Chemotherapeutic Drugs

Dr. April Dawn R. Lucero

Chemotherapeutic Drugs

1. Principles of Antimicrobial Therapy

2. Beta-lactam Antibiotics and other Cell Wall Synthesis Inhibitors

3. Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogamins, &

Linezolid

4. Aminoglycosides

5. Sulfonamides, Trimethoprim, & Fluoroquinolones

6. Antimycobacterial Drugs
Principles of Antimicrobial Therapy
Selection of Antimicrobial Agents
Selection of the most appropriate antimicrobial agent requires knowledge of

1) the organism's identity

2) the organism's susceptibility to a particular agent

3) the site of the infection

4) patient factors

5) the safety of the agent

6) the cost of therapy

However, some critically ill patients require empiric therapy - that is, immediate
administration of drug(s) prior to bacterial identification and susceptibility
testing.
A. Identification of the infecting organism

• Characterization of the organism is central to selection of the proper drug.

• A rapid assessment of the nature of the pathogen can sometimes be made on the basis of
the Gram stain.

• However, it is generally necessary to culture the infective organism to arrive at a conclusive

diagnosis and to determine the susceptibility of the bacteria to antimicrobial agents.

• Thus, it is essential to obtain a sample culture of the organism PRIOR TO INITIATING

TREATMENT.

• identification of the infecting organism may require other laboratory techniques

B. Empiric therapy prior to identification of the
organism

• Ideally, the antimicrobial agent used to treat an infection is selected after the
organism has been identified and its drug susceptibility established.

• However, in the critically ill patient, such a delay could prove fatal, and immediate
empiric therapy is indicated.

• Therapy is initiated after specimens for laboratory analysis have been obtained but
before the results of the culture are available.

• Broad-spectrum therapy may be needed initially for serious infections when the
identity of the organism is unknown or the site makes a polymicrobial infection likely.
C. Determination of antimicrobial susceptibility of
infective organisms

• After a pathogen is cultured, its susceptibility to specific antibiotics serves as a

guide in choosing antimicrobial therapy.

• Some pathogens, such as Streptococcus pyogenes and Neisseria meningitidis,

usually have predictable susceptibility patterns to certain antibiotics.

• In contrast, most gram-negative bacilli, enterococci, and staphylococcal species

often show unpredictable susceptibility patterns to various antibiotics and
require susceptibility testing to determine appropriate antimicrobial therapy.
D. Effect of the site of infection on therapy

• Adequate levels of an antibiotic must reach the site of infection for the invading
microorganisms to be effectively eradicated.

• Capillaries with varying degrees of permeability carry drugs to the body tissues.

• However, natural barriers to drug delivery are created by the structures of the
capillaries of some tissues, such as the prostate, the vitreous body of the eye, and
the central nervous system (CNS). Of particular significance are the capillaries in
the brain, which help to create and maintain the blood-brain barrier.
D. Effect of the site of infection on therapy

The penetration and concentration of an antibacterial agent in the CSF is particularly

influenced by the following:

• Lipid solubility of the drug

 For example, lipid-soluble drugs, such as the quinolones and metronidazole, have
significant penetration into the CNS.

 Penicillin is ionized at physiologic pH and have low solubility in lipids. They therefore have
limited penetration through the intact blood-brain barrier under normal circumstances. In
infections such as meningitis, in which the brain becomes inflamed, the barrier does not
function effectively, and local permeability is increased.
D. Effect of the site of infection on therapy

• Molecular weight of the drug

 A compound with a low molecular weight has an enhanced ability to cross the
blood-brain barrier, whereas compounds with a high molecular weight (for example,
vancomycin) penetrate poorly, even in the presence of meningeal inflammation.

• Protein binding of the drug

 High degree of protein binding of a drug in the serum restricts its entry into the CSF.
Therefore, the amount of free (unbound) drug in serum, rather than the total amount
of drug present, is important for CSF penetration.
E. Patient factors

Immune system

• Elimination of infecting organisms from the body depends on an intact immune

system.

• Alcoholism, diabetes, infection with the human immunodeficiency virus, malnutrition,

or advanced age can affect a patient's immunocompetence, as can therapy with
immunosuppressive drugs.

• Higher-than-usual doses of bactericidal agents or longer courses of treatment are

required to eliminate infective organisms in these individuals.
E. Patient factors

Renal dysfunction

• Poor kidney function (10 percent or less of normal) causes accumulation in

the body of antibiotics that ordinarily are eliminated by this route.

• Elderly patients are particularly vulnerable to accumulation of drugs

eliminated by the kidneys. Antibiotics that undergo extensive metabolism or
are excreted via the biliary route may be favored in such patients
E. Patient factors

Hepatic Dysfunction

• Antibiotics that are concentrated or eliminated by the liver (for example,

erythromycin and tetracycline) are contraindicated in treating patients with liver
disease.

Poor Perfusion

• Decreased circulation to an anatomic area, such as the lower limbs of a diabetic,

reduces the amount of antibiotic that reaches that area, making infections
notoriously difficult to treat.
E. Patient factors

Age

• Renal or hepatic elimination processes are often poorly developed in newborns, making
neonates particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides.

• Young children should not be treated with tetracyclines, which affect bone growth.

Pregnancy

• All antibiotics cross the placenta. Adverse effects to the fetus are rare, except the for
tooth dysplasia and inhibition of bone growth encountered with the tetracyclines.
E. Patient factors

Pregnancy

• Aminoglycosides should be avoided in pregnancy because of their ototoxic

effect on the fetus.
E. Patient factors

Lactation

• Drugs administered to a lactating mother may enter the nursing infant via the
breast milk. Although the concentration of an antibiotic in breast milk is
usually low, the total dose to the infant may be enough to cause problems.
F. Safety of the agent

Many of the antibiotics, such as the penicillins, are among the least toxic of all
drugs, because they interfere with a site unique to the growth of
microorganisms.

Other antimicrobial agents (for example, chloramphenicol) are less

microorganism specific and are reserved for life-threatening infections because
of the drug's potential for serious toxicity to the patient.
G. Cost of therapy

• Often, several drugs may show similar efficacy in treating an infection but
vary widely in cost.
Chemotherapeutic Spectra
A. Narrow-spectrum antibiotics

• Chemotherapeutic agents acting only on a single or a limited group of

microorganisms are said to have a narrow spectrum.

• For example, isoniazid is active only against mycobacteria

B. Extended-spectrum antibiotics

• Extended spectrum is the term applied to antibiotics that are effective against
gram-positive organisms and also against a significant number of gram-
negative bacteria.

• For example, ampicillin is considered to have an extended spectrum,

because it acts against gram-positive and some gram-negative bacteria.
C. Broad-spectrum antibiotics

• Drugs such as tetracycline and chloramphenicol affect a wide variety of

microbial species and are referred to as broad-spectrum antibiotics

• Administration of broad-spectrum antibiotics can drastically alter the nature of

the normal bacterial flora and precipitate a superinfection of an organism
such as Candida albicans, the growth of which is normally kept in check by
the presence of other microorganisms.
Beta-Lactam Antibiotics & Other Cell Wall
Synthesis Inhibitors
High-Yield Terms

Bactericidal

• An antimicrobial drug that can eradicate an infection in the absence of host

defense mechanisms; kills bacteria

Bacteriostatic

• An antimicrobial drug that inhibits antimicrobial growth but requires host

defense mechanisms to eradicate the infection; does not kill bacteria
High-Yield Terms

Beta-lactam antibiotics

• Drugs with structures containing a beta-lactam ring: includes the penicillins,

cephalosporins and carbapenems. This ring must be intact for antimicrobial
action

Beta-lactamases

• Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the

beta-lactam ring of certain penicillins and cephalosporins
High-Yield Terms

Beta-lactam inhibitors

• Potent inhibitors of some bacterial beta-lactamases used in combinations to

protect hydrolyzable penicillins from inactivation

Minimal inhibitory concentration (MIC)

• Lowest concentration of antimicrobial drug capable of inhibiting growth of an

organism in a defined growth medium
High-Yield Terms

Penicillin-binding proteins (PBPs)

• Bacterial cytoplasmic membrane proteins that act as the initial receptors for
penicillins and other beta-lactam antibiotics

Peptidoglycan

• Chains of polysaccharides and polypeptides that are cross-linked to form the

bacterial cell wall
High-Yield Terms

Selective toxicity

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

Transpeptidases

• Bacterial enzymes involved in the cross-linking of linear peptidoglycan

chains, the final step in cell wall synthesis
• Penicillins and cephalosporins are the major antibiotics that inhibit bacterial cell
wall synthesis.

• They are called beta-lactams because of the unusual 4-member ring that is
common to all their members.

• The beta-lactams include some of the most effective, widely used, and well-
tolerated agents available for the treatment of microbial infections.

• Vancomycin, fosfomycin, and bacitracin also inhibit cell wall synthesis but are not
nearly as important as the beta-lactam drugs.
PENICILLINS
A. Classification

• All penicillins are derivatives of 6-aminopenicillanic acid and contain a beta-

lactam ring structure that is essential for antibacterial activity.
B. Pharmacokinetics

• Penicillins vary in their resistance to gastric acid and therefore vary in their
oral bioavailability.

• Parenteral formulations of ampicillin, piperacillin, and ticarcillin are available

for injection.

• Penicillins are polar compounds and are not metabolized extensively.

• They are usually excreted unchanged in the urine.

 B. Pharmacokinetics

• The plasma half-lives of most penicillins vary

from 30 min to 1 h.

• Procaine and benzathine forms of penicillin G

are administered intramuscularly and have
long plasma half-lives because the active drug
is released very slowly into the bloodstream.

• Most penicillins cross the blood-brain barrier

only when the meninges are inflamed.
C. Mechanisms of Action and Resistance

• Beta-lactam antibiotics are bactericidal drugs.

• They act to inhibit cell wall synthesis by the following steps:

(1) Binding of the drug to specific enzymes (penicillin-binding proteins

[PBPs]) located in the bacterial cytoplasmic membrane

(2) Inhibition of the transpeptidation reaction that cross-links the linear

peptidoglycan chain constituents of the cell wall

(3) Activation of autolytic enzymes that cause lesions in the bacterial cell wall
C. Mechanisms of Action and Resistance

• Enzymatic hydrolysis of the beta-lactam ring results in loss of antibacterial

activity.

• The formation of beta-lactamases (penicillinases) by most staphylococci and

many gram-negative organisms is a major mechanism of bacterial resistance.

• Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam,

tazobactam) are often used in combination with penicillins to prevent their
inactivation.
D. Clinical Uses

1. Narrow-spectrum penicillinase-susceptible agents

• Penicillin G is the prototype of a subclass of penicillins that have a limited

spectrum of antibacterial activity and are susceptible to beta-lactamases.

• Clinical uses include therapy of infections caused by common streptococci,

meningococci, gram-positive bacilli, and spirochetes.

• Many strains of pneumococci are now resistant to penicillins (penicillin-

resistant Streptococcus pneumoniae [PRSP] strains).
D. Clinical Uses

1. Narrow-spectrum penicillinase-susceptible agents

• Most strains of Staphylococcus aureus and a significant number of strains of

Neisseria gonorrhoeae are resistant via production of beta-lactamases.

• Penicillin G remains the drug of choice for syphilis.

• Penicillin V is an oral drug used mainly in oropharyngeal infections.

• Penicillin V is more acid-stable than penicillin G. It is often employed orally in the

treatment of infections, where it is effective against some anaerobic organisms.
D. Clinical Uses

2. Very-narrow-spectrum penicillinase-resistant drugs

• This subclass of penicillins includes methicillin (the prototype, but rarely used
owing to its nephrotoxic potential), nafcillin, and oxacillin.

• Their primary use is in the treatment of known or suspected staphylococcal

infections.

• Methicillin-resistant (MR) staphylococci (S aureus [MRSA] and S epidermidis

[MRSE]) are resistant to all penicillins and are often resistant to multiple
antimicrobial drugs.
D. Clinical Uses

Wider-spectrum penicillinase-susceptible drugs

a. Ampicillin and amoxicillin

• These drugs make up a penicillin subgroup that has a wider spectrum of

antibacterial activity than penicillin G but remains susceptible to
penicillinases.

• Ampicillin is the drug of choice for the gram-positive bacillus Listeria

monocytogenes.
• These agents are also widely
used in the treatment of
respiratory infections
• Amoxicillin is employed
prophylactically by dentists for
patients with abnormal heart
valves who are to undergo
extensive oral surgery.
D. Clinical Uses

Wider-spectrum penicillinase-susceptible drugs

a. Ampicillin and amoxicillin

• Resistance to these antibiotics is now a major clinical problem because of

inactivation by plasmid-mediated penicillinase.

• Formulation with a beta-lactamase inhibitor, such as clavulanic acid or

sulbactam, protects amoxicillin or ampicillin, respectively, from enzymatic
hydrolysis and extends their antimicrobial spectrum.
 D. Clinical Uses

Wider-spectrum penicillinase-susceptible drugs

b. Piperacillin and ticarcillin

• Are called antipseudomonal penicillins because of their activity against P. aeruginosa.

• Piperacillin is the most potent of these antibiotics.

• They are effective against many gram-negative bacilli, but not against klebsiella, because of its
constitutive penicillinase.

• Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam, respectively, extends

the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms.
 E. Toxicity

1. Allergy

• This is the most important adverse effect of the penicillins.

• The major antigenic determinant of penicillin hypersensitivity is its metabolite, penicilloic

acid, which reacts with proteins and serves as a hapten to cause an immune reaction.

• Approximately five percent of patients have some kind of reaction, ranging from

maculopapular rash to angioedema (marked swelling of the lips, tongue, and periorbital

area) and anaphylaxis.

 E. Toxicity

1. Allergy

• Methicillin causes interstitial nephritis, and nafcillin is associated with neutropenia.

• Complete cross-allergenicity between different penicillins should be assumed.

• Ampicillin frequently causes maculopapular skin rash that does not appear to be an

allergic reaction.
E. Toxicity

2. Gastrointestinal disturbances

• Nausea and diarrhea may occur with oral penicillins, especially with
ampicillin.

• Gastrointestinal upsets may be caused by direct irritation or by overgrowth of

gram-positive organisms or yeasts.

• Ampicillin has been implicated in pseudomembranous colitis.

CEPHALOSPORINS
A. Classification

• The cephalosporins are derivatives of 7-aminocephalosporanic acid and

contain the beta-lactam ring structure.

• Many members of this group are in clinical use.

• They vary in their antibacterial activity and are designated first-, second-,
third-, or fourth-generation drugs according to the order of their introduction
into clinical use.
B. Pharmacokinetics

• Several cephalosporins are available for oral use, but most are administered
parenterally.

• Cephalosporins with side chains may undergo hepatic metabolism, but the major
elimination mechanism for drugs in this class is renal excretion via active tubular
secretion.

• Cefoperazone and ceftriaxone are excreted mainly in the bile.

• Most first- and second-generation cephalosporins DO NOT ENTER the

cerebrospinal fluid even when the meninges are inflamed.
B. Pharmacokinetics

• Adequate therapeutic levels in the CSF, regardless of inflammation, are achieved only with the
third-generation cephalosporins.

• For example, ceftriaxone or cefotaxime are effective in the treatment of neonatal and
childhood meningitis caused by H. influenzae.

• Cefazolin finds application as a single prophylaxis dose prior to surgery because of its 1.8-
hour half-life and its activity against penicillinase-producing S. aureus. However, additional
intraoperative cefazolin doses may be required if the surgical procedure lasts longer than 3
hours. Cefazolin is effective for most surgical procedures, including orthopedic surgery
because of its ability to penetrate bone.

• All cephalosporins cross the placenta.

C. Mechanisms of Action and Resistance

• Cephalosporins bind to PBPs on

bacterial cell membranes to inhibit
bacterial cell wall synthesis by
mechanisms similar to those of the
penicillins.

• Cephalosporins are bactericidal against

susceptible organisms.
C. Mechanisms of Action and Resistance

• Structural differences from penicillins render cephalosporins less susceptible

to penicillinases produced by staphylococci, but many bacteria are resistant
through the production of other beta-lactamases that can inactivate
cephalosporins.

• Resistance can also result from decreases in membrane permeability to

cephalosporins and from changes in PBPs.

• Methicillin-resistant staphylococci are also resistant to cephalosporins.

D. Clinical Uses

1. First-generation drugs

• Cefazolin (parenteral) and cephalexin (oral) are examples of this subgroup.

• Active against gram-positive cocci, including staphylococci and common

streptococci.

• They are resistant to the staphylococcal penicillinase and also have activity
against Proteus mirabilis, E. coli, and Klebsiella pneumoniae (the acronym
PEcK has been suggested).
D. Clinical Uses

2. Second-generation drugs

• The second-generation cephalosporins display greater activity against three

additional gram-negative organisms: H. influenzae, Enterobacter
aerogenes, and some Neisseria species, whereas activity against gram-
positive organisms is weaker (the acronym HENPEcK has been suggested
with the second generation’s increased coverage).
D. Clinical Uses

3. Third-generation drugs

• Although inferior to first-generation cephalosporins in regard to their activity against

gram-positive cocci, the third-generation cephalosporins have enhanced activity
against gram-negative bacilli, including those mentioned above, as well as most other
enteric organisms plus Serratia marcescens (HENPEcK + enteric + S. marcescens)

• Ceftriaxone or cefotaxime have become agents of choice in the treatment of

meningitis.

• Ceftazidime has activity against P. aeruginosa.

D. Clinical Uses

• Drugs in this subclass should usually be reserved for treatment of serious

infections.

• Ceftriaxone (parenteral) and cefixime (oral), currently drugs of choice in

gonorrhea, are exceptions.

• Likewise, in acute otitis media, a single injection of ceftriaxone is usually as

effective as a 10-day course of treatment with amoxicillin.
D. Clinical Uses

4. Fourth-generation drugs

• Cefepime is classified as a fourth-generation cephalosporin and must be

administered parenterally.

• Cefepime combines the gram-positive activity of first-generation agents with

the wider gram-negative spectrum of third-generation cephalosporins.
E. Toxicity

1. Allergy

• Patients who have had an anaphylactic response to penicillins should not

receive cephalosporins.

• The cephalosporins should be avoided or used with caution in individuals who

are allergic to penicillins (about 5-15 percent show cross-sensitivity).

• In contrast, the incidence of allergic reactions to cephalosporins is one to two

percent in patients without a history of allergy to penicillins.
E. Toxicity

2. Other adverse effects

• Cephalosporins may cause pain at intramuscular injection sites and phlebitis

after intravenous administration.

• They may increase the nephrotoxicity of aminoglycosides when the two are
administered together.
OTHER BETA-LACTAM
DRUGS
A. Monobactams

• The monobactams, which also disrupt bacterial cell wall synthesis, are unique,
because the beta-lactam ring is not fused to another ring.

• Aztreonam, which is the only commercially available monobactam, has

antimicrobial activity directed primarily against the enterobacteriaceae, but it
also acts against aerobic gram-negative rods, including P. aeruginosa.

• It LACKS activity against gram-positive organisms and anaerobes.

• This narrow antimicrobial spectrum precludes its use alone in empiric therapy.
 A. Monobactams

• Aztreonam is resistant to the action of beta-lactamases.

• It is administered either IV or IM and is excreted in the urine. It can accumulate in patients with renal
failure.

• Aztreonam is relatively nontoxic, but it may cause phlebitis, skin rash, and occasionally, abnormal
liver function tests.

• This drug has a low immunogenic potential, and it shows little cross-reactivity with antibodies
induced by other beta-lactams.

• Thus, this drug may offer a safe alternative for treating patients who are allergic to penicillins and/or
cephalosporins.
B. Carbapenems

• Carbapenems are synthetic beta-lactam antibiotics that differ in structure

from the penicillins in that the sulfur atom of the thiazolidine ring has been
externalized and replaced by a carbon atom.

• Imipenem, meropenem and ertapenem are the only drugs of this group
currently available.

• Imipenem is compounded with cilastatin to protect it from metabolism by

renal dehydropeptidase.
B. Carbapenems

Antibacterial spectrum:

• Imipenem/cilastatin and meropenem are the BROADEST-SPECTRUM beta-lactam

antibiotic preparations currently available.

• Imipenem resists hydrolysis by most beta-lactamases, but not the metallo-beta-

lactamases.

• The drug plays a role in empiric therapy because it is active against penicillinase-

producing gram-positive and gram-negative organisms, anaerobes, and P. aeruginosa.

B. Carbapenems

Antibacterial spectrum:

• Meropenem has antibacterial activity similar to that of imipenem.

• Ertapenem is not an alternative for P. aeruginosa coverage, because most

strains exhibit resistance.
B. Carbapenems

Pharmacokinetics:

• Imipenem and meropenem are administered IV and penetrate well into body tissues and
fluids, including the CSF when the meninges are inflamed.

• They are excreted by glomerular filtration.

• Imipenem undergoes cleavage by a dehydropeptidase found in the brush border of the

proximal renal tubule. This enzyme forms an inactive metabolite that is potentially
nephrotoxic.

• Compounding the imipenem with cilastatin protects the parent drug and, thus, prevents the
formation of the toxic metabolite.
B. Carbapenems

Pharmacokinetics:

• This allows the drug to be used in the treatment of urinary tract infections.

• Meropenem does not undergo metabolism.

• Ertapenem can be administered via IV or IM injection.

• Note: Doses of these agents must be adjusted in patients with renal

insufficiency.
B. Carbapenems

Adverse effects:

• Imipenem/cilastatin can cause nausea, vomiting, and diarrhea.

• High levels of imipenem may provoke SEIZURES, but meropenem is less

likely to do so.
C. Beta-Lactamase Inhibitors

• Contain a beta-lactam ring but, by themselves, do not have significant

antibacterial activity. Instead, they bind to and inactivate beta-lactamases,
thereby protecting the antibiotics that are normally substrates for these
enzymes.

• Clavulanic acid, sulbactam, and tazobactam are used in fixed combinations

with certain hydrolyzable penicillins.

• They are most active against plasmid-encoded beta-lactamases such as those

produced by gonococci, streptococci, E coli, and H influenzae.
OTHER CELL WALL OR
MEMBRANE-ACTIVE AGENTS
A. Vancomycin

• Vancomycin is a tricyclic glycopeptide that has become increasingly

important because of its effectiveness against multiple drug-resistant
organisms, such as MRSA and enterococci.

• The medical community is presently concerned with emergence of

vancomycin resistance in these organisms.
A. Vancomycin

A. Mode of action

• Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as

peptidoglycan polymerization by binding to the D-Ala-D-Ala side chain of the
precursor pentapeptide.

• This prevents the transglycosylation step in peptidoglycan polymerization,

thus weakening the cell wall and damaging the underlying cell membrane.
A. Vancomycin

B. Antibacterial spectrum

• Vancomycin is effective primarily against gram-positive organisms.

• It has been lifesaving in the treatment of MRSA and methicillin-resistant Staphylococcus

epidermidis (MRSE) infections as well as enterococcal infections.

• With the emergence of resistant strains, it is important to curtail the increase in

vancomycin-resistant bacteria by restricting the use of vancomycin to the treatment of
serious infections caused by beta-lactam resistant, gram-positive microorganisms or for
patients with gram-positive infections who have a serious allergy to the beta-lactams.
A. Vancomycin

• Oral vancomycin is limited to treatment for potentially life-threatening,

antibiotic-associated colitis due to C. difficile or staphylococci.

• Vancomycin is used in individuals with prosthetic heart valves and in patients

undergoing implantation with prosthetic devices.

• Vancomycin acts synergistically with the aminoglycosides, and this

combination can be used in the treatment of enterococcal endocarditis.
A. Vancomycin

C. Pharmacokinetics

• Slow IV infusion (60-90 minutes) is employed for treatment of systemic

infections or for prophylaxis. Because vancomycin is not absorbed after oral
administration, this route is employed only for the treatment of antibiotic-induced
colitis due to C. difficile when metronidazole has proven to be ineffective.

• Inflammation allows penetration into the meninges. However, it is often

necessary to combine vancomycin with other antibiotics, such as ceftriaxone for
synergistic effects when treating menigitis.
A. Vancomycin

C. Pharmacokinetics

• Metabolism of the drug is minimal, and 90 to 100 percent is excreted by

glomerular filtration.

• Note: Dosage must be adjusted in renal failure, because the drug will
accumulate. The normal half-life of vancomycin is 6 to 10 hours, compared to
over 200 hours in end-stage renal disease.
 A. Vancomycin

D. Adverse effects

• Side effects are a serious problem with vancomycin and include fever, chills, and/or
phlebitis at the infusion site.

• Flushing (red man syndrome) and shock results from histamine release associated with a
rapid infusion.

 If an infusion-related reaction occurs, slow the infusion rate to administer vancomycin over 2
hours, increase the dilution volume, or pretreat with an antihistamine 1 hour prior to administration.

 Additionally, reactions can be treated with antihistamines and steroids.

A. Vancomycin

D. Adverse effects

• Dose-related hearing loss has occurred in patients with renal failure who
accumulate the drug.

• Ototoxicity and nephrotoxicity are more common when vancomycin is

administered with another drug (for example, an aminoglycoside) that can
also produce these effects.
B. Bacitracin

• Bacitracin is a peptide antibiotic that interferes with a late stage in cell wall
synthesis in gram-positive organisms.

• Because of its marked nephrotoxicity, the drug is limited to topical use.

C. Cycloserine

• Cycloserine is an antimetabolite that blocks the incorporation of D-Ala into

the pentapeptide side chain of the peptidoglycan.

• Because of its potential neurotoxicity (tremors, seizures, psychosis),

cycloserine is only used to treat TUBERCULOSIS caused by organisms
resistant to first-line antituberculous drugs.
D. Daptomycin

• Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin

but active against VANCOMYCIN-RESISTANT STRAINS of enterococci and
staphylococci.

• The drug is eliminated via the kidney.

• Creatine phosphokinase should be monitored since daptomycin may cause

myopathy.
Questions
The primary mechanism of antibacterial action of the
penicillins involves inhibition of

(A) Beta-lactamases

(B) N-acetylmuramic acid synthesis

(C) Peptidoglycan cross-linking

(D) Synthesis of cell membranes

(E) Transglycosylation
Answer = C

• Penicillins (and cephalosporins) bind to PBPs acting at the transpeptidation

stage of cell wall synthesis (the final step) to inhibit peptidoglycan cross-linking.

• The beta-lactam antibiotics also activate autolysins, which break down the
bacterial cell wall.

• Synthesis of N-acetylmuramic acid is inhibited by fosfomycin.

• Vancomycin inhibits transglycolase preventing elongation of peptidoglycan

chains.
Questions 2 & 3

A 52-year-old man (weight 70

kg) is brought to the hospital
emergency department in a
confused and delirious state.
He has had an elevated
temperature for more than 24 h,
during which time he had
complained of a severe
headache and had suffered from
nausea and vomiting.
Lumbar puncture reveals an
elevated opening pressure, and
cerebrospinal fluid findings
include elevated protein,
decreased glucose, and
increased neutrophils.
Question 2

Gram stain of a smear of

cerebrospinal fluid reveals
gram-positive diplococci, and a
preliminary diagnosis is made
of purulent meningitis.

The microbiology report informs

you that for approximately 15%
of S pneumoniae isolates in the
community, the minimal
inhibitory concentration for
penicillin G is 20 mcg/mL.
The most appropriate treatment of gonorrhea in this
patient is

(A) Ampicillin orally for 7 d

(B) Ceftriaxone intramuscularly as a single dose

(C) Procaine penicillin G intramuscularly as a single dose plus oral probenecid

(D) Tetracycline orally for 5 d

(E) Vancomycin intramuscularly as a single dose

Answer = C

• Pneumococcal isolates with a minimal inhibitory concentration for penicillin G of greater than
2 mcg/mL are highly resistant.

• Such strains are not killed by the concentrations of penicillin G or ampicillin that can be
achieved in the cerebrospinal fluid.

• Nafcillin has minimal activity against penicillin-resistant pneumococci, and ticarcillin is used
mainly for infections caused by gram-negative rods.

• Cefotaxime and ceftriaxone are the most active cephalosporins against penicillin-resistant
pneumococci, and the addition of vancomycin is recommended in the case of highly resistant
strains.