Infectious Disease and Antimicrobial Therapy

Infectious diseases remain a leading cause of morbidity and mortality in South Africa, driven by the dual burden of HIV/AIDS and tuberculosis, high rates of opportunistic infections, and an emerging threat of antimicrobial resistance. The pharmacist’s role in antimicrobial therapy spans from ensuring appropriate antimicrobial selection, dosing, and monitoring, to managing drug interactions, counselling on adherence, and contributing to antimicrobial stewardship programmes. For the SAPC examination, candidates must demonstrate a thorough understanding of antimicrobial classes, mechanisms of action, resistance mechanisms, spectrum of activity, and the principles governing rational antimicrobial use in the South African healthcare context.

This topic builds on pharmacology fundamentals and integrates with pharmacokinetics (pharma-003 through pharma-007), drug interactions (pharma-008), and adverse drug reactions (pharma-009).

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General Principles of Antimicrobial Therapy

Mechanisms of Antimicrobial Action

Mechanism	Drug Class Examples	Notes
Inhibit cell wall synthesis	β-lactams (penicillins, cephalosporins, carbapenems), glycopeptides (vancomycin), fosfomycin	Bactericidal; human cells lack cell walls
Inhibit protein synthesis (30S ribosome)	Aminoglycosides, tetracyclines, tigecycline	Bactericidal (aminoglycosides) or bacteriostatic (tetracyclines)
Inhibit protein synthesis (50S ribosome)	Macrolides, lincosamides (clindamycin), chloramphenicol, linezolid	Mostly bacteriostatic
Inhibit DNA replication/transcription	Quinolones (fluoroquinolones), rifampicin, metronidazole	Bactericidal
Inhibit folate synthesis	Sulfonamides, trimethoprim, trimetrexate	Bacteriostatic; sequential blockade in co-trimoxazole
Inhibit mycobacterial cell wall	Isoniazid, ethambutol, pyrazinamide	Specific for Mycobacterium tuberculosis
Inhibit viral enzymes	NRTIs, NNRTIs, protease inhibitors, integrase inhibitors	HIV, HBV, HCV therapy
Disrupt cell membrane	Daptomycin, polymyxins (colistin), azole antifungals	Bactericidal; daptomycin for Gram-positive

Spectrum of Activity and Empiric Therapy

Narrow-spectrum vs broad-spectrum:

• Narrow-spectrum: targets specific organisms (e.g., benzylpenicillin for Streptococcus pneumoniae)
• Broad-spectrum: covers many organisms including Gram-positive, Gram-negative, and sometimes anaerobes
• Problems with broad-spectrum use: resistance selection, C. difficile infection, increased costs

Empiric therapy is initiated before culture results are available, based on:

• Likely pathogens for the clinical syndrome
• Local resistance patterns
• Patient factors (allergies, renal/hepatic function)
• Severity of infection

Directed (pathogen-directed) therapy is narrowed or changed once culture and susceptibility results are available.

Bacterial classification by Gram stain:

Gram-Positive Cocci	Gram-Negative Cocci	Gram-Negative Bacilli
Staphylococci (S. aureus, coagulase-negative)	Neisseria gonorrhoeae	Enterobacteriaceae (E. coli, Klebsiella, Salmonella, Shigella)
Streptococci (S. pneumoniae, Group A Strep)	N. meningitidis	Pseudomonas aeruginosa
Enterococcus faecalis/faecium	Moraxella catarrhalis	Acinetobacter spp.
		Haemophilus influenzae
		Bordetella pertussis
		Legionella pneumophila

Antimicrobial Resistance

Mechanisms of bacterial resistance:

1. Enzymatic inactivation — β-lactamases (penicillinases, cephalosporinases), aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases)
2. Target site alteration — altered PBPs (methicillin-resistant S. aureus/MRSA, penicillin-resistant S. pneumoniae/PRSP), altered quinolone targets (gyrA mutations), altered ribosomal targets (erm methylase conferring macrolide resistance)
3. Reduced permeability — loss of porin channels in Gram-negative bacteria (e.g., Pseudomonas resistance to carbapenems via loss of OprD)
4. Efflux pumps — active transport of drug out of bacterial cell (tetracycline resistance, macrolide resistance)
5. Plasmid acquisition — genes acquired via plasmids, transposons, integrons (e.g., ESBL-producing Enterobacteriaceae, carbapenemase-producing K. pneumoniae/KPC)
6. Biofilm formation — protective matrix that reduces antibiotic penetration (e.g., Pseudomonas in cystic fibrosis, Staphylococcus on prosthetic devices)

MRSA (Methicillin-Resistant S. aureus):

• mecA gene encodes altered PBP (PBP2a) with low affinity for all β-lactams
• Resistant to all penicillins, cephalosporins, carbapenems (unless still susceptible based on testing)
• Treatment: vancomycin (IV), teicoplanin (IV), linezolid (IV/PO), daptomycin (IV), clindamycin (if susceptible), trimethoprim-sulfamethoxazole (co-trimoxazole), doxycycline, minocycline
• In South Africa, MRSA is common in both hospital (HA-MRSA) and community (CA-MRSA) settings

VRE (Vancomycin-Resistant Enterococcus):

• vanA or vanB genes confer resistance
• Resistant to vancomycin and teicoplanin
• Treatment: linezolid, daptomycin (note: not effective against E. faecium for daptomycin in some guidelines), tigecycline, nitrofurantoin (for UTI)

ESBL-producing Enterobacteriaceae:

• Extended-spectrum β-lactamases (TEM, SHV, CTX-M families) hydrolyse penicillins, cephalosporins, aztreonam
• Treatment: carbapenems (imipenem, meropenem, ertapenem); cefoxitin (some); combination therapy for serious infections
• In South Africa, CTX-M ESBLs are prevalent; community UTIs with ESBL-producing E. coli are increasingly common

Carbapenem-resistant Enterobacteriaceae (CRE) and Acinetobacter:

• Carbapenemases (KPC, NDM, VIM, IMP families) hydrolyse carbapenems
• Colistin (polymyxin E) and tigecycline last resort; resistance emerging
• In South Africa, carbapenem-resistant Acinetobacter baumannii is a major ICU pathogen; national surveillance (MARAN) monitors resistance trends

Clostridioides difficile infection (CDI):

• Antibiotic-associated diarrhoea/colitis
• Disrupts normal gut flora → C. difficile overgrowth and toxin production
• High-risk antibiotics: clindamycin, fluoroquinolones, cephalosporins (especially 2nd/3rd generation), ampicillin
• Treatment: oral vancomycin (or fidaxomicin) for non-severe/severe CDI; metronidazole for very mild cases
• Relapse rate high (~20%); fidaxomicin preferred over vancomycin for reduced relapse

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Antibacterial Drug Classes

β-Lactams

Penicillins

Subclass	Examples	Spectrum	Notes
Benzylpenicillin (G)	Penicillin G	Streptococci, Neisseria, anaerobes, spirochetes	IV/IM; susceptible to β-lactamases
Phenoxypenicillins	Amoxicillin, ampicillin	Extended spectrum vs benzyl; includes H. influenzae, E. faecalis	Often combined with β-lactamase inhibitors (co-amoxiclav)
Anti-staphylococcal	Flucloxacillin, cloxacillin	β-lactamase-producing staphylococci	Not active against MRSA
Antipseudomonal	Piperacillin (+ tazobactam as Zosyn)	Broad Gram-negative including Pseudomonas, anaerobes	Requires tazobactam for stability
Anti-anaerobic	Benzylpenicillin, ampicillin-sulbactam (Unasyn)	Bacteroides, other anaerobes	Sulbactam also inhibits some ESBLs

β-lactam/β-lactamase inhibitor combinations:

• Co-amoxiclav (amoxicillin + clavulanic acid): covers β-lactamase producers; clavulanic acid is a “suicide inhibitor”
• Piperacillin-tazobactam: broader spectrum including Pseudomonas and anaerobes
• Ampicillin-sulbactam: same concept as co-amoxiclav

Mechanism: β-lactams bind to penicillin-binding proteins (PBPs) → inhibit transpeptidation (cross-linking of peptidoglycan) → bacterial cell wall weakening → osmotic lysis.

Penicillin allergy: Cross-reactivity between penicillins and cephalosporins is approximately 1–2% (lower than historically assumed). Avoid cephalosporins if history of immediate/anaphylactic penicillin reaction. Use alternative classes or perform skin testing if history non-severe.

Cephalosporins

Generations based primarily on Gram-negative coverage:

Generation	Examples	Spectrum	Notes
1st	Cefalexin, cefazolin	Gram-positive cocci (not MRSA), some Gram-negatives	Oral (cefalexin) and IV (cefazolin)
2nd	Cefuroxime, cefaclor	Gram-positive + improved Gram-negative; some H. influenzae	Oral and IV
3rd	Ceftriaxone, cefotaxime, ceftazidime	Broad Gram-negative; ceftriaxone good CNS penetration; ceftazidime has antipseudomonal activity	Serious infections; meningitis
4th	Cefepime	3rd gen spectrum + Pseudomonas + improved Gram-positive	Gram-negative coverage including AmpC β-lactamase producers
5th	Ceftolozane-tazobactam	Antipseudomonal cephalosporin + β-lactamase inhibitor	Resistant Pseudomonas infections

Important cephalosporins in South Africa:

• Ceftriaxone: first-line for bacterial meningitis (S. pneumoniae, N. meningitidis, H. influenzae), severe community-acquired pneumonia, typhoid fever, gonorrhoea (where ciprofloxacin resistance is high)
• Cefotaxime: alternative to ceftriaxone; preferred in neonates (avoids bilirubin displacement)
• Ceftazidime: reserved for Pseudomonas infections in hospital settings

Carbapenems

Drug	Spectrum	Notes
Meropenem	Very broad; Gram-positive, Gram-negative (including Pseudomonas), anaerobes	Drug of choice for ESBL producers; good CNS penetration
Imipenem-cilastatin	Broad; similar to meropenem	Cilastatin protects imipenem from renal dehydropeptidase
Ertapenem	Broad but NOT Pseudomonas or Enterococcus	Once-daily dosing; community infections
Doripenem	Similar to meropenem	Pseudomonas coverage

Note: Meropenem and imipenem are reserved for serious multi-drug resistant infections due to resistance risk. In South Africa, carbapenem resistance in Acinetobacter and Klebsiella is an increasing concern.

Other β-Lactams

Aztreonam: Monobactam; only effective against Gram-negative aerobes (including Pseudomonas); no cross-reactivity with penicillins or cephalosporins; useful in patients with serious penicillin allergy needing Gram-negative cover.

Fosfomycin: Cell wall inhibitor; urinary tract infections only (IV formulation for serious infections); active against multi-drug resistant Gram-negatives including ESBL producers; single dose for uncomplicated UTI.

Glycopeptides

Vancomycin:

• Bactericidal for most Gram-positive organisms (but bacteriostatic against some isolates)
• Standard for MRSA infections, serious Gram-positive infections when MRSA suspected
• Not absorbed orally (oral formulation for C. difficile only)
• Requires TDM: trough 10–15 mg/L for serious infections (SA therapeutic range)
• Nephrotoxicity (audiotoxicity less common now at current doses); monitor renal function and vancomycin levels
• Red man syndrome (histamine release during infusion; managed by slowing infusion rate, pre-treatment with antihistamine)

Teicoplanin:

• Glycopeptide similar to vancomycin but with longer half-life
• Can be administered IV or IM (vancomycin requires IV)
• Lower nephrotoxicity than vancomycin
• Loading doses required for rapid attainment of therapeutic levels

Aminoglycosides

Agents: Gentamicin, amikacin, tobramycin, streptomycin (less common now)

Characteristics:

• Bactericidal; concentration-dependent killing
• Post-antibiotic effect (PAE) — bacterial killing continues after drug levels fall
• Effective primarily against Gram-negative aerobes; some Gram-positive activity (synergy with β-lactams against Enterococcus, Staphylococcus)
• Poor CNS penetration; no intracellular penetration
• Nephrotoxic (accumulate in proximal tubular cells); ototoxic (cochlear and vestibular)
• Requires TDM (peak and trough levels for gentamicin; trough for amikacin)
• Monitor: serum creatinine, audiometry (if prolonged use)

Dosing:

• Once-daily (extended interval) preferred over multiple daily dosing (better efficacy, less toxicity)
• Hartford nomogram or Makinton formula for once-daily gentamicin

Gentamicin dosing in South Africa (public sector):

• 5–7 mg/kg/day IV (once daily or divided 8-hourly)
• Target trough: <2 mg/L; peak: 5–10 mg/L
• Adjust for renal impairment

Macrolides

Agents: Erythromycin, azithromycin, clarithromycin

Mechanism: Bind to 50S ribosomal subunit → inhibit translocation → bacteriostatic

Spectrum:

• Erythromycin: Gram-positive cocci (including some macrolide-resistant S. pneumoniae), Mycoplasma, Chlamydia, Legionella, pertussis
• Azithromycin: Similar + enhanced Gram-negative activity (H. influenzae, Moraxella), and atypical mycobacteria
• Clarithromycin: Similar + used in H. pylori triple therapy, MAC prophylaxis

Important interactions:

• CYP3A4 inhibition (erythromycin, clarithromycin > azithromycin) → many drugs affected (statins, benzodiazepines, carbamazepine, etc.)
• QT prolongation: all macrolides (erythromycin most; azithromycin moderate)

Clarithromycin and CYP3A4 in South Africa: Commonly used for respiratory infections and H. pylori; significant interactions with statins (simvastatin contraindicated, pravastatin safer), warfarin (increased INR), and carbamazepine.

Fluoroquinolones

Agents: Ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, norfloxacin (UTI only)

Mechanism: Inhibit bacterial DNA gyrase (gyrA) and topoisomerase IV → DNA replication halted → bactericidal

Spectrum:

• Ciprofloxacin: Excellent Gram-negative coverage (including Pseudomonas, Neisseria); some Gram-positive (NOT Streptococcus pneumoniae reliably); atypical coverage (Mycoplasma, Chlamydia)
• Levofloxacin: Enhanced Gram-positive (S. pneumoniae); slightly less Gram-negative than ciprofloxacin
• Moxifloxacin: Best Gram-positive and anaerobic coverage; no Pseudomonas activity

Important adverse effects:

• Tendinopathy/tendon rupture (ciprofloxacin > levofloxacin > moxifloxacin): risk factors: age >60, corticosteroids, renal impairment, transplant patients; avoid in children <18 years
• QT prolongation
• Photosensitivity
• CNS effects (seizures, especially with concomitant NSAIDs or theophylline)
• C. difficile infection

Resistance concerns in South Africa: High rates of fluoroquinolone resistance in Gram-negative organisms in some settings; ciprofloxacin resistance in TB (ciprofloxacin used as second-line TB drug — should not be used as empiric therapy for diarrhoea where TB is a differential in high-burden settings).

Sulfonamides and Trimethoprim

Co-trimoxazole (trimethoprim-sulfamethoxazole / TMP-SMX):

• Sequential blockade of folate synthesis: SMX inhibits dihydropteroate synthase; TMP inhibits dihydrofolate reductase
• Bactericidal together; each alone is bacteriostatic
• Broad spectrum: Gram-positive (including Listeria, Nocardia, Stenotrophomonas maltophilia), many Gram-negatives (not Pseudomonas)
• Used in SA for: PCP prophylaxis (pneumocystis pneumonia in HIV/AIDS), toxoplasmosis prophylaxis, bacterial UTI (uncomplicated), shigellosis, bronchiectasis prophylaxis

Dosing:

• Uncomplicated UTI: 160 mg TMP/800 mg SMX (one tablet) BD for 3 days
• PCP prophylaxis: 160/800 (one tablet) 3× per week (or daily for primary prophylaxis)
• Sepsis/serious infection: higher doses IV

Adverse effects:

• Hyperkalaemia (TMP inhibits renal potassium secretion)
• Bone marrow suppression (folate antagonism)
• Stevens-Johnson syndrome / Toxic Epidermal Necrolysis (especially in HIV patients)
• Renal impairment (crystalluria with high doses; ensure adequate hydration)
• Warfarin interaction (increases INR)

SAHPRA note: Co-trimoxazole scheduling — general sales for some indications; prescription-only for higher doses.

Tetracyclines and Glycylcyclines

Tetracyclines: Tetracycline, doxycycline, minocycline

• Bacteriostatic; inhibit 30S ribosomal protein synthesis
• Broad spectrum: Rickettsia, Mycoplasma, Chlamydia, Lyme disease, some Gram-positive (MRSA susceptible to doxycycline/minocycline), anthrax
• Doxycycline preferred over tetracycline (better absorption, fewer GI effects, less frequent dosing)
• NOT for children <8 years (teeth staining, bone growth effects) unless life-threatening and no alternative
• Photosensitivity (doxycycline most)
• Oesophageal ulceration (take with food and full glass of water; avoid before bedtime)

Tigecycline:

• Glycylcycline (derivative of tetracycline); not affected by common tetracycline resistance mechanisms
• Bacteriostatic; very broad spectrum including MRSA, VRE, Acinetobacter, ESBL producers
• No renal or hepatic dose adjustment required (but monitor GI side effects)
• Reserved for serious multi-drug resistant infections when no other options
• Higher mortality observed in some trials vs comparators (particular infections, including ventilator-associated pneumonia); use with caution

Oxazolidinones

Linezolid:

• Bacteriostatic; binds to 50S ribosomal subunit (23S rRNA) → prevents 70S initiation complex
• Active against Gram-positive organisms: MRSA, VRE, coagulase-negative staphylococci, Streptococcus pneumoniae
• Available IV and PO (bioavailability ~100%); can be used for step-down from IV
• Long-term use: bone marrow suppression (thrombocytopenia most common), peripheral neuropathy, optic neuropathy (monitor FBC, ophthalmology if >28 days)
• Serotonin syndrome risk (weak MAOI) if combined with serotonergic drugs (SSRIs, SNRIs, tramadol, meperidine)
• No dosage adjustment for renal impairment

Tedizolid: Similar spectrum; once-daily dosing; less bone marrow suppression; IV and PO.

Polymyxins

Colistin (polymyxin E) and polymyxin B:

• Bactericidal; disrupts bacterial cell membrane (Gