Antimicrobial drugs: Sulfonamides, -lactam

antibiotics, Tetracyclines, Amphenicols,

Aminoglycosides
Tutorial

Aleksandar Jovanović
Professor of Clinical Pharmacology and Therapeutics
Learning objectives

This tutorial cover LOBs 1-5 (parts)

 Q1
A 67-year-old African-American man comes to the physician because of
fever, increased frequency of urination, and perineal pain. He has a history
of type 2 diabetes and an X-linked recessive disorder, which causes red cell
hemolysis. Digital rectal examination shows a boggy and tender prostate.
Cultures of urine grow E. coli. The physician then prescribes an
antimicrobial agent used in the treatment of this condition. Which of the
following would most likely be contraindicated for use in this patient?
 Options

A. Ampicillin
B. Cefaclor
C. Nitrofurantoin
D. Sulfamethoxazole/trimethoprim
E. Tetracycline
 Explanation/Solution (I)
• Ampicillin (choice A) is a broad-spectrum penicillin antibiotic commonly used to treat
infections of the genitourinary, respiratory, and gastrointestinal tracts, and skin and soft-
tissue infections, as well as several other types of bacterial infections.
• Cefaclor (choice B) is a second-generation cephalosporin indicated for a variety of
bacterial infections, including those of the respiratory and gastrointestinal tracts.
• Nitrofurantoin (choice C) is an antibacterial commonly used in the treatment and
prophylaxis of uncomplicated cystitis. Although this medication is contraindicated for use
in patients with G6PD deficiency, it is not used in the treatment of acute bacterial
prostatitis, and is an incorrect answer choice.
 Explanation/Solution (II)
• Tetracycline (choice E) is most commonly used in the treatment of acne vulgaris
and gonococcal infections.
• The correct answer is D. This patient is presenting with signs and symptoms
suggestive of acute bacterial prostatitis, which is associated with fever, chills,
perineal/prostatic pain, dysuria, obstructive urinary tract symptoms, and potentially
lower back or abdominal pain. This condition is generally treated with a 14 to 28
day course of antibiotics that includes sulfamethoxazole/trimethoprim (SMX-
TMP) or a fluoroquinolone (e.g., ciprofloxacin, levofloxacin).
 Explanation/Solution (III)
• Glucose-6-phosphate dehydrogenase (G6PD) is part of the hexose monophosphate
(HMP) shunt (pentose phosphate pathway) and catalyzes the oxidation of glucose-6-
phosphate and the reduction of nicotinamide adenine dinucleotide phosphate
(NADP+) to NADPH. NAPDH maintains glutathione in its reduced form, which
acts as a scavenger for dangerous reactive oxygen species (ROS). Because red blood
cells (RBCs) contain a large amount of oxygen, they are prone to spontaneously
generate ROS that damage protein and lipid in the cell. In the presence of ROS,
hemoglobin may precipitate (Heinz bodies) and membrane lipids may undergo
peroxidation, weakening the membrane and causing hemolysis.
 Explanation/Solution (IV)
Patients with glucose-6-phosphate dehydrogenase (G6PD or G6PDH)
deficiency (an X-linked recessive disorder affecting 10-15% of African-American
males) may develop hemolytic anemia as a result of oxidative stress (due
insufficient NADPH to reduce glutathione) in red blood cells (RBCs), generated
either by infections or exposure to
certain drugs (e.g., sulfamethoxazole/trimethoprim, nitrofurantoin,
fluoroquinolones, isoniazid, dapsone, primaquine, and quinine) or ingesting fava
beans.
 Q2
A 57-year-old man is admitted to the intensive care unit because of
acute respiratory distress syndrome. He is intubated and sedated.
Three days later, a sputum culture grows Pseudomonas aeruginosa.
Antibiotic therapy with ceftazidime and gentamicin is begun. If the
half-life of gentamicin is 3 hours in this patient, what percentage of
the initial dose of the drug will most likely remain in his body 6
hours later?
 Options

A. 12.5
B. 25
C. 37.5
D. 50
E. 75
 Explanation/Solution

For any given first-order elimination process, 50% of the initial amount of
drug is eliminated at the end of the first half-life, 50% of the remaining
amount of drug in the body is eliminated at the end of the second half-life,
and so on. Therefore, after 3 hours, 50% of the gentamicin will be remaining
in the body. After another 3 hours (6 hours total), 50% of the remaining
50% will be eliminated. In other words, after 6 hours, 75% of the gentamicin
will be eliminated, and 25% of the initial dose will remain. The correct
answer is B.
 Q3
A 14-day-old infant is brought to the physician by his parents
because of decreased alertness and poor feeding. Physical
examination shows jaundice and hypotonia. Laboratory studies
show an unconjugated bilirubin level of 33 mg/dL. Which of the
following drugs taken by the mother during the third trimester is
most likely responsible for this patient's condition?
 Options

