33.3 Genitourinary Pharmacology I: Antimicrobial Classes and Toxicities, and Drug Treatment of UTI, Pyelonephritis, Gonorrhea, Chlamydia, Syphilis, Genital Herpes, Genital Warts, PID, Vaginitis, Prostatitis and Orchitis

Why this area matters

The TOS genitourinary area asks you to choose drugs for urinary infections, STIs, genital ulcers and warts, and PID, and to know their adverse effects and interactions. Antimicrobial resistance (ESBL E. coli, fluoroquinolone-resistant gonorrhea) is a growing problem in the Philippines, so first-line choices follow current guidelines and local antibiograms.

Antibacterial Cell Wall Inhibitors: Beta-Lactams & Glycopeptides

Bacterial cell walls consist of peptidoglycan polymers cross-linked by transpeptidase enzymes, collectively known as Penicillin-Binding Proteins (PBPs). Beta-lactam antibiotics contain a four-membered beta-lactam ring that acts as a structural analog of the D-Ala-D-Ala substrate, irreversibly inhibiting PBPs and triggering bacterial autolysin-mediated cell wall lysis.

Penicillins

• Natural Penicillins (Penicillin G IV, Penicillin V oral): Active against Treponema pallidum (syphilis drug of choice), Streptococcus pyogenes (Group A Strep), Actinomyces, and Clostridium perfringens. Rapidly degraded by staphylococcal penicillinase.
• Aminopenicillins (Ampicillin, Amoxicillin): Extended Gram-negative spectrum covering "HELPSS" (H. influenzae, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella) and Enterococcus faecalis. Sensitive to beta-lactamases; combined with beta-lactamase inhibitors (Amoxicillin-Clavulanic acid, Ampicillin-Sulbactam) to restore activity against beta-lactamase-producing MSSA, H. influenzae, and Bacteroides fragilis. Ampicillin causes a non-allergic maculopapular rash when administered in patients with Epstein-Barr Virus (EBV) infectious mononucleosis.
• Antistaphylococcal Penicillins (Oxacillin, Nafcillin, Cloxacillin, Dicloxacillin): Contain bulky lipophilic R-groups that sterically shield the beta-lactam ring from staphylococcal penicillinase. Narrow spectrum; active against Methicillin-Susceptible Staphylococcus aureus (MSSA) and streptococci. Completely inactive against MRSA (MRSA alters PBP2a, conferring resistance to all standard beta-lactams). Nafcillin causes interstitial nephritis and neutropenia; eliminated via biliary excretion (no dosage adjustment in renal failure).
• Antipseudomonal Penicillins (Piperacillin-Tazobactam): Broad spectrum covering Pseudomonas aeruginosa, enteric Gram-negative bacilli, and anaerobes.

Cephalosporins (Generations 1 through 5)

• 1st Generation (Cefazolin IV, Cephalexin oral): Active against Gram-positive cocci (MSSA, streptococci) and "PEcK" (Proteus, E. coli, Klebsiella). Cefazolin is the surgical antimicrobial prophylaxis drug of choice.
• 2nd Generation (Cefuroxime oral/IV, Cefoxitin IV, Cefotetan IV): Expanded Gram-negative activity ("HenPEcK": H. influenzae, Enterobacter, Neisseria, Proteus, E. coli, Klebsiella). Cefoxitin and cefotetan cover anaerobes (Bacteroides fragilis) and are used in pelvic inflammatory disease and intra-abdominal surgery. Cefotetan contains an N-methylthiotetrazole (NMTT) side chain that inhibits aldehyde dehydrogenase, causing disulfiram-like reactions with alcohol, and inhibits vitamin K epoxide reductase, causing hypoprothrombinemia and bleeding.
• 3rd Generation (Ceftriaxone, Cefotaxime, Ceftazidime): Enhanced Gram-negative coverage, resistant to many beta-lactamases, penetrate the blood-brain barrier. Ceftriaxone is first-line for community-acquired bacterial meningitis (S. pneumoniae, N. meningitidis), Neisseria gonorrhoeae, and severe CAP; eliminated predominantly via biliary excretion (no dosage adjustment in renal failure); avoided in hyperbilirubinemic neonates (it displaces bilirubin from albumin) and never given to neonates with IV calcium-containing solutions (fatal precipitates); it can also cause biliary sludging ("pseudolithiasis"). Ceftazidime has potent activity against Pseudomonas aeruginosa but poor Gram-positive coverage.
• 4th Generation (Cefepime): Broad spectrum combining Gram-positive coverage of 1st gen and antipseudomonal/Gram-negative coverage of 3rd gen. Stable against plasmid- and chromosomally mediated AmpC beta-lactamases. Causes neurotoxicity (encephalopathy, myoclonus, seizures) in renal impairment if dose is unadjusted.
• 5th Generation (Ceftaroline): Binds with high affinity to modified PBP2a, conferring bactericidal activity against Methicillin-Resistant Staphylococcus aureus (MRSA) and multidrug-resistant S. pneumoniae. Lacks activity against Pseudomonas aeruginosa.

