Antimicrobial Agents

1. Chloramphenicol,
Tetracyclines,
Sulphonamides
by Shivankan Kakkar, MD

2. CHLORAMPHENICOL
It inhibits protein synthesis by binding to 50S ribosomal subunit and causing
the inhibition of peptidyl transferase. Chloramphenicol undergoes enterohepatic
circulation and is mainly inactivated by hepatic glucuronidation. It is a
bacteriostatic drug with wide spectrum of antimicrobial activity. Resistance
develops to this drug due to the formation of inactivating enzyme acetyl
transferase. Because of the rapid development of resistance and high toxicity,
this drug has very few systemic uses. Earlier, it was the drug of choice for
typhoid fever (enteric fever) but due to the development of resistance,
ceftriaxone or ciprofloxacin are now the preferred drugs. It is also active
against anaerobes. Due to its wide spectrum, it may cause superinfection
diarrhea. It can also cause dose dependent and reversible bone marrow
suppression as well as idiosyncratic, irreversible myelosuppression (can
occur even after ocular administration). Neonates and premature infants are
deficient in hepatic glucuronyl transferase and because it is excreted in the
kidney after glucuronidation, these are very sensitive to its toxicity. In such
patients, it may lead to grey baby syndrome characterized by decreased
RBCs, cyanosis and cardiovascular collapse.

3. Blocks peptidyltransferase at 50S ribosomal subunit.
Bacteriostatic.
Meningitis (Haemophilus influenzae, Neisseria meningitidis,
Streptococcus pneumoniae) and
rickettsial diseases (eg, Rocky Mountain spotted fever
[Rickettsia rickettsii]).
Limited use due to toxicity but often still used in developing
countries because of low cost.
Anemia (dose dependent), aplastic anemia (dose independent),
gray baby syndrome (in premature
infants because they lack liver UDP-glucuronosyltransferase).
CHLORAMPHENICOL
Mechanism
Uses
Toxicity

4. TETRACYCLINES
Tetracyclines bind to 30S ribosomal subunit and inhibit the binding of
aminoacyl-tRNA to the A site. These are classified as
• Group I: Tetracycline, chlortetracycline, oxytetracycline
• Group II: Demeclocycline, lymecycline
• Group III: Doxycycline, minocycline
• New drugs: Eravacycline, omadacycline, sarecycline
Pharmacokinetics
• Oral absorption of tetracyclines is impaired by food and multivalent cations
(calcium, iron, aluminium etc.). Yoghurt decreases the absorption of
tetracyclines because it contains cations like calcium and magnesium.
• Tetracyclines cross the placenta and affect the fetus, if administered to a
pregnant female.
• All tetracyclines undergo enterohepatic circulation.
• All tetracyclines are excreted primarily in the urine except doxycycline.
Doxycycline is excreted in the feces and thus can be used in the
presence of renal failure.
• Half life of doxycycline and minocycline is longer than other tetracyclines.

5. Clinical Uses
Tetracyclines are broad spectrum bacteriostatic drugs. Development of
resistance to tetracyclines is mainly due to the development of efflux pumps.
Tetracyclines are first choice drugs for
• Lymphogranuloma venereum (LGV)
• Granuloma inguinale
• Atypical pneumonia due to chlamydia (Now preferred drug is
azithromycin)
• Cholera
• Brucellosis (with rifampicin)
• Plague prophylaxis (Drug of choice for treatment is streptomycin)
• Relapsing fever (Doxycycline)
• Lyme’s disease (Doxycycline)
• Rickettsial infections (Doxycycline)
• Chlamydial infections (Doxycycline)

6. Other uses of individual tetracyclines include
• Meningococcal carrier state (Minocycline)
• Malaria prophylaxis (Doxycycline)
• Amoebiasis (Doxycycline)
• Syndrome of inappropriate ADH secretion (Demeclocycline)
• As secondary drugs for gonorrhoea, syphilis and chlamydial infections
• For pleurodesmosis in malignant pleural effusion.
• Leprosy (minocycline)
• Peptic ulcer by H. pylori (tetracycline)

7. Toxicity
• Tetracyclines may cause superinfection diarrhea and pseudomembranous
colitis. Gastrointestinal side effects are most common adverse effects.
• These are contra-indicated in pregnancy due to the risk of fetal tooth
enamel dysplasia and irregularities in the fetal bone growth.
• Treatment of young children (< 8 years) with tetracyclines may cause
dentition abnormalities. Doxycycline is less likely to cause this adverse
effect.
• High dose of tetracyclines may lead to hepatic necrosis especially in
pregnant females.
• Outdated tetracycline use may lead to Fanconi’s syndrome (a type of renal
tubular acidosis).
• Tetracyclines may exacerbate pre-existing renal dysfunction although these
are not directly nephrotoxic.
• Demeclocycline (maximum) and doxycycline can result in photosensitivity.
• Minocycline may lead to dose dependent vestibular toxicity (more in
women).
• Diabetes insipidus may be precipitated by ADH antagonistic action of
demeclocycline.
• Tetracyclines also possess anti-anabolic effects.

9. Figure: Steps of protein synthesis and the mechanism of action of drugs
Table: Mechanism of action of protein synthesis inhibiting antimicrobial drugs
Drugs Binds to Mechanism of action
Tetracyclines 30S ribosome • Inhibit aminoacyl-tRNA attachment to A
Site
Chloramphenicol 50S ribosome • Inhibits peptidyl transferase that results in
the inhibition of peptide bond formation and
transfer of peptide chain from P to A site

10. SULFONAMIDES
• These drugs are bacteriostatic agents and act by inhibiting folate
synthase competitively.
• The selective toxicity to bacteria is due to the reason that
mammalian cells do not synthesize folic acid and utilize preformed folic
acid in the diet.
• Sulfonamides are not effective in the presence of pus because it
contains large amount of PABA.
• These drugs undergo hepatic metabolism by ACETYLATION
(Drugs undergoing acetylation are SHIP: Sulfonamides including dapsone,
Hydralazine, Isoniazid and Procainamide) and can cause SLE.
• The solubility of sulfonamides decrease in the acidic urine, which may
result in precipitation of the drug causing crystalluria. Risk is minimum
with soluble drugs like sulfisoxazole.
• Sulfadoxine is longest acting whereas sulfacytine is shortest acting
sulfonamide.

11. Classification
• For systemic use as oral agents
Short acting: Sulfisoxazole, sulfamethiazole, Sulfacytine
Intermediate acting: Sulfamethoxazole, Sulfadiazine
Long acting: Sulfadoxine
• For use in GIT: Sulfasalazine, olsalazine
• For topical use: Sulfacetamide, silver sulfadiazine, mafenide
Clinical Uses
• Sulfacetamide is used for ocular infections whereas mafenide and silver
sulfadiazine are used in burn patients as topical agents.
• Sulfadiazine can be used for nocardiosis and sulfisoxazole for urinary
tract infections.
• Sulfasalazine and olsalazine are used for the treatment of ulcerative
colitis.
• Sulfadoxine plus pyrimethamine is used for malaria.
• Sulfadiazine and pyrimethamine combination can be used for the
treatment of toxoplasmosis and prophylaxis of Pneumocystis jiroveci
pneumonia in AIDS patients.
• Silver sulfadiazine is also used for fungal keratomycosis.

12. Toxicity
• Skin rash due to hypersensitivity is the most common adverse effect.
• These can also cause granulocytopenia, thrombocytopenia and aplastic
anemia (more common in HIV infected patients).
• Sulfonamides can cause acute hemolysis in patients with G-6 PD
deficiency.
• These can precipitate in the urine at acidic pH and may result in
crystalluria and hematuria.
• These can displace bilirubin from plasma protein binding sites and
may result in kernicterus in the new born (if given in third
trimester of pregnancy).

13. TRIMETHOPRIM
It is a bacteriostatic antimetabolite that inhibits dihydrofolate reductase. It
attains high concentrations in the prostate and vaginal fluids. For most of
the indications, it is combined with sulfonamides; however it can be used
alone in prostatitis and UTI. It can cause megaloblastic anemia (can be
ameliorated by folinic acid), leucopenia and pancytopenia. It can also
result in hyperkalemia
(due to amiloride like action i.e., inhibition of epithelial Na+ channels in
CD).
Note:
• Other DHFRase inhibitors are pyrimethamine, methotrexate,
proguanil and pentamidine.
• All DHFRase inhibitors can cause megaloblastic anemia.

14. COTRIMOXAZOLE
This is a fixed dose combination of sulfamethoxazole and trimethoprim in a ratio
of 5:1. Commercially available double strength septran contains 800
mg sulfamethoxazole and 160 mg trimethoprim. Both drugs have similar
half life and the combination is bactericidal to most pathogens. Due to
different bioavailability (more for sulfamethoxazole), plasma concentration
of the two drugs attained is 20:1.
The bactericidal activity is due to sequential blockade at two steps in the
DNA synthesis (sulfamethoxazole inhibits folate synthase and
trimethoprim inhibits DHFRase). Cotrimoxazole is effective in UTI,
respiratory tract infections, MRSA, middle ear and sinus infections caused
by hemophilus and moraxella. It is the drug of choice for pneumocystosis,
nocardiosis and infections caused by Burkholderia cepacia. Adverse effects
are similar to sulfonamides and trimethoprim.