Chapter 10: Antimicrobial Drugs

Mechanism of action

Antimicrobial Drug Stewardship

1. Importance of Antimicrobials
o Significant medical advancement, reducing morbidity and mortality.
o Overuse has led to multidrug-resistant pathogens and reduced drug efficacy.
2. Problems Due to Overuse
o Emergence of resistant pathogens.
o Increased healthcare costs.
o Adverse effects such as Clostridium difficile colitis.
3. Need for Stewardship
o The Centers for Disease Control and Prevention (CDC) reports 2+ million
infections yearly in the U.S. due to resistant bacteria, leading to 20,000 deaths.
o Major resistant pathogens: Methicillin-resistant Staphylococcus aureus (MRSA),
Escherichia coli, Klebsiella pneumoniae.
4. Principles of Good Stewardship
o Reduce inappropriate antibiotic use.
o Encourage targeted therapy with narrow-spectrum drugs.
o Limit adverse effects of antibiotics.
5. Inappropriate Antibiotic Use
o Often done to satisfy patient expectations.
o Example: Prescribing antibiotics for viral respiratory infections.
6. Targeted Therapy Approach
o Obtain microbiologic diagnosis and select the most effective and safest antibiotic.
o Avoid excessive use of broad-spectrum antibiotics.
o Switch from intravenous to oral antibiotics when appropriate to reduce catheter-
associated infections.
7. Limiting Adverse Effects
o Reduce antibiotic duration to the minimum needed.
o Adjust doses in patients with reduced kidney function.
8. Antibiotic Allergies
o Should be properly identified and investigated before treatment.

Table 10-1: Basic Principles of Antimicrobial Drug Stewardship

1. Inappropriate Use of Antibiotics

o Use antibiotics only when microbiologic diagnosis confirms effectiveness.
o Tailor empiric therapy to the most likely pathogens.
o Send appropriate cultures before starting antibiotics.
2. Overuse of Broad-Spectrum Antibiotics
o Use narrow-spectrum antibiotics whenever possible.
o Require approval for advanced-generation broad-spectrum antibiotics.
 3. High Rate of Adverse Effects
o Stop antibiotics as soon as appropriate to prevent issues like Clostridium difficile
colitis.
o Adjust dosage based on renal function.
o Assess true hypersensitivity to antibiotics.
o Warn patients about potential side effects, such as photosensitivity.

Principles of Antimicrobial Therapy

1. Selective Toxicity
o Antibiotics selectively inhibit bacterial growth without harming the host.
o This is achieved by targeting bacterial structures that differ from human cells,
such as the cell wall, ribosomes, nucleic acids, and cell membranes.
2. Broad-Spectrum vs. Narrow-Spectrum Antibiotics
o Broad-spectrum: Active against a wide range of bacteria (e.g., tetracyclines
affect gram-negative rods, chlamydia, mycoplasma, and rickettsia).
o Narrow-spectrum: Effective against specific bacteria (e.g., vancomycin targets
gram-positive cocci like Staphylococcus and Enterococcus).
3. Antifungal Drugs
o Have unique targets such as fungal cell walls, cell membranes, and nucleic acid
synthesis.

Bactericidal vs. Bacteriostatic Activity

1. Bactericidal Drugs
o Kill bacteria directly.
o Essential in life-threatening infections or in immunocompromised patients.
o Required for conditions like endocarditis, where bacteriostatic drugs may not be
effective.
2. Bacteriostatic Drugs
o Inhibit bacterial growth without killing them.
o Rely on host immune mechanisms like phagocytosis to clear the infection.

Table 10-2: Mechanism of Action of Important Antibacterial and Antifungal Drugs

1. Inhibition of Cell Wall Synthesis

o Antibacterial: Penicillins, cephalosporins, imipenem, aztreonam, vancomycin
o Peptidoglycan synthesis inhibitors: Cycloserine, bacitracin
o Antifungal (β-glucan synthesis inhibitors): Caspofungin
2. Inhibition of Protein Synthesis
o 50S ribosomal subunit: Chloramphenicol, erythromycin, clindamycin, linezolid
o 30S ribosomal subunit: Tetracyclines, aminoglycosides
3. Inhibition of Nucleic Acid Synthesis
 oNucleotide synthesis inhibitors: Sulfonamides, trimethoprim
oDNA synthesis inhibitors: Quinolones (e.g., ciprofloxacin)
omRNA synthesis inhibitors: Rifampin
4. Alteration of Cell Membrane Function
o Antibacterial: Polymyxin, daptomycin
o Antifungal: Amphotericin B, nystatin, terbinafine, azoles (e.g., itraconazole)
5. Other Mechanisms of Action
o Antibacterial: Isoniazid, metronidazole, ethambutol, pyrazinamide
o Antifungal: Griseofulvin, pentamidine

Mechanism of Action: Inhibition of Cell Wall Synthesis

1. Inhibition of bacterial ceall wall synthesis

Penicillins

o Inhibit transpeptidases (enzymes that cross-link peptidoglycan).

o Mimic D-alanyl-D-alanine, binding to the active site of transpeptidases and blocking
their function.
2. Key Factors in Penicillin Action
o Binding to Penicillin-Binding Proteins (PBPs):
▪ PBPs are crucial for cell wall synthesis.
▪ Changes in PBPs can cause resistance.
o Activation of Autolytic Enzymes (Murein Hydrolases):
▪ These enzymes degrade peptidoglycan, leading to bacterial lysis.
▪ Some bacteria (S. aureus) are tolerant because their autolytic enzymes are
inactive.
3. Penicillin-Treated Bacterial Death
o Causes cell lysis due to osmotic pressure changes.
o Bactericidal but only kills actively growing cells.
o Inhibits transpeptidation, preventing peptidoglycan cross-linking.
o More effective during log phase of bacterial growth.

Figure 10-1: Bactericidal vs. Bacteriostatic Activity

• Bactericidal drugs kill bacteria, leading to a decline in viable bacterial count.

• Bacteriostatic drugs inhibit growth but do not kill; bacteria can resume growth if the drug is
removed.

4. β-Lactam Structure & Inactivation

• Essential β-lactam ring required for antibacterial activity.

• Cleaved by β-lactamases (penicillinases), leading to drug inactivation.

5. Types of Penicillin G
• Aqueous Penicillin G: Rapid metabolism.
• Procaine Penicillin G: Slow metabolism, less painful (contains anesthetic).
• Benzathine Penicillin G: Slowest metabolism, depot preparation.

6. Disadvantages of Benzylpenicillin (Penicillin G)

• Limited effectiveness against gram-negative rods.

• Hydrolysis by gastric acids (not orally effective).
• Inactivation by β-lactamases.
• Hypersensitivity reactions (e.g., anaphylaxis).

7. Modification of Penicillin

• Ampicillin & Amoxicillin have improved gram-negative activity.

• Nafcillin resists β-lactamase due to bulky side chains.
• Chemical modifications enhance acid stability & β-lactamase resistance.

8. Resistance & β-Lactamase Inhibitors

• β-Lactamase inhibitors (clavulanic acid, tazobactam, sulbactam, avibactam) protect β-

lactam antibiotics from degradation.
• Amoxicillin + Clavulanic Acid (Augmentin) is a common combination to overcome
resistance.

9. Hypersensitivity Reactions

• Penicillins are generally safe but can cause IgE-mediated hypersensitivity (e.g.,
anaphylaxis, urticaria).
• Cephalosporins may be tolerated in penicillin-allergic patients but still pose a 10%
cross-reactivity risk.
• Allergy testing (skin test with penicilloyl-polylysine) can help determine true
hypersensitivity.

10. Activity of Selected Penicillins

• Penicillin G: Effective against gram-positive cocci, gram-positive rods, Neisseria,

spirochetes, and some anaerobes (except Bacteroides fragilis).
• Ampicillin/Amoxicillin: Effective against certain gram-negative rods (e.g., Haemophilus
influenzae, Escherichia coli, Proteus, Salmonella, Shigella), but not Pseudomonas
aeruginosa.
• Ticarcillin: Used for P. aeruginosa, especially in synergy with aminoglycosides.
• Piperacillin: Similar to ticarcillin but with stronger P. aeruginosa and Klebsiella
pneumoniae activity.
• Nafcillin/Dicloxacillin: Resistant to β-lactamases, mainly used for Staphylococcus
aureus.
 Cephalosporins:

β-Lactam drugs with a six-membered ring, structurally different from penicillins.

Inhibit peptidoglycan cross-linking like penicillins.

First-generation cephalosporins mainly target gram-positive cocci.

Later generations (2nd–5th) progressively expand gram-negative coverage.