Carbapenems & Monobactams

• Carbapenems (Meropenem, Imipenem-Cilastatin, Ertapenem): Ultra-broad-spectrum bactericidal agents; stable against extended-spectrum beta-lactamases (ESBLs). Imipenem is always formulated with cilastatin, an inhibitor of renal dehydropeptidase I on brush border membranes; cilastatin prevents renal inactivation of imipenem and prevents formation of a nephrotoxic metabolite. Imipenem lowers the seizure threshold; Meropenem has lower seizure potential and is preferred for CNS infections. Ertapenem lacks coverage against "PEA" (Pseudomonas aeruginosa, Enterococcus, Acinetobacter).
• Monobactams (Aztreonam): Binds PBP3; active strictly against aerobic Gram-negative bacilli (including Pseudomonas); completely lacks Gram-positive and anaerobic activity. Possesses zero cross-reactivity with other beta-lactams (safe in patients with severe IgE-mediated penicillin allergies, except those with specific ceftazidime allergy due to identical side chain).

Glycopeptides: Vancomycin

• Mechanism: Inhibits cell wall synthesis by binding directly with high affinity to the D-Ala-D-Ala terminus of peptidoglycan precursors, sterically blocking transglycosylase polymerization and transpeptidase cross-linking. Active strictly against Gram-positive bacteria (MRSA, coagulase-negative staphylococci, Enterococcus faecalis). Oral vancomycin is not absorbed systemically and is reserved exclusively for Clostridioides difficile colitis.
• Adverse Effects:
  1. Red Man Syndrome: Rate-dependent, non-IgE direct activation of mast cells and histamine release, resulting in diffuse pruritus, erythema, and flushing of the face, neck, and upper torso. Prevented by slowing infusion rate ($> 60\text{--}120\text{ minutes}$) and pretreating with antihistamines.
  2. Nephrotoxicity: Dose-dependent acute tubular injury and interstitial nephritis; risk multiplied when combined with aminoglycosides or piperacillin-tazobactam.
  3. Ototoxicity: High trough levels cause cochlear hair cell injury; often permanent.
• Vancomycin Resistance (VRE and VRSA): Plasmid-mediated replacement of the terminal D-Ala-D-Ala dipeptide with D-Ala-D-Lactate (or D-Ala-D-Serine), reducing vancomycin binding affinity by 1,000-fold.

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Ribosomal Protein Synthesis Inhibitors (30S & 50S)

Bacterial 70S ribosomes consist of a 30S and a 50S subunit. Inhibitors exploit structural differences from eukaryotic 80S ribosomes.

30S Subunit Inhibitors ("Buy AT 30")

• Aminoglycosides (Gentamicin, Amikacin, Tobramycin):
  • Mechanism: Irreversibly bind the 30S subunit, freezing the 30S initiation complex and inducing mRNA codon misreading; bactericidal. Entry into bacterial cytoplasm requires an oxygen-dependent active transport system; completely inactive against obligate anaerobes (Clostridium, Bacteroides). Synergistic with beta-lactams, which disrupt the cell wall to facilitate aminoglycoside entry. Exhibit concentration-dependent killing and prolonged post-antibiotic effect (PAE), enabling once-daily (extended-interval) dosing.
  • Toxicities:
    1. Nephrotoxicity ($10\text{--}25\%$): Non-oliguric acute tubular necrosis (ATN); accumulates in renal proximal tubular cells; usually reversible.
    2. Ototoxicity: Destroys hair cells in the organ of Corti (cochleotoxicity: hearing loss; Amikacin) and vestibular apparatus (vestibulotoxicity: vertigo, ataxia; Gentamicin); permanent and irreversible.
    3. Neuromuscular Blockade: Inhibits presynaptic calcium influx and acetylcholine release; contraindicated in Myasthenia Gravis.
• Tetracyclines (Doxycycline, Minocycline, Tetracycline):
  • Mechanism: Reversibly bind the 30S ribosomal subunit, blocking aminoacyl-tRNA attachment to the ribosomal acceptor (A) site; bacteriostatic. Broad spectrum covering atypicals (Mycoplasma, Chlamydia), zoonoses (Rickettsia, Borrelia, Leptospira). Doxycycline is the first-line agent for leptospirosis chemoprophylaxis and treatment in the Philippines.
  • Toxicities: Chelated by multivalent cations ($Ca^{2+}, Mg^{2+}, Fe^{2+}, Al^{3+}$; dairy, antacids, iron supplements impair absorption); binds calcium in newly formed bone and teeth, causing permanent teeth discoloration (yellow-brown) and enamel hypoplasia; generally avoided in pregnancy and in children under 8, although short courses of doxycycline are used at any age for serious infections such as rickettsial disease. Also causes photosensitivity and chemical pill esophagitis (must take with a full glass of water sitting upright). Doxycycline is eliminated non-renally via feces and requires no renal dosage adjustment.

50S Subunit Inhibitors ("CELL at 50")

• Macrolides (Azithromycin, Clarithromycin, Erythromycin):
  • Mechanism: Bind 23S rRNA of the 50S subunit, blocking peptidyltransferase and transpeptidase translocation. Active against atypical respiratory pathogens (Mycoplasma, Chlamydia, Legionella), Bordetella pertussis, and CAP.
  • Toxicities:
    1. QT Interval Prolongation: Risk of Torsades de pointes.
    2. CYP3A4 Inhibition: Erythromycin and clarithromycin are potent CYP3A4 inhibitors (raise levels of statins, theophylline, warfarin); Azithromycin does not inhibit CYP3A4.
    3. Gastrointestinal Motility Stimulation: Erythromycin directly binds smooth muscle motilin receptors, producing abdominal cramping and diarrhea.
• Chloramphenicol:
  • Mechanism: Reversibly binds 50S subunit, inhibiting peptidyl transferase; bacteriostatic. Broad spectrum with excellent CNS penetration.
  • Toxicities:
    1. Dose-dependent bone marrow suppression (reversible anemia/leukopenia).
    2. Idiosyncratic, dose-independent Aplastic Anemia (irreversible and usually fatal pancytopenia; occurs weeks to months after therapy).
    3. Gray Baby Syndrome: In neonates and premature infants lacking mature hepatic UDP-glucuronyltransferase enzyme activity with low renal excretion. Toxic accumulation disrupts mitochondrial ribosomes, manifesting as vomiting, flaccidity, hypothermia, ashen gray skin discoloration, metabolic acidosis, and cardiovascular collapse.
• Clindamycin:
  • Mechanism: Lincosamide; binds 50S subunit, inhibiting peptide bond formation. Active against Gram-positive cocci (including community-acquired MRSA) and anaerobes above the diaphragm (oral cavity anaerobes, Fusobacterium; aspiration pneumonia, lung abscesses, dental infections). Major adverse effect: Pseudomembranous colitis caused by Clostridioides difficile overgrowth.

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Nucleic Acid Inhibitors, Antifungals & Antivirals

Fluoroquinolones & Antifolates

• Fluoroquinolones (Ciprofloxacin, Levofloxacin, Moxifloxacin):
  • Mechanism: Inhibit bacterial DNA gyrase (topoisomerase II) in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria, inducing double-stranded DNA breaks; bactericidal. Ciprofloxacin has high potency against Pseudomonas aeruginosa and Gram-negative enteric bacilli. Levofloxacin and Moxifloxacin are "respiratory quinolones" with expanded coverage against Streptococcus pneumoniae and atypicals.
  • Toxicities:
    1. Tendinitis and Tendon Rupture (most commonly Achilles tendon; boxed warning; risk increased in patients $> 60$ years, athletes, and concurrent systemic corticosteroids).
    2. QT Interval Prolongation and dysglycemia.
    3. Neurotoxicity, peripheral neuropathy, and collagen degradation (aortic aneurysm/dissection warning).
    4. Generally avoided in pregnancy, breastfeeding and children (cartilage damage in juvenile animals), unless no safer alternative exists.
• Trimethoprim-Sulfamethoxazole (TMP-SMX / Cotrimoxazole):
  • Mechanism: Sequential folate synthesis inhibition. Sulfamethoxazole competitively inhibits dihydropteroate synthase (structural analog of PABA); Trimethoprim inhibits dihydrofolate reductase (DHFR). Synergistic bactericidal combination. Spectrum: Pneumocystis jirovecii pneumonia (PCP; treatment and prophylaxis in HIV/AIDS), community-acquired MRSA, Nocardia, Stenotrophomonas maltophilia, urinary tract infections.
  • Toxicities:
    1. Hypersensitivity reactions: Rash, erythema multiforme, Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN).
    2. Hematologic: Megaloblastic anemia (preventable with folinic acid / leucovorin), leukopenia, and acute hemolytic anemia in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency.
    3. Hyperkalemia: Trimethoprim structurally resembles amiloride and blocks apical epithelial sodium channels (ENaC) in renal collecting tubule principal cells.
    4. Kernicterus: Sulfonamides displace unconjugated bilirubin from albumin binding sites; strictly contraindicated in the third trimester of pregnancy and in neonates $< 2$ months of age.

