
2. Chloramphenicol inhibits
peptide synthetase. It has bacteriostatic activity against a broad spectrum of
pathogens. The chemically simple molecule is now produced synthetically.
3. Erythromycin suppresses
advancement of the ribosome. Its action is predominantly bacteriostatic and
directed against gram-positve organisms.
For oral administration, the
acid-labile base (E) is dispensed as a salt (E. stearate) or an ester (e.g., E.
succinate). Erythromycin is well tolerated. It is a suitable substitute in
penicillin allergy or resistance. Azithromycin, clarithromycin, and roxithromycin
are derivatives with greater acid stability and better bioavailability. The
compounds mentioned are the most important members of the macrolide antibiotic
group, which includes josamycin and spiramycin. An unrelated
action of erythromycin is its mimicry of the gastrointestinal hormone motiline
(interprandial bowel motility).
Clindamycin has antibacterial activity
similar to that of erythromycin. It exerts a bacteriostatic effect mainly on
gram-positive aerobic, as well as on anaerobic pathogens. Clindamycin is a
semisynthetic chloro analogue of lincomycin, which derives from a Streptomyces
species. Taken orally, clindamycin is better absorbed than lincomycin, has
greater antibacterial efficacy and is thus preferred. Both penetrate well into
bone tissue.
Tetracyclines are absorbed from the gastrointestinal tract to differing degrees,
depending on the substance, absorption being nearly complete for doxycycline
and minocycline. Intravenous injection is rarely needed (rolitetracycline
is available only for i.v. administration).
The most common unwanted effect is gastrointestinal
upset (nausea, vomiting, diarrhea, etc.) due to (1) a direct mucosal
irritant action of these substances and (2) damage to the natural bacterial gut
flora (broad-spectrum antibiotics) allowing colonization by pathogenic
organisms, including Candida fungi. Concurrent ingestion of antacids or milk
would, however, be inappropriate because tetracyclines form insoluble complexes
with plurivalent cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) resulting
in their inactivation; that is, absorbability, antibacterial activity, and
local irritant action are abolished. The ability to chelate Ca2+ accounts for
the propensity of tetracyclines to accumulate in growing teeth and bones. As a
result, there occurs an irreversible yellowbrown discoloration of teeth and
a reversible inhibition of bone growth.
Because
of these adverse effects, tetracycline should not be given after the second
month of pregnancy and not prescribed to children aged 8 y and under. Other
adverse effects are increased photosensitivity of the skin and hepatic
damage, mainly after i.v. administration. The broad-spectrum antibiotic chloramphenicol
is completely absorbed after oral ingestion. It undergoes even distribution
in the body and readily crosses diffusion barriers such as the blood-brain
barrier. Despite these advantageous properties, use of chloramphenicol is
rarely indicated (e.g., in CNS infections) because of the danger of bone marrow
damage. Two types of bone marrow depression can occur:
(1) a dose-dependent, toxic,
reversible form manifested during therapy and, (2) a frequently fatal form that
may occur after a latency of weeks and is not dose dependent. Due to high
tissue penetrability, the danger of bone marrow depression must also be taken
into account after local use (e.g., eye drops).
Aminoglycoside
antibiotics consist of glycoside-linked
amino-sugars (cf. gentamicin C1, a constituent of the gentamicin mixture). They
contain numerous hydroxyl groups and amino groups that can bind protons. Hence,
these compounds are highly polar, poorly membrane permeable, and not absorbed
enterally. Neomycin and paromomycin are given orally to eradicate
intestinal bacteria (prior to bowel surgery or for reducing NH3 formation by
gut bacteria in hepatic coma). Aminoglycosides for the treatment of serious
infections must be injected (e.g.,
gentamicin, tobramycin,
amikacin, netilmicin, sisomycin). In addition,
local inlays of a gentamicin-releasing carrier can be used in infections of
bone or soft tissues.
Aminoglycosides gain access to the bacterial
interior by the use of bacterial transport systems. In the kidney, they
enter the cells of the proximal tubules via an uptake system for oligopeptides.
Tubular cells are susceptible to damage (nephrotoxicity, mostly
reversible). In the inner ear, sensory cells of the vestibular apparatus and
Corti’s organ may be injured (ototoxicity, in part irreversible).
Brand names: Achromycin,
Tetracycline.
Class of
drug: Tetracycline antibiotic.
Mechanism of
action: Inhibits bacterial protein synthesis after
specific
ribosomal binding.
Susceptible
organisms in vivo: Borrelia burgdorferi, Borrelia
recurrentis,
Brucella sp, Calymmatobacterium granulomatis,
Chlamydia
pneumoniae, Chlamydia psittaci, Chlamydia trachomatis,
Ehrlichia sp,
Helicobacter pylori, Rickettsia (Q fever),
Rickettsia sp,
Vibrio sp.
Indications/dosage/route:
Oral, IV, IM.
• Usual dose
Ð Adults: PO
1–2 g/d in 2 or 4 equal doses.
Ð Children 8
years: Daily dose is 10–20 mg/lb (25–50 mg/kg in 4 equal doses).
• Brucellosis
Ð PO 500 mg 4
times/d for 3 weeks, accompanied by
• Syphilis
Ð PO 30–40 g in
equally divided doses over 10–15 days. Perform close follow-up and laboratory
tests.
• Uncomplicated urethral, endocervical, or rectal
infections caused by C.rachomatis.
Ð PO 500 mg 4
times/d for at least 7 days.
• Severe acne
Ð PO: Initial:
1 g/d in divided doses. Maintenance: 125–500 mg/d.
• Lymphogranuloma venereum: genital, inguinal or
anorectal Ð PO 500 mg 4 times/d for at least 2 weeks.
• Nongonococcal urethritis
Ð PO 500 mg 4
times/d for 7 days.
• Acute pelvic inflammatory disease, ambulatory
treatment
Ð Adults:
ampicillin, 4.8 106 units IM aqueous procaine
penicillin G at 2 sites or 250 mg IM ceftriaxone. Each (except ceftriaxone)
should be accompanied by
Ð Children 8
years: 150 mg/kg/d IV cefuroxime or 100 mg/kg/d IV ceftriaxone followed by 30
mg/kg/d IV tetracycline in 3 doses, continued for at least 4 days. Thereafter,
continue tetracycline orally to complete at least 14 days of therapy.
Adjustment of dosage
• Kidney disease: None.
• Liver disease: None.
• Elderly: None.
• Pediatric: Not to be used in children 8
years unless all other
drugs are either ineffective or contraindicated.