A. Acetaminophen
B. Azithromycin
C. Chloramphenicol
D. Diethylstilbestrol
E. Trimethoprim-sulfamethoxazole
 Explanation/Solution (I)

Jaundice is a common condition seen in newborns that requires medical

attention. As a result of an accumulation of unconjugated bilirubin, there
may be a yellow coloration of the skin and sclera in newborns with
jaundice. Neonatal jaundice can result from increased breakdown of fetal
erythrocytes coupled with low hepatic excretory capacity. Thus high levels
of unconjugated bilirubin (a breakdown product of hemoglobin) causes can
cause jaundice and even kernicterus, which is a complication of neonatal
jaundice.
 Explanation/Solution (II)
Kernicterus is the chronic and permanent neurologic sequelae of bilirubin-induced
neurologic dysfunction (BIND). Brain regions most commonly affected include
the basal ganglia and brainstem nuclei involved in oculomotor and auditory
function. Acute hyperbilirubinemia can lead to decreased alertness, hypotonia and
poor feeding. Kernicterus is associated with opisthotonos, a high-pitched cry, an
abnormal Moro reflex, and abnormal eye movements. Although kernicterus can
occur pathologically, this condition may also occur if the mother takes sulfonamide
antibiotics, such as trimethoprim-sulfamethoxazole or sulfisoxazole during the
2nd or 3rd trimester of pregnancy.
 Explanation/Solution (III)
Sulfonamides can displace bilirubin from its albumin-binding site,
thereby increasing the serum concentration of free bilirubin available to
cross the blood-brain barrier. Trimethoprim-sulfamethoxazole is not
recommended for use in infants less than 2 months old. When
hyperbilirubinemia occurs in an infant, the treatment of choice is to remove
the bilirubin from the blood by phototherapy or exchange transfusion.
 Explanation/Solution (IV)
• Acetaminophen (choice A) is an analgesic and antipyretic agent that can be safely taken during
pregnancy.
• Azithromycin (choice B) is a macrolide antibiotic used for the treatment of a variety of
infections.
• Chloramphenicol (choice C) is a broad-spectrum antibiotic effective against a wide variety of
gram-negative, gram-positive, and anaerobic organisms. The use of this antibiotic in infants is
associated with a condition referred to as "gray baby syndrome," which is associated with
cyanosis and vascular collapse.
• Diethylstilbestrol (DES) (choice D) is an older agent that can be used in estrogen-deficiency states
and for the treatment of prostatic carcinoma.
 Q4
A 45-year-old man comes to his physician because of a swollen, hard lump just above
his mandible. The mass has been present for several months and occasionally becomes
painful. There is also bluish discoloration of the skin overlying the lesion. He has a low-
grade fever and occasional night sweats. On physical examination, it is noted that there
is purulent drainage from a small pit located on the lateral portion of his neck. Contrast-
enhanced computerized tomography (CT) scans of the patient’s head and neck reveal an
inflammatory soft tissue mass with a fistulous tract ending at the skin. Culture of the
purulent drainage reveals branching, filamentous gram-positive rods. Which of the
following is the most appropriate pharmacotherapy?
 Options

A. Ciprofloxacin
B. Doxycycline
C. Penicillin
D. Trimethoprim-sulfamethoxazole
E. Voriconazole
 Explanation/Solution (I)
This patient has the classic presentation of oral-cervicofacial actinomycosis, which is the most
common. This condition is characterized by cervicofacial abscesses with formation of sinus
tracts that express purulent drainage. Within these tracts, there are often characteristic yellow
purulent granules, also known as sulfur granules, filled with bacterial progeny. The disease
can also involve thoracic, abdominal, and pelvic regions with similar presentations, although
they most commonly present in the head and neck. Risk factors include poor hygiene and
history of radiation. The culpable microbe is Actinomyces israelii, a gram-positive anaerobic
bacteria that forms long, branching filamentous rods when cultured. This organism is
actually part of normal oral flora and can occur in immunocompetent patients.
 Explanation/Solution (II)
• Ciprofloxacin (choice A) is a fluoroquinolone that can treat gram-negative rods, such as Neisseria gonorrhoeae, which causes
gonorrhea, and some gram-positive cocci organisms. This class of medications inhibits topoisomerase II in bacteria.
• Doxycycline (choice B) is particularly effective for intracellular bacteria, such as Rickettsia rickettsii, which causes Rocky
Mountain spotted fever, and inhibits bacterial translation.
• Trimethoprim-sulfamethoxazole (choice D), a folate synthesis inhibitor, is a tempting distractor because it is the treatment
for nocardiosis. Nocardia species are gram-positive, aerobic, stain weakly acid-fast, branching rods that
are ubiquitous environmental bacteria, which have a similar basic microbiology to Actinomyces species.
• Voriconazole (choice E), an ergosterol synthesis inhibitor, is used to treat fungal infections, particularly aspergillosis.
Though Actinomyces and Nocardia species can have a similar branching pattern to Aspergillus species, the similarities end
there. Aspergillosis manifests as mycetomas (fungal balls), allergic reactions, sinusitis, and invasive fungal disease. Forming
sinus tracts would be highly unusual.
 Explanation/Solution (III)

The correct answer is C. Penicillin is the first-line therapy.

 Q5
An 18-year-old woman comes to the physician because of severe
pustular acne. She states that she has had these lesions occasionally
over the past several years; however, the lesions have increased in
quantity recently. She has no history of any major medical illness.
Treatment is begun with an oral antibiotic. Which of the following
best describes the mechanism of action of the most likely
prescribed drug?
 Options

A. Blocks formation of ribosomal initiation complex

B. Causes misreading at translation initiation
C. Inhibits cell wall synthesis
D. Inhibits DNA gyrase and topoisomerase IV
E. Prevents binding of aminoacyl-tRNA to ribosomes
 Explanation/Solution (I)
Acne vulgaris is a disorder of the skin that affects the pilosebaceous unit and is
characterized by pustules, nodules, comedones, papules, cysts, and scarring from
previous lesions. Acne vulgaris is most commonly seen during adolescence, but it may
occur at any age. Acne is often classified either by type (comedonal/papular,
pustular/nodulocystic) or by severity (mild/moderate/moderately severe/severe). Skin
lesions can be described as inflammatory or noninflammatory. In contrast to polycystic
acne, which often requires treatment with isotretinoin, severe pustular acne is often
responsive to oral antibiotic therapy.
 Explanation/Solution (II)
• Linezolid blocks initiation complex formation (choice A) and is used for vancomycin-resistant
infections.
• Aminoglycosides such as streptomycin and gentamicin act by causing misreading at translation
initiation (choice B) and are commonly used for treating gram-negative rods.
• Penicillins act by inhibiting bacterial cell wall synthesis (choice C). Specifically, they act by inhibiting
peptidoglycan cross-linking in bacterial cell walls. Penicillin is used against gram-positive organisms.
• Fluoroquinolones such as levofloxacin and ciprofloxacin inhibit DNA gyrase and topoisomerase
IV (choice D). These medications are used in the treatment of severe gram-negative infections and
selected gram-positive infections.
 Explanation/Solution (III)
Treatment of inflammatory pustular acne generally involves the use of an
oral antibiotic such as tetracycline, minocycline, or doxycycline with or
without the use of a topical retinoid. Tetracycline acts by preventing the
binding of aminoacyl-tRNA to ribosomes. The correct answer is E.
 Explanation

Patients who are allergic to first line antibiotics are often placed on
gentamicin for urinary tract infections. Gentamicin is an
aminoglycoside antibiotic that works by irreversibly binding the
30S subunit of the bacterial ribosome and thus interrupting protein
synthesis. Gentamicin can impair renal function by inhibiting
protein synthesis in renal cells. This is especially true at high doses
but, in the elderly, this effect may also occur at lower doses.
Therefore care must be used to monitor renal function.
 Explanation

Syphilis is caused by Treponema pallidum, which has the ability to

cross the placenta and infect the fetus. If left untreated, it may cause
congenital syphilis, prematurity and stillbirth. The treatment of
choice is a penicillin which achieves very high cure rates compared
with other antibiotics. Benzathine penicillin G is often used, and is
given as an intramuscular injection.
 Explanation

This patient has evidence of acute hepatitis. One of the common

causes of hepatitis is drug induced. Erythromycin is a macrolide
antibiotic, which is metabolised by demethylation in the liver by the
hepatic enzyme CYP3A4. Therefore, Erythromycin can cause
increased liver enzyme levels and hepatocellular hepatitis, with or
without jaundice. A cholestatic reaction is the most common adverse
effect and usually begins within 1-3 weeks of therapy.