Antifungal Therapeutics

• Amphotericin B: Polyene macrolide; binds to ergosterol in fungal cell membranes, forming polar transmembrane pores that leak intracellular potassium ($K^+$) and magnesium ($Mg^{2+}$), causing fungal cell death. Broadest spectrum for life-threatening systemic fungal infections (cryptococcal meningitis, invasive mucormycosis, histoplasmosis).
  • Toxicities: Acute infusion reactions ("shake and bake": fever, chills, rigors; managed with premedication); dose-dependent Nephrotoxicity (induces renal afferent arteriolar vasoconstriction and tubular damage, causing renal tubular acidosis Type 1, massive potassium and magnesium wasting, and normocytic normochromic anemia due to decreased erythropoietin production). Hydration with normal saline prior to infusion reduces renal toxicity. Liposomal formulations (AmBisome) significantly reduce nephrotoxicity. Nystatin is a polyene with identical mechanism, used topically for oral candidiasis (swish and swallow) or diaper dermatitis due to systemic toxicity.
• Azoles (Fluconazole, Itraconazole, Voriconazole, Posaconazole): Inhibit fungal cytochrome P450 enzyme $14\alpha$-sterol demethylase, blocking the conversion of lanosterol to ergosterol, destabilizing the fungal cell membrane.
  • Fluconazole: Excellent CSF penetration, high urinary excretion; first-line for cryptococcal meningitis maintenance and Candida infections.
  • Voriconazole: Drug of choice for invasive Aspergillosis. Causes transient visual disturbances (photopsia, altered color perception in 30%) and visual hallucinations.
  • Class toxicity: All azoles are potent CYP450 inhibitors and can cause hepatotoxicity and QT prolongation.
• Echinocandins (Caspofungin, Micafungin, Anidulafungin): Inhibit $\beta$-(1,3)-D-glucan synthase, disrupting fungal cell wall synthesis (analogous to beta-lactams in bacteria). Active against Candida (including azole-resistant strains) and Aspergillus. Extremely well tolerated with low toxicity.

Antiviral Therapeutics & Philippine HIV Regimens

• Acyclovir & Valacyclovir: Guanosine analogs selectively monophosphorylated by viral thymidine kinase (present in HSV-1, HSV-2, and VZV), then converted by host cellular kinases into acyclovir triphosphate, which inhibits viral DNA polymerase and acts as a DNA chain terminator. Uninfected host cells do not phosphorylate the drug, conferring high selectivity. Valacyclovir is an L-valyl ester prodrug with 3- to 5-fold higher oral bioavailability. Toxicities: Crystalline nephropathy (intravenous acyclovir precipitates in renal tubules; preventable by slow infusion and aggressive intravenous hydration) and neurotoxicity/delirium.
• Oseltamivir: Oral prodrug converted to oseltamivir carboxylate; selectively inhibits influenza A and B neuraminidase, preventing the enzymatic cleavage of sialic acid residues and trapping newly replicated virions on host cell surfaces, halting viral spread. Must be initiated within 48 hours of symptom onset to significantly shorten illness duration.
• Philippine DOH HIV Antiretroviral Therapy (ART):
  • The national first-line regimen for adolescents and adults living with HIV is the fixed-dose combination TLD:
    1. Tenofovir Disoproxil Fumarate (TDF): Nucleotide Reverse Transcriptase Inhibitor (NRTI); competitive inhibitor of viral reverse transcriptase and chain terminator. Toxicities: Proximal renal tubular dysfunction (Fanconi syndrome) and loss of bone mineral density (osteopenia/osteoporosis); monitor serum creatinine and urinalysis.
    2. Lamivudine (3TC): Nucleoside Reverse Transcriptase Inhibitor (NRTI); well tolerated; dual activity against Hepatitis B virus (HBV).
    3. Dolutegravir (DTG): Second-generation Integrase Strand Transfer Inhibitor (INSTI); binds the active site of HIV integrase, preventing insertion of proviral viral DNA into the host genome. Rapid viral load suppression, high genetic barrier to resistance; adverse effects: headache, insomnia, weight gain.

Regimens for genitourinary infections

• Metronidazole:
  • forms toxic free radicals in anaerobes and protozoa;
  • adverse effects are a metallic taste, nausea, neuropathy with long use, and a possible disulfiram-like reaction with alcohol.
• Nitrofurantoin:
  • concentrates in urine, so it is not used for pyelonephritis;
  • avoid it with low creatinine clearance;
  • it causes pulmonary reactions, neuropathy, and hemolysis in G6PD deficiency or in a newborn exposed near term.
• Penicillin allergy:
  • most reported penicillin allergies are not true allergies;
  • cephalosporins with dissimilar side chains can usually be given unless the reaction was severe;
  • desensitization is needed for syphilis in pregnancy.