Food: Take 1 hour
before or 2 hours after meals. Dairy products interfere with tetracycline
absorption.
Pregnancy: Category
D.
Lactation: Appears
in breast milk. Considered compatible by American Academy of Pediatrics.
Contraindications:
Hypersensitivity to any tetracycline, patients with
esophageal obstruction, children ≤8 years.
Warnings/precautions
• Use with caution in patients with impaired
kidney function.
• Administer IM by deep injection into large muscle.
If injected inadvertently SC or into fat layer, severe pain may result. This
can be relieved by means of an ice pack. IM solution should be used within 24
hours of preparation.
• The drug may permanently discolor (yellow brown
to gray) deciduous or permanent teeth or cause enamel hypoplasia. Premature
infants may experience decreased fibula growth.
• Do not administer antacids that contain
calcium, aluminum, or magnesium.
Advice to patient
• Discard drug if it is beyond expiration date.
Outdated drug can cause severe kidney toxicity (Fanconi-like syndrome).
• To minimize possible photosensitivity reaction,
apply adequate sunscreen and use proper covering when exposed to strong
sunlight.
• Store drug away from light, heat, and high
humidity.
• Use two forms of birth control including
hormonal and barrier methods.
• Do not take drug at bedtime.
Adverse reactions
• Common:
nausea, vomiting, diarrhea, anorexia.
• Serious:
renal toxicity, hypersensitivity reactions, benign intracranial hypertension
(pseudotumor cerebri), pericardits, diabetes insipidus, pseudomembranous
colitis, hepatitis, anaphylaxis.
Clinically important drug
interactions
• Drugs that decrease effects/toxicity of
tetracyclines: aluminum antacids, iron preparations, calcium salts, magnesium
salts, sodium bicarbonate, zinc salts, bismuth salts, cimetidine.
• Tetracyclines increase effects/toxicity of oral
anticoagulants, bumetanide, digoxin, thiazide diuretics, ethacrynic acid,
furosemide, insulin, methoxyflurane.
• Tetracyclines decrease effects/toxicity of
penicillins.
Parameters to monitor
• Serum BUN and creatinine, liver enzymes.
• Signs of possible oliguria, which may result in
accumulation of the drug.
• Signs and symptoms of pseudotumor cerebri in
adults: headaches, diplopia.
• Signs and symptoms of pseudomembraneous
colitis: Discontinue drug if possible. If necessary, treat with vancomycin,
metronidazole, and cholestyramine.
• Signs and symptoms of phlebitis from IV
injections.
• Renal function in patients with preexisting renal
impairment. If indicated, monitor serum drug levels. Maintain level below 15 g/mL.
• Serum enzymes in patients with preexisting
kidney or liver disease or those receiving concomitant hepatotoxic drug.
Editorial comments
• Uses for tetracyclines include treatment of
early Lyme disease, Vibrio infections such as cholera, and rickettsial
infections including typhus, Q fever, and Rocky Mountain spotted fever.
They are also used to treat genital infections
(granuloma inguinale, nongonococcal urethritis, pelvic inflammatory disease,
and other infections caused by C. rachomatis).
Streptomycin
Brand name: Streptomycin.
Class of drug: Antibiotic,
aminoglycoside.
Mechanism of action: Binds
to ribosomal units in bacteria, inhibits protein synthesis.
Susceptible organisms in vivo :
Mycobacterium tuberculosis, Yersinia pestis,
Francisella tularensis, Brucella; synergism against
enterococci and streptococcoi.
Indications/dosage/route: IM
only.
• Inguinal granuloma, chancroid; respiratory, endocardial, meningeal infections
(Hemophilus influenzae), pneumonia, UTIs, bacteremia (gram-negative
bacillary)
Ð Adults: 15
mg/kg/d. Maximum: 1 g/d.
Ð Children:
20–40 mg/kg/d. Maximum: 1 g/d.
• Tuberculosis
Ð Adults:
Ð Children: IM
20–40 mg/kg/d. Maximum: 1 g/d.
• Tularemia
Ð Adults: 1–2
g/d in divided doses, 7–14 days.
• Plague
Ð Adults: 2 g/d
in 2 divided doses, minimum 10 days.
• Streptococal endocarditis (for synergism with a
-lactam)
Ð Initial:
• Enterococcal endocarditis (with penicillin)
(for synergism with
ampicillin or vancomycin)
Ð Initial:
Adjustment of dosage
• Kidney disease: Creatinine clearance 10–50
mL/min: administration interval 24–72 hours; creatinine clearance 10
mL/ min: administration interval 72–96 hours.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: No
restrictions.
Pregnancy: Category
D.
Lactation: Appears
in breast milk. Considered compatible by American Academy of Pediatrics.
Contraindications:
Hypersensitivity to aminoglycoside antibiotics.
Warnings/precautions
• Use with caution in patients with renal
disease, neuromuscular disorders (eg, myasthenia gravis, parkinsonism), hearing
disorders.
• Do not combine this drug with any other drug in
the same IV bag.
Adverse
reactions:
• Common:
none.
• Serious:
renal toxicity, ototoxicity, neuromuscular paralysis, respiratory depression
(infants), superinfection.
Clinically important drug
interactions
• Drugs that increase effects/toxicity of
aminoglycosides: loop diuretics, amphotericin B, enflurane, vancomycin, NSAIDs.
• Drugs that decrease effects/toxicity of
aminoglycosides: penicillins (high dose), cephalosporins.
Parameters to monitor
• Peak and trough serum levels 48 hours after
beginning therapy and every 3–4 days thereafter as well as after changing
doses. Peak (therapeutic): 15–40 g/mL;
trough: 4
g/mL.
• Signs of ototoxicity: tinnitus, vertigo,
hearing loss. The drug should be stopped if tinnitus or vertigo occurs. Limit
administration to 7–10 days to decrease the risk of ototoxicity.
• Renal function periodically. If serum
creatinine increases by more than 50% over baseline value, it may be advisable
to discontinue drug treatment and use a less nephrotoxic agent, eg, a quinolone
or cephalosporin.
• Efficacy of drug action. If there is no
response in 3–7 days, reculture and consider another drug.
• Neuromuscular function when administering the
drug IV. Too rapid administration may cause paralysis and apnea. Have calcium
gluconate or pyridostigmine available to reverse such an effect.
• Neurologic status if the drug is given for
hepatic encephalopathy.
• Signs and symptoms of allergic reaction.
Editorial comments
• Streptomycin has the greatest activity of all
the aminoglycosides against M. tuberculosis. It is a first-line drug for
tuberculosis though not as effective as isoniazid and rifampin.