Fourth & fifth generations cover some gram-positive bacteria, including MRSA (e.g.,
ceftaroline).

Cephalosporins are widely used due to their broad spectrum & lower hypersensitivity
reactions.

First Generation (Cefazolin, Cephalexin): Effective against gram-positive cocci

(staphylococci, streptococci) but not MRSA or enterococci.

Second Generation (Cefuroxime, Cefoxitin): Expanded gram-negative coverage

(Haemophilus influenzae, Bacteroides fragilis).

Third Generation (Ceftriaxone, Ceftazidime): Stronger gram-negative coverage (E. coli,

Klebsiella, Proteus, Neisseria gonorrhoeae, Pseudomonas aeruginosa).

Fourth Generation (Cefepime): Broad spectrum, covering Pseudomonas, extended-spectrum

β-lactamase (ESBL) bacteria, and Streptococcus pneumoniae.

Fifth Generation (Ceftaroline, Ceftolozane): Covers MRSA and Pseudomonas aeruginosa

(ceftolozane is combined with tazobactam)

Carbapenems (Broad-Spectrum β-Lactams)

• Structurally distinct from penicillins and cephalosporins.

• Imipenem: Extremely broad-spectrum, effective against gram-positive, gram-negative,
and anaerobic bacteria.
• Administered with cilastatin, which inhibits kidney enzyme dehydropeptidase (prevents
drug breakdown).
• Other carbapenems (Ertapenem, Meropenem): Not degraded by dehydropeptidase
and do not require cilastatin.
• Often last-resort drugs for multidrug-resistant infections.

Monobactams (Aztreonam)

• Monocyclic β-lactam ring (structurally different from penicillins & cephalosporins).

• Active only against gram-negative bacteria, including Enterobacteriaceae.
 • No cross-reactivity with penicillin allergy, making it safer for allergic patients.

Vancomycin (Glycopeptide Antibiotic)

• Inhibits bacterial cell wall synthesis by blocking transpeptidation.

• Effective against gram-positive bacteria (e.g., MRSA, Staphylococcus epidermidis,
Streptococcus pneumoniae, Enterococcus).
• Not degraded by β-lactamases (unlike penicillins).
• Used for penicillin-resistant infections and vancomycin-resistant enterococci (VRE).
• Side effect: "Red man syndrome" (flushing due to histamine release).
• Derivatives: Telavancin, Oritavancin, and Dalbavancin (more effective against MRSA &
VRE).

Cycloserine & Bacitracin

• Cycloserine: Inhibits peptidoglycan synthesis; second-line drug for tuberculosis.

• Bacitracin: Blocks lipid carrier regeneration in cell wall synthesis.
o Bactericidal but too toxic for systemic use; used for superficial skin infections.

2. Inhibition of Fungal Cell Wall Synthesis

Echinocandins (e.g., Caspofungin, Micafungin):

o Block β-glucan synthesis, essential for fungal cell walls.

o Used against Candida & Aspergillus, but not Cryptococcus or Mucor.
o Anidulafungin treats esophageal candidiasis.

Inhibition of Protein Synthesis (Selective for Bacteria)

• Bacteria have 70S ribosomes (50S + 30S subunits), while humans have 80S ribosomes,
allowing selective targeting.
• 50S ribosome inhibitors:
o Macrolides (Azithromycin, Erythromycin, Clindamycin, Linezolid).
• 30S ribosome inhibitors:
o Aminoglycosides (Gentamicin, Streptomycin).
o Tetracyclines (Doxycycline).

1. Drug that Acts on the 30S Subunit

Aminoglycosides (30S Ribosome Inhibitors)

• Bactericidal drugs effective against gram-negative rods.

• Work by inhibiting bacterial protein synthesis at the 30S ribosomal subunit.
• Common examples: Gentamicin, Streptomycin, Amikacin, Tobramycin.
• Clinical Uses:
o Streptomycin: Used in tuberculosis multidrug therapy.
 o Gentamicin: Used with penicillin G for enterococcal infections.
• Structure: Named after amino sugar components linked by glycosidic bonds.
• Mechanism of Action:
o Bind irreversibly to the 30S subunit, blocking the initiation complex and
causing misreading of mRNA.
• Bactericidal, inhibit protein synthesis by blocking initiation and causing mRNA
misreading.
• Toxicity: Nephrotoxicity (kidneys) and ototoxicity (auditory/vestibular nerve).
• Limitations:
o Poor oral absorption.
o Poor penetration into cerebrospinal fluid (CSF).
o Ineffective against anaerobes (requires oxygen for uptake).

Table 10-5: Mode of Action of Protein Synthesis Inhibitors

• Aminoglycosides (30S): Blocks initiation complex, causes mRNA misreading

(Bactericidal).
• Tetracyclines (30S): Blocks tRNA binding (Bacteriostatic).
• Chloramphenicol (50S): Blocks peptidyltransferase (Bacteriostatic/Bactericidal).
• Macrolides (50S): Blocks translocation (Primarily Bacteriostatic).
• Clindamycin (50S): Blocks peptide bond formation (Primarily Bacteriostatic).
• Linezolid (50S): Blocks early ribosome assembly (Bacteriostatic/Bactericidal).
• Streptogramins (50S): Premature peptide chain release (Bacteriostatic/Bactericidal).

Table 10-6: Spectrum of Activity

• Aminoglycosides (e.g., Gentamicin, Streptomycin, Amikacin): Used for gram-

negative infections, tuberculosis, plague. Toxicities: Ototoxicity, nephrotoxicity.
• Tetracyclines: Effective for Rickettsial, chlamydial infections. Not for children or
pregnancy.
• Macrolides (e.g., Erythromycin, Azithromycin): Treats pneumonia, Legionella,
Mycoplasma.
• Clindamycin: Covers anaerobes (e.g., Clostridium, Bacteroides fragilis). Major risk:
Pseudomembranous colitis.
• Linezolid: Used for vancomycin-resistant enterococci (VRE), MRSA, penicillin-
resistant pneumococci.
• Streptogramins: Treats VRE bacteremia, no cross-resistance with other 50S inhibitors.
• Retapamulin: Skin infections caused by S.pyogens methicillin-sensitive S.aureus.

Tetracycline:

• Bacteriostatic, bind to 30S ribosomal subunit, blocking aminoacyl-tRNA entry.

• Broad-spectrum: effective against gram-positive, gram-negative, mycoplasma,
chlamydia, rickettsiae.
• Side effects:
o Suppresses normal flora → diarrhea, fungal infections.
 o Candida overgrowth → Vaginitis.
o Teeth discoloration (due to calcium chelation) → contraindicated in
pregnancy & children <8 years.
o Chelates iron; iron-containing supplements should be avoided.
o Photosensitivity (sunlight exposure causes skin reactions).

Tigecycline (Glycylcycline class)

• Similar to tetracyclines but effective against MRSA, VRE, and anaerobic bacteria.
• Used for skin and intra-abdominal infections.

2. Drugs that Act on the 50S Subunit

Chloramphenicol

• Broad-spectrum (gram-positive, gram-negative, anaerobes).

• Mode of action:
o Inhibits peptidyltransferase (blocks peptide bond formation) at the 50S
ribosomal subunit.
• Clinical Uses:
o Treats Salmonella typhi, Haemophilus influenzae (meningitis), Streptococcus
pneumoniae, Neisseria meningitidis.
• Toxicity:
o Affects mitochondrial protein synthesis.
o Can cause bone marrow toxicity (aplastic anemia).
o Side effects: Bone marrow toxicity, aplastic anemia, "gray baby" syndrome.

Macrolides (Azithromycin, Erythromycin, Clarithromycin)

• Inhibit translocation (50S ribosomal subunit).

• Uses: Respiratory & genital tract infections (e.g., Chlamydia, Mycoplasma,
Streptococcus pneumoniae).
• Side effects: GI issues, QT prolongation (cardiac risk).

Clindamycin

• Blocks peptide bond formation (50S subunit).

• Uses: Anaerobes (e.g., Clostridium perfringens, B. fragilis).
• Side effect: Pseudomembranous colitis (C. difficile overgrowth).

Linezolid

• Binds 23S rRNA in 50S subunit, inhibits early initiation.

• Uses: MRSA, VRE, penicillin-resistant pneumococci.
Telithromycin

• Ketolide antibiotic, similar to macrolides but more effective against resistant bacteria.

Streptogramins (Synercid)

• Uses: VRE, MRSA, penicillin-resistant S. pneumoniae.

• Action: Causes premature peptide chain release (50S subunit).

Retapamulin

• Topical antibiotic for skin infections (e.g., impetigo).

• Binds 23S rRNA in 50S subunit, blocks tRNA attachment.

Inhibition of nucleic acid synthesis

1. Inhibition of precursor synthesis
Sulfonamides

• Inhibits folic acid synthesis (PABA analog, inhibits dihydropteroate synthetase).

• Uses: UTIs (E. coli), otitis media, pneumonia (Pneumocystis, MRSA).

Trimethoprim

• Inhibits DHFR (dihydrofolate reductase), blocks folic acid synthesis.

• Used with sulfonamides for UTIs, pneumonia.

2. Inhibition of DNA Synthesis

Fluoroquinolones (Ciprofloxacin, Levofloxacin)

• Inhibits DNA gyrase, prevents replication.

• Uses: GI infections (Shigella, Salmonella), respiratory infections (penicillin-resistant S.
pneumoniae).

Flucytosine

• Inhibits thymidylate synthetase, blocks DNA synthesis.

• Uses: Fungal infections (cryptococcal meningitis with amphotericin B).
• Antifungal drug, inhibits thymidylate synthetase.
• Used with amphotericin B for cryptococcal & candida infections
 3. Inhibition of mRNA Synthesis
Rifampin

• Inhibits bacterial RNA polymerase, blocking mRNA synthesis.

• Uses: Tuberculosis, meningitis prophylaxis (N. meningitidis, H. influenzae), S.
epidermidis endocarditis.
• Causes orange-colored secretions.

Rifabutin

• Similar to rifampin, used for Mycobacterium avium-intracellulare in AIDS patients.

Fidaxomicin

• Inhibits RNA polymerase of C. difficile, used for pseudomembranous colitis.

Alteration of cell membrane function

1. Alteration of bacterial Cell Membranes
Polymyxins (e.g., Colistin - Polymyxin E)

• Disrupts bacterial cell membranes, acts as a detergent.

• Uses: Gram-negative bacteria (P. aeruginosa, Acinetobacter, Enterobacteriaceae).

Daptomycin

• Disrupts bacterial cell membranes, bactericidal for Gram-positive cocci.

• Uses: MRSA, VRE, complicated skin infections.

2. Alteration of Fungal Cell Membrane

Amphotericin B

• Binds ergosterol, disrupts fungal cell membrane.

• Uses: Systemic fungal infections.
• Toxicity: Nephrotoxicity, fever, chills.

Nystatin

• Similar to amphotericin B, used topically for Candida infections.

Terbinafine

• Inhibits ergosterol synthesis (squalene epoxidase inhibitor).

• Uses: Skin, nail, and hair infections (dermatophytes).
Azoles

• Inhibit ergosterol synthesis (block lanosterol demethylation).

• Uses: Various fungal infections.
• Fluconazole, ketoconazole, voriconazole, posaconazole, itraconazole used for systemic fungal
infections.
• Miconazole, clotrimazole used topically for Candida & dermatophytes.\

Additional Drug Mechanism

1. Anti-Bacterial Activity
Isoniazid (INH)

• Bactericidal for Mycobacterium tuberculosis.

• Mechanism: Inhibits mycolic acid synthesis (essential for mycobacterial cell walls).
• Side effect: Liver toxicity, given with pyridoxine (Vitamin B6) to prevent neuropathy.

Metronidazole

• Bactericidal for anaerobes (Bacteroides fragilis, C. difficile) & protozoa (Giardia,

Trichomonas).
• Mechanism: Acts as electron sink & generates toxic intermediates damaging DNA.

Ethambutol

• Bacteriostatic for Mycobacterium tuberculosis.

• Mechanism: Inhibits arabinogalactan synthesis (cell wall component).

Pyrazinamide (PZA)

Bactericidal, inhibits fatty acid synthase, used in TB lesions.

2. Antifungal Activity

• Griseofulvin: Treats hair & nail dermatophyte infections, binds tubulin to inhibit
mitosis.

Pentamidine: Treats Pneumocystis jiroveci pneumonia, inhibits DNA synthesis (unknown

mechanism).
Chemoprophylaxis (Disease Prevention)

• Used in three cases: Before surgery, for immunocompromised patients, and for
exposed individuals.
• Examples:
o Penicillin: Prevents rheumatic fever, syphilis, pneumococcal sepsis.
o Cefazolin: Prevents surgical wound infections.
o Fluconazole: Prevents cryptococcal meningitis in AIDS patients.
o Trimethoprim-Sulfamethoxazole: Prevents Pneumocystis pneumonia & UTIs.