• Streptomycin is the drug of choice to treat
plague and brucellosis.
• Streptomycin and gentamicin are the drugs of
choice to treat tularemia.
Succinylcholine (Suxamethonium)
Brand names: Anectine,
Sucostrin, Quelicin.
Class of drug: Skeletal
muscle relaxant (depolarizing).
Mechanism of action: Depolarizes
motor endplate at myoneural junction, preventing stimulation by endogenous
acetylcholine.
Indications/dosage/route: IV,
IM.
• Skeletal muscle paralysis after induction of
anesthesia for surgical procedures Ð Adults: Short procedures: IV or
IM 0.3–1.1 mg/kg over 10–30 seconds. Maintenance: 0.04–0.07 mg/kg q5–10min.
Maximum: 150 mg. Ð Infants: IV 1–2
mg/kg. Maintenance: 0.3–0.6 mg/kg q5– 10 min. – Older children, adolescents: 1
mg/kg IV or 3-4 mg/kg IM. Maximum 150 mg.
Note:
Succinylcholine should be reserved for use in children who require emergency
intubation, who do not have an accessible vein, and for whom an airway can be
readily secured.
Adjustment of dosage
• Kidney disease: Use with caution; may precipitate
hyperkalemia in renal failure patients.
• Liver disease: Use cautiously, high risk for
side effects; reduce dose.
• Elderly: Use with caution.
• Pediatric: See above.
Pregnancy: Category
C.
Lactation: No
data available; best to avoid.
Contraindications:
Hypersensitivity to succinylcholine, low plasma
pseudocholinesterase (hepatocellular disease), atypical plasma cholinesterase,
malnutrition, severe anemia, severe burns, cancer, dehydration, collagen
diseases, family or personal history of acute malignant hyperthermia, acute
narrow-angle glaucoma, myopathies (high serum creatinine phosphokinase),
penetrating eye injuries, multiple traumas, denervation of skeletal muscle (due
to CNS injury).
Warnings/precautions
• Use with caution in patients undergoing cesarean
section; in patients with kidney and severe liver disease, respiratory
depression, severe anemia, severe burns, hyperkalemia, cerebrovascular
accident, myasthenia gravis, thyroid disorders, porphyria, eye surgery,
pheochromocytoma, chronic abdominal infection, subarchnoid hemorrhage,
degenerative neuromuscular disease, patients receiving cardiac glycosides,
fractures, dislocations; and in patients recovering from severe trauma.
• Patient should be premedicated with atropine or
scopolamine to prevent excessive salivation.
• Neostigmine or pyridostigmine should be
available to counteract neuromuscular blockade after drug is stopped.
• Patient is fully conscious and thus aware of
surroundings, including conversations.
• Tachyphylaxis may occur with continuous
infusion or repeated administration. It is preferable to administer the drug by
continuous infusion rather than fractional doses to minimize tachyphylaxis.
• Atest dose of succinylcholine may be
administered initially to determine the degree of sensitivity of the patient as
well as recovery time. This test dose should consist of 5–10 mg or 0.1 mg/kg.
• Patient with fracture or muscle spasm may
experience additional trauma because of muscle fasciculations. Administer
tubocurarine to prevent this.
Adverse
reactions
• Common:
muscle fasciculations, postoperative muscle pain, increased intraocular
pressure, hypertension, salivation.
• Serious:
malignant hyperthermia, bradycardia, hypotension, tachycardia, arrthymias,
cardiac arrest, hyperkalemia, severe prolonged neuromuscular blockade, severe
prolonged respiratory depression or apnea.
Clinically important drug
interactions: Drugs that increase effects/toxicity of
succinylcholine: cholinesterase inhibitors, oral contraceptives,
cyclophosphamide, thiotepa, inhalation anesthetics, aminoglycosides,
tetracyclines, vancomycin, cyclosporine, isofluorophate, echothiophate,
aminoglycosides, clindamycin, quinidine, procainamide, blockers,
lithium, non-potassiumsparing diuretics, opioids, digitalis glycosides.
Parameters to monitor
• Signs and symptoms of toxicity, particularly in
those with low plasma pseudocholinesterase activity.
• Respiratory status continuously. If
respirations do not return in a few seconds after discontinuing administration,
use of oxygen is necessary.
• Neuromuscular response using a peripheral nerve
stimulator.
Responses should be determined during and after
surgery to monitor efficacy and recovery.
• Cardiovascular status throughout. Monitor for
bradycardia, arrhythmias, hypotension.
• Signs of malignant hyperthermia: muscle spasm,
particularly of the jaw, loss of laryngeal relaxation, hyperthermia, unstable
BP, tachyarrthymias, hypercarbia. Hyperthermia is a late manifestation. Stop
infusion if these symptoms are noted.
• Electrolytes: calcium and in particular
potassium for hyperkalemia. This is especially necessary for patients with
severe trauma or burns.
• Signs and symptoms of increased intraocular
pressure. This is usually transient; if it persists this could be dangerous to
the eyes.
Editorial comments
• Succinylcholine should be used only by
individuals who are well versed and experienced in endotracheal intubation.
Equipment for intubation should be available immediately if needed.
• Succinylcholine has no effect on pain
threshold. If a painful or long procedure is anticipated, an analgesic must be
administeredalong with succinylcholine. A benzodiazepine or conventional
analgesic should be used.
Carbenicillin
Brand name: Geocillin.
Class of
drug: Antibiotic, penicillin family, carboxypenicillin.
Mechanism of
action: Inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Staphylococci, Streptococcus
pneumoniae, beta-hemolytic streptococci, Escherichia coli, Proteus mirabilis,
Morganella morganii, Proteus vulgaris, Providencia rettgeri, Enterobacter sp,
Pseudomonas aeruginosa.
Is destroyed
by -lactamases.
• Less
effective than ampicillin against Streptococcus pyogenes (Group A), Streptococcus
pneumoniae, Enterococcus faecalis.
Most Staphylococcus
aureus are resistant. Inactive against Klebsiella.
Indications/dosage/route: Oral
only (to treat UTI and prostatitis due to aerobic gram-negative bacteria).
• UTIs due to Escherichia coli, Proteus Ð
382-764 mg q.i.d.
• UTIs caused by Pseudomonas, enterococci Ð
764 mg q.i.d.
• Prostatitis caused by E. coli, Proteus
mirabilis, Enterobacter, enterococci Ð 764 mg q.i.d.
Adjustment of dosage
• Kidney disease: creatinine clearance 10–20
mL/min: dosage adjustment may be necessary, exact guidelines are not available;
creatinine clearance 10 mL/min: therapeutic urine levels
will not be achieved.
• Liver disease: Increase dosage.
• Elderly: None.
• Pediatric: Safety and efficacy have not been
established.
Food: Take on empty
stomach, 1 hour before or 2 hours after eating.
Pregnancy: Category
B.
Lactation: No
data available. Best to avoid.
Contraindications: Hypersensitivity
to penicillin or cephalosporins.
Editorial comments: This
was the first penicillin with activity against Pseudomonas aeruginosa.
It is not used frequently because other more effective drugs are available.
Oral carbenicillin is currently used to treat UTIs and prostatitis. The
parenteral form is no longer available in the United States. In general,
carbenicillin is not used in patients with kidney disease because of the
requirement for large doses, increased toxicity, and the availability of better
alternatives.
Cefaclor
Brand name: Ceclor.
Class of
drug: Cephalosporin, second generation.
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Comparable to cefuroxime axetil, but
less active against Hemophilus influenzae and Moraxella catarrhalis.
Indications/dosage/route: Oral
only. Capsules, oral suspension: all uses Ð Adults: 250 mg
q8h.
Ð Children: 20
mg/kg in divided doses q8h.
• More severe infections
Ð Adults: 500
mg q8h.
Ð Children: 40
mg/kg in divided doses q8h.
• Otitis media, pharyngitis
Ð Children: give
total daily dose q12h.
Extended-release tablets: all uses
• Acute exacerbations (bacterial), chronic
bronchitis, secondary bacterial infections of acute bronchitis
Ð Adults: 500
mg q12h, 10 days.
Ð Adults: 375
mg q12h, 10 days.
• Uncomplicated skin and skin structure
infections
Ð Adults: 375
mg q12h, 7–10 days.
Adjustment of dosage
• Kidney disease: creatinine clearance 50
mL/min: 250–500 mg q8h; creatinine clearance 10–50 mL/min: 125–500 mg q8h.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Take with
yogurt or buttermilk (4 oz/d) to maintain bacterial flora and reduce the
possibility of severe GI effects.
Pregnancy: Category
B.
Lactation: Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding.
Contraindications:
Hypersensitivity to other cephalosporins or related
antibiotics, eg, penicillin.
Warnings/precautions
• Use with caution in patients with the following
condition: kidney disease.
• It is recommended to continue therapy for at
least 2–3 days after symptoms are no longer present. For group A beta-hemolytic
streptococcal infections, therapy should be continued for 10 days.
• Before use, determine if patient had previous
hypersensitivity reaction to cephalosporins or penicillins. Incidence of
crosssensitivity to penicillins is 1–16%. Anegative response to penicillin does
not preclude allergic reaction to a cephalosporin.
Advice to patient: Allow
at least 1 hour between taking this medication and a bacteriostatic antibiotic,
eg, tetracycline or amphenicol.
Adverse
reactions
• Common:
none.
• Serious:
hypersensitivity, serum sickness, hepatitis, confusion, bone marrow
suppression, renal dysfunction, seizures.
Clinically important drug interactions:
Cefaclor increases effects/ toxicity of oral
anticoagulants.
Parameters to monitor
• CBC with differential and platelets, serum BUN
and creatinine, PT, PTT, and INR (if patient on anticoagulants).
• Serum glucose levels initially and periodically
during therapy.
• Temperature for sign of drug-induced persistent
fever.
• Signs and symptoms of antibiotic-induced
bacterial or fungal superinfection.
• Signs and symptoms of renal toxicity.
Editorial comments: Cefuroxime
is more effective than cefeclor for otitis media and pharyngitis due to
improved coverage for Hemophilus influenzae and Moraxella catarrhalis.
Cefadroxil
Brand name: Duricef.
Class of drug: Cephalosporin,
first generation.
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible organisms in vivo:
Similar to cephalexin.
Indications/dosage/route: Oral
only.
• Pharyngitis, tonsillitis
Ð Adults: 1 g/d
in single or two divided doses for 10 days.
Ð Children: 30
mg/kg/d in single or two divided doses.
• Skin and skin structure infections
Ð Adults: 1 g/d
in single or two divided doses.
Ð Children: 30
mg/kg/d in divided doses.
• UTIs
Ð Adults: 1–2
g/d in single or two divided doses for uncomplicated lower UTI (eg, cystitis). For
all other UTIs, the usual dose is 2 g/d in two divided doses.
Ð Children: 30
mg/kg/d in divided doses.
Adjustment of dosage
• Kidney disease: creatinine clearance <50
mL/min: no adjustment; creatinine clearance 25–50 mL/min: 12-hour intervals;
creatinine clearance 10–25 mL/min: 24-hour intervals; creatinine clearance 0–10
mL/min: 36-hour intervals.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Take with
yogurt or buttermilk (4 oz/d) to maintain bacterial flora and reduce the possibility
of severe GI effects.
Pregnancy: Category
B.
Lactation: Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding.
Contraindications: Hypersensitivity
to other cephalosporins or related antibiotics, eg, penicillin.
Editorial comments
• Oral
first-generation cephalosporins are used for Staphylococcusaureus and
streptococcal infection when penicillins are to be avoided, generally due to
rash. Common uses are cellulitis, other infections of the skin, osteomyelitis,
streptococcal pharyngitis. They should not be used for sinusitis, otitis media,
or lower respiratory infections because of poor coverage of Streptococcus
pneumoniae and especially Moraxella catarrhalis and Hemophilus
influenzae. They are not suitable coverage for bite wounds as they do not
cover Pasteurella multocida.
Cefamandole
Brand name: Mandol.
Class of drug: Cephalosporin,
second generation.
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Comparable to cefuroxime axetil, but
less active against Hemophilus influenzae and Moraxella catarrhalis.
Indications/dosage/route:
IV, IM (same dose both routes).
• Uncomplicated pneumonia, skin structure
infections
Ð Adults: 500
mg to
• Uncomplicated UTIs
Ð Adults: 500
mg q8h.
• Severe infections
Ð Adults:
• Life-threatening infections
Ð Adults:
• Most infections
Ð Children, infants:
50–100 mg/d, in equally divided doses
q4–8h. Maximum: 150 mg/kg.
Adjustment of dosage
• Kidney disease: creatinine clearance 50–80
mL/min: less severe infections 0.75–1.5 g q6h, life-threatening infections
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Take with
yogurt or buttermilk (4 oz/d) to maintain bacterial flora and reduce the
possibility of severe GI effects.
Pregnancy: Category
B.
Lactation: Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding.
Contraindications: Hypersensitivity
to other cephalosporins or related antibiotics, eg, penicillin.
Editorial comments
• Oral
first-generation cephalosporins are used for Staphylococcus aureus and
streptococcal infection when penicillins are to be avoided, generally due to
rash. Common uses are cellulitis, other infections of the skin, osteomyelitis,
streptococcal pharyngitis.
They should
not be used for sinusitis, otitis media, or lower respiratory infections
because of poor coverage of Strepto-coccus pneumoniae and especially Moraxella
catarrhalis and Hemophilus influenzae. They are not suitable
coverage for bite
wounds as
they do not cover Pasteurella multocida.
Cefazolin
Brand name: Ancef.
Class of drug: Cephalosporin,
first generation, parenteral.
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Very effective against staphylococci
and streptococci, potentially active against Streptococcus pneumoniae,
active against enterococci. Not effective against MRSA. Gram-negative
spectrum is limited to communityacquired Escherichia coli, Moraxella
catarrhalis, indolenegative Proteus mirabilis, and some Klebsiella
pneumoniae. Not useful against nosocomial gram-negative oral anaerobes.
Indications/dosage/route: IM,
IV (same dose both routes).
• Mild infections
Ð Adults:
250–500 mg q8h.
Ð Children 1
month: 25–50 mg/kg/d in three to four doses.
• Moderate to severe infections
Ð Adults: 0.5–1
g q6–8h.
• Acute, uncomplicated UTIs
Ð Adults:
• Endocarditis, septicemia (especially
staphylococci or streptococci when allergic to penicillin)
Ð Adults: 1–1.5
g q6h (rarely, up to 12 g/d).
• Preoperative prophylaxis (not for procedures
involving the colon, rectum, or appendix)
Ð Adults:
• Postoperative prophylaxis
Ð Adults: 0.5–1
g q6–8h for 24 hours.
Adjustment of dosage
Kidney disease: creatinine clearance 10
mL/min: 250–500 mg q18–24h; creatinine clearance 11–34 mL/min: 250–500 mg q12h;
creatinine clearance 35–54 mL/min: 500–1000 mg q8h.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Not
applicable.
Pregnancy: Category
B.
Lactation: Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding.
Contraindications:
Hypersensitivity to other cephalosporins or related
antibiotics, eg, penicillin.
Warnings/precautions
• Use with caution in patients with the following
condition:
kidney disease.
• It is recommended therapy be continued for at
least 2–3 days after symptoms are no longer present. For group A betahemolytic
streptococcal infections, therapy should be continued for 10 days.
• Before use, determine if patient had previous
hypersensitivity reaction to cephalosporins or penicillins. Incidence of
crosssensitivity to penicillins is 1–16%. Anegative response to penicillin does
not preclude allergic reaction to a cephalosporin.
Advice to patient:
Allow at least 1 hour between taking this
medication and a bacteriostatic antibiotic, eg, tetracycline or amphenicol.
Adverse
reactions
• Common:
None.
• Serious:
Hypersensitivity reactions, seizures, confusion, bone marrow suppression, liver
toxicity.
Clinically important drug
interactions
• Drug that increases effects/toxicity of
cefazolin: probenecid.
• Cefazolin increases effects/toxicity of
following: furosemide.
Parameters to monitor
• CBC with differential and platelets, serum BUN
and creatinine, liver enzymes.
• Temperature for sign of drug-induced persistent
fever.
• Signs and symptoms of antibiotic-induced
bacterial or fungal superinfection.
• Signs and symptoms of renal toxicity.
• Signs and symptoms of fluid retention,
particularly in patients receiving sodium salts of cephalosporins.
Editorial comments
• Cefazolin
is the prophylactic antibiotic of choice for surgery, foreign body
implantation, and clean or clean/contaminated procedures (cardiac surgery,
orthopedic device implantation, head and neck surgery with opening of the
oropharyngeal mucosa, gastric surgery, biliary surgery, hysterectomy, cesarean
section). It is not used for colon surgery because it does not cover Bacteroides
fragilis or when MRSA is a likely pathogen in postsurgical infections.
• Parenteral
cephalosporins do not give adequate CSF levels and, therefore, are not used in
CNS infections.
• Effective
against uncomplicated UTIs but other antibiotics are preferable.
• Not effective
in nosocomial infections caused by gram-negative organisms (eg, UTI).
Cefdinir
Brand name: Omnicef.
Class of drug: Cephalosporin,
third generation.
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Comparable to cefixime, but less
active against gram-negative organisms.
Indications/dosage/route: Oral
only.
• Community-acquired pneumonia, skin and skin
structure infections
Ð Adults,
children 13
years: 300 mg q12h for 10 days.
• Acute exacerbations of chronic bronchitis,
acute maxillary sinusitis, pharyngitis/tonsillitis
Ð Adults,
children 13
years: 300 mg q12h or 600 mg q24h for 10 days.
• Acute bacterial otitis media, acute maxillary
sinusitis, pharyngitis/tonsillitis
Ð Children 6–12
years: 7 mg/kg q12h or 14 mg/kg q24h for 10 days.
• Skin and skin structure infections
Ð Children 6–12
years: 7 mg/kg q12h for 10 days.
Adjustment of dosage
• Kidney disease: creatinine clearance 30
mL/min: 300 mg, once/daily.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Take with
yogurt or buttermilk (4 oz/d) to maintain bacterial flora and reduce the
possibility of severe GI effects.
Pregnancy: Category
B.
Lactation: Apparently
not present in breast milk. American Academy of Pediatrics considers
cephalosporins to be compatible with breastfeeding.
Contraindications:
Hypersensitivity to other cephalosporins or related
antibiotics, eg, penicillin.
Cefepime
Brand name: Maxipime.
Class of drug: Cephalosporin,
fourth generation (with antipseudomonal
activity and improved gram-positive activity).
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Compared with ceftazidime, cefepime
has much improved gram-positive coverage including
Staphylococcus
aureus (not MRSA), streptococci, Streptococcus pneumoniae;
comparable Pseudomonas aeruginosa activity; superior activity against
ESBL-producing Enterobacteriaceae.
Indications/dosage/route: IV
(should be used in severe infections only), IM.
• Mild to moderate uncomplicated or complicated
UTIs caused by Escherichia coli, Klebsiella pneumoniae, or Proteus
mirabilis (should be used in severe infections only) Ð Adults, children
12
years: IV or IM 0.5–1 g q12h for 7–10
days.
• Severe UTIs caused by E. coli or K.
pneumoniae
Ð Adults,
children 12
years: IV
• Moderate to severe pneunomia caused by S.
pneumoniae, P.
aeruginosa, K. pneumoniae,
or Enterobacter species
Ð Adults,
children 12
years: IV 1–2 g q12h for 10 days.
• Skin and skin structure infections caused by S.
aureus or
Streptococcus pyogenes
Ð Adults,
children 12
years: IV
• Febrile neutropenia (severe infections caused
by Pseudomonas
aeruginosa)
Ð IV
Adjustment of dosage
• Kidney disease: creatinine clearance 60
mL/min: 500 mg q12h; creatinine clearance 30–60 mL/min: 500 mg q24h; creatinine
clearance 11–29 mL/min: 500 mg q24h; creatinine clearance 10
mL/min: 250 mg q24h. At higher risk for CNS toxicity.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Not
applicable.
Pregnancy: Category
B.
Lactation: Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding.
Contraindications: Hypersensitivity
to other cephalosporins or related antibiotics, eg, penicillin.
Warnings/precautions
• It is recommended to continue therapy for at
least 2–3 days after symptoms are no longer present. For group A beta-hemolytic
streptococcal infections, therapy should be continued for 10 days.
• Before use, determine if patient had previous
hypersensitivity reaction to cephalosporins or penicillins. Incidence of
cross-sensitivity to penicillins is 1–5%. A negative response to penicillin
does not preclude allergic reaction to a cephalosporin.
Advice to patient: None.
Adverse
reactions
• Common:
Positive Coombs’ test.
• Serious:
encephalopathy, myoclonus, seizures, bone marrow suppression, hypersensitivity
reactions, hepatitis, hemolytic anemia.
Clinically important drug
interactions: Cefepime increases effects/toxicity of
aminoglycosides, loop diuretics.
Parameters to monitor
• CBC with differential and platelets, serum BUN
and creatinine, liver enzymes.
• Patient’s temperature for signs of drug-induced
persistent fever.
• Signs and symptoms of antibiotic-induced
bacterial or fungal superinfection.
• Signs and symptoms of renal toxicity.
• Signs and symptoms of fluid retention,
particularly in patients receiving sodium salts of cephalosporins.
Editorial comments
• Use of cefepime should be reserved to noscomial
infections especially when constant gram-negative infections are suspected or
proven (preferably).
• Also useful in neutropenic fever as monotherapy
and in mixed infection, such as nosocomial pneumonia and line infections.
• Like all cephalosporins, cefepime does not
cover enterococci and MRSA.
Cefixime
Brand name: Suprax.
Class of drug: Cephalosporin,
third generation.
Mechanism of
action: Binds to penicillin-binding proteins and
disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Highly effective against
betahemolytic
streptococci,
penicillin-susceptible Streptococcus pneumoniae, Hemophilus influenzae,
Moraxella catarrhalis, Neisseria gonorrhoeae, and many Enterobacteriaceae.
Poor activity against Staphylococcus aureus.
Indications/dosage/route: Oral
only.
• Uncomplicated UTIs, otitis media, pharyngitis,
tonsillitis, acute bronchitis, acute exacerbations of or chronic bronchitis Ð
Adults: 400 mg once daily or 200 mg q12h.
Ð Children: 8
mg/kg/d or 4 mg/kg q12h.
• Uncomplicated gonorrhea
Ð 400 mg/d.
Adjustment of dosage
• Kidney disease: creatinine clearance 60
mL/min: standard dosage; creatinine clearance 21–60 mL/min: 75% of standard
dosage; creatinine clearance 20 mL/min: 50% of standard dosage.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Take with
yogurt or buttermilk (4 oz/d) to maintain bacterial flora and reduce the
possibility of severe GI effects.
Pregnancy: Category
B.
Lactation: No
data available. American Academy of Pediatrics considers cephalosporins
compatible with breastfeeding.
Contraindications: Hypersensitivity
to other cephalosporins or related antibiotics, eg, penicillin.
Warnings/precautions
• Use with caution in patients with the following
condition: kidney disease.
• It is recommended to continue therapy for at
least 2–3 days after symptoms are no longer present. For group A beta-hemolytic
streptococcal infections, therapy should be continued for 10 days.
• Before use, determine if patient had previous
hypersensitivity reaction to cephalosporins or penicillins. Incidence of cross–
sensitivity to penicillins is 1–16%. A negative response to penicillin does not
preclude allergic reaction to a cephalosporin.
Advice to
patient: Allow at least 1 hour between taking this medication
and a bacteriostatic antibiotic, eg, tetracycline or amphenicol.
Adverse
reactions
• Common:
diarrhea, other GI symptoms.
• Serious:
pseudomembranous colitis, hypersensitivity reactions, hepatitis,
nephrotoxicity, bone marrow suppression, increased PT, seizures.
Clinically important drug
interactions: Cefixime increases effects/ toxicity of
carbamazepine.
Parameters to monitor
• CBC with differential and platelets, PT, serum
BUN and creatinine, liver enzymes.
• Temperature for signs of drug-induced
persistent fever.
• Signs and symptoms of antibiotic-induced bacterial
or fungal superinfection.
• Signs and symptoms of renal toxicity.
• Signs and symptoms of fluid retention,
particularly in patients receiving sodium salts of cephalosporins.
Editorial comments: Uses
of cefixime include single-dose therapy of gonorrhea, upper and lower
respiratory infections, UTIs, respiratory infections, COPD exacerbators.
Cefoperazone
Brand name: Cefobid.
Class of drug: Cephalosporin,
third generation.
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo: Has activity against 50%
of Pseudomonas aeruginosa strains but is less effective than cefotaxime
and ceftriaxone against gram-positive and gram-negative bacteria other than P.
aeruginosa.
Indications/dosage/route: IV,
IM.
• Respiratory
tract infections, peritonitis and other intraabdominal infections, bacterial
septicemia, skin and skin structure infections, pelvic inflammatory disease,
UTIs.
Ð Adults: 2–4
g/d in equally divided doses. Maximum: 12–16 g/d.
Adjustment of dosage
• Kidney disease: None.
• Liver disease: Advanced cirrhosis: 50% of usual
dose. Maximum: 4 g/d.
• Elderly: None.
• Pediatric: Safety and efficacy have not been
established.
Food: Not
applicable.
Pregnancy: Category
B.
Lactation: Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding.
Contraindications: Hypersensitivity
to other cephalosporins or related antibiotics, eg, penicillin.
Editorial comments
• Monitor PT for coagulation abnormalities.
• This drug significantly inhibits vitamin K
activation.
• Adisulfiram-like effect occurs when
cefoperazone is combined with alcohol.
Cefotaxime
Brand name: Claforan.
Class of drug: Cephalosporin,
third generation.
Mechanism of
action: Binds to penicillin-binding proteins and disrupts or
inhibits bacterial cell wall synthesis.
Susceptible
organisms in vivo
• Gram-positive: excellent against streptococci and Streptococcus
pneumoniae. Does not cover staphylococci and Enterococcus.
• Gram-negative: excellent against Neisseria
meningitidis, Neisseria gonorrhoeae, Escherichia coli, Proteus mirabilis, Klebsiella
pneumoniae, Morganella sp.
Indications/dosage/route: IV,
IM.
• Gonococcal urethritis
Ð Adults, males
and females: IM
• Rectal gonorrhea
Ð Adults,
female: IM
Ð Adults, male:
IM
• Disseminated gonococcal infection
ÐIV 500 mg, 4
times/d (CDC recommendation).
• Uncomplicated infections
ÐAdults: IM or
IV
• Moderate to severe infections
ÐAdults: IM or
IV 1–2 g q8h.
• Septicemia
ÐAdults: IV,
• Life-threatening infections
ÐAdults: IV
• Pediatric patients, uncomplicated infections
ÐInfants 0–1
wk: IV 50 mg/kg q12h.
ÐInfants 1–4
wks: IV 50 mg/kg q8h.
ÐChildren 1
month to 12 years: IV or IV 50–100 mg/kg/d in 4–6 divided doses.
Adjustment of dosage
• Kidney disease: creatinine clearance 20
mL/min: reduce dose by 50%.
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food:Not applicable.
Pregnancy: Category
B.
Lactation:Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding.
Contraindications: Hypersensitivity to other
cephalosporins or related antibiotics, eg, penicillin. Warnings/precautions
• It is recommended to continue therapy for at
least 2–3 days after symptoms are no longer present. For group A beta-hemolytic
streptococcal infections, therapy should be continued for 10 days.
• Before use, determine if patient had previous
hypersensitivity reaction to cephalosporins or penicillins. Incidence of
crosssensitivity to penicillins is 1–16%. Anegative response to penicillin does
not preclude allergic reaction to a cephalosporin.
Advice to patient: None.
Adverse
reactions
• Common:
None.
• Serious:
bone marrow suppression, hepatitis, nephrotoxicity.
Clinically important drug interactions
• Drug that
increases effects/toxicity of cefotaxime: probenecid.
• Cefotetan
increases effects/toxicity of following: aminoglycosides,
loop
diuretics.
Parameters to monitor
• CBC with differential and platelets, serum BUN
and creatinine,
liver enzymes.
• Temperature for signs of drug-induced
persistent fever.
• Signs and symptoms of antibiotic-induced
bacterial or fungal superinfection.
• Use with caution in patient with penicillin
allergy, kidney disease.
• Signs and symptoms of renal toxicity.
• Signs and symptoms of fluid retention,
particularly in patients receiving sodium salts of cephalosporins.
Editorial comments
• Cefotaxime is used similarly to ceftriaxone
except less useful for home antibiotic therapy because of the higher frequency
of dosing.
• Useful in liver transplant patients because
hepatobiliary toxicity is rare. ent of
dosage ing proteins and
Ceftriaxone
Brand name: Rocephin.
Class of drug: Cephalosporin, third generation.
Mechanism of
action: Binds to
penicillin-binding proteins and
disrupts or
inhibits bacterial cell wall synthesis.
Susceptible organisms in vivo
• Gram
positive: excellent against streptococci and Streptococcus
pneumoniae.
Does not cover staphylococci and Enterococcus.
• Gram
negative: excellent against Neisseria meningitidis,
Neisseria
gonorrhoeae, Escherichia coli, Proteus mirabilis,
Klebsiella
pneumoniae, Morganella.
Indications/dosage/route:
IV or IM.
• General infections
ÐAdults: IV,
IM 1–2 g/d q24h. Maximum: 4 g/d.
ÐChildren,
other than meningitis: IV, IM 50–75 mg/d in divided
doses. Maximum: 2 g/d.
• Meningitis
ÐAdults: IV,
IM 2 g/d q12h (or 1 g/d q12h).
ÐChildren: IV,
IM 100 mg/kg/d, once daily or 2 doses/d.
Maximum: 4 g/d. Usual duration of therapy: 7–14
days.
• Serious miscellaneous infections other than
meningitis including
skin and skin structure infections
ÐChildren: IV,
IM 50–75 mg/kg/d, divided doses q12h. Maximum:
2 g/d.
• Acute otitis media (bacterial)
ÐChildren: IM
50 mg/kg as single dose. Maximum:
ÐUncomplicated
gonorrhea
ÐAdults: IM
250 mg as single dose.
Adjustment of dosage: None.
Food:Not
applicable.
Pregnancy: Category B.
Lactation: Appears in breast milk. American Academy of Pediatrics
considers cephalosporins to be compatible with
breastfeeding.
Contraindications: Hypersensitivity
to other cephalosporins or
related antibiotics, eg, penicillin.
Warnings/precautions
• Use with caution in patients with the following
conditions:
kidney disease, penicillin allergy, elderly.
• Avoid in orthotopic liver transplant because of
the risk of biliary
sludge formation.
• It is recommended to continue therapy for at
least 2–3 days after symptoms are no longer present. For group A beta-hemolytic
streptococcal infections, therapy should be continued for 10 days.
• Before use, determine if patient had previous
hypersensitivity reaction to cephalosporins or penicillins. Incidence of
cross-sensitivity to penicillins is 1–16%. Anegative response to penicillin
does not preclude allergic reaction to a cephalosporin.
•Watch bilirubin levels if the use is prolonged.
Advice to patient: None.
Adverse
reactions
• Common:
None.
• Serious:
hepatitis, hypersensitivity reactions, pseudomembranous colitis, nephrotoxicity,
bone marrow suppression, hemolytic anemia.
Clinically important drug interactions
• Drug that
increases effects/toxicity of ceftriaxone: probenecid.
• Ceftriaxone
increases effects/toxicity of following drugs: aminoglycosides, loop diuretics.
Parameters to monitor
• CBC with differential and platelets, serum BUN
and creatinine, liver enzymes.
• Temperature for sign of drug-induced persistent
fever.
• Signs and symptoms of antibiotic-induced
bacterial or fungal superinfection.
• Signs and symptoms of renal toxicity.
• Signs and symptoms of fluid retention,
particularly in patients receiving sodium salts of cephalosporins.
Editorial comments
• Uses for ceftriaxone are as follows: Acute
bacterial meningitis: effective against Neisseria meningitidis, Hemophilus
influenzae, and, most importantly, Streptococcus pneumoniae even
when not susceptible to penicillin. It does not cover Listeria.
Community-acquired pneumonia: effective against
all important pathogens other than atypical organisms for which a macrolide or
a quinolone is added (Legionella, Mycloplasma, Chlamydia). Nosocomial infection, eg, pneumonia; not
recommended as monotherapy because of resistance from Pseudomonas aeruginosa
and ESBL-producing Enterobacteriaceae.
• Agreat advantage of ceftriaxone is once-a-day
use (other than in meningitis). It is therefore often used for home IV
infusion.
Cefuroxime
Brand names: Ceftin, Kefurox, Zinacef.
Class of drug: Cephalosporin, second generation.
Mechanism of
action: Binds to
penicillin-binding proteins and
disrupts or
inhibits bacterial cell wall synthesis.
Susceptible organisms in vivo: Staphylococcus
aureus, Streptococcus
pneumoniae,
beta-hemolytic streptococci, gram-negative
organisms
(especially Hemophilus influenzae, Moraxella
catarrhalis,
Escherichia coli, Proteus mirabilis, Klebsiella,
Citrobacter,
Morganella, Neisseria gonorrhoeae, Neisseria
meningitidis.
Indications/dosage/route: Oral, IV, IM.
Cefuroxime
axetil tablets
• Pharyngitis, tonsillitis
ÐAdults,
children 13
years: 250 mg q12h for 10 days.
ÐChildren,
under 3 years: 125 mg q12h for 10 days.
• Exacerbations of chronic bronchitis, secondary
bacterial infections of acute bronchitis, uncomplicated skin and skin structure
infections
Ð Adults,
children 13
years: 250 or 500 mg q12h for 10 days.
• Uncomplicated UTIs (other agents more cost
effective)
ÐAdults,
children 13
years: 125 or 250 mg q12h for 7–10 days.
ÐChildren 12
years: 125 mg b.i.d.
• Acute otitis media
ÐChildren: 250
mg b.i.d. for 10 days.
• Uncomplicated gonorrhea
ÐAdults,
children 13
years: 1000 mg as a single dose.
• Early Lyme disease (alternative treatment,
doxycycline is first
line)
Ð500 mg/d for
20 days.
Cefuroxime
suspension
• Pharyngitis, tonsillitis
ÐChildren 3
months–12 years: 20 mg/kg/d in 2 divided doses.
Maximum: 500-mg total dose/d, for 10 days.
• Acute otitis media, impetigo
ÐChildren 3
months–12 years: 30 mg/kg/d in 2 divided doses.
Maximum: 1000-mg total dose/d, for 10 days.
Cefuroxime
sodium
• UTI, uncomplicated pneumonia, disseminated
gonococcal,
skin and skin structure infections
ÐAdults: IV,
IM 750 mg q8h.
ÐChildren 3
months: IV, IM 50–100 mg/kg/d in divided
doses q6–8h (not to exceed adult dose of severe
infections).
• Severe complicated infections, bone and joint
infections
Ð Adults: IV,
IM
ÐChildren 3
months: IV 150 mg/kg/d in divided doses q8h (not to exceed adult dose).
• Life-threatening infections
ÐAdults: IV,
IM
• Bacterial meningitis
ÐAdults: IV,
IM 1–3 g q8h.
ÐChildren 3
months: Initial: IV 200–240 mg/kg in divided doses q6–8h, then 100 mg/kg/d.
• Gonorrhea (uncomplicated)
ÐAdults: IM
• Prophylaxis in surgery
ÐAdults: IV
• Open heart surgery, prophylaxis
ÐAdults: IV
Total:
Adjustment of dosage
• Kidney disease: Creatinine clearance 20
mL/min: 750 mg–
• Liver disease: None.
• Elderly: None.
• Pediatric: See above.
Food: Take with yogurt or buttermilk (4 oz/d) to maintain
bacterial flora and reduce the possibility of severe GI effects.
Pregnancy: Category B.
Lactation:Appears
in breast milk. American Academy of Pediatrics considers cephalosporins to be
compatible with breastfeeding. Contraindications:
Hypersensitivity to other cephalosporins or related antibiotics, eg,
penicillin.
Warnings/precautions
• Use with caution in patients with the following
condition: kidney disease.
• It is recommended to continue therapy for at
least 2–3 days after symptoms are no longer present. For group A beta-hemolytic
streptococcal infections, therapy should be continued for 10 days.
• Before use, determine if patient had previous
hypersensitivity reaction to cephalosporins or penicillins. Incidence of
crosssensitivity to penicillins is 1–16%. A negative response to penicillin
does not preclude allergic reaction to a cephalosporin. Advice to patient: Allow at least 1 hour between taking this
medication and a bacteriostatic antibiotic, eg, tetracycline or amphenicol.
Adverse reactions
• Common: None.
• Serious: hepatotoxicity, nephrotoxicity,
pseudomembranous colitis, hypersensitivity reactions, bone marrow suppression.
Clinically important
drug interactions
• Drug that increases effects/toxicity of
cefuroxime: probenecid.
• Cefuroxime increase effects/toxicity of
following drugs: aminoglycosides, loop diuretics.
Parameters to monitor
• CBC with differential and platelets, serum BUN
and creatinine, liver enzymes.
• Temperature for sign of drug-induced persistent
fever.
• Signs and symptoms of antibiotic-induced
bacterial or fungal superinfection.
• Signs and symptoms of renal toxicity.
• Signs and symptoms of fluid retention,
particularly in patients receiving sodium salts of cephalosporins.
Editorial comments
• Cefuroxime
axetil is the best oral second-generation cephalosporin for treatment of otitis
media, sinusitis, COPD exacerbation, and streptococcal pharyngitis.
• The oral
second-generation cephalosporins are also effective in skin, soft tissue, and
urinary tract infections, but other antibiotics are more cost effective.
• IV
cefuroxime is effective in meningitis caused by Hemophilus influenzae and
Neisseria meningitidis. In children, however, ceftriaxone is superior to
cefuroxime in the treatment of H. influenzae meningitis.
1. http://www.youtube.com/watch?v=RedO6rLNQ2o&feature=related
2. 2 http://www.youtube.com/watch?v=SqRVLIPof90&feature=related
3. http://www.youtube.com/watch?v=sMp-y8qx9D0&feature=related
4. http://www.youtube.com/watch?v=yG2PWCJnX2Q&feature=related
5. http://www.apchute.com/moa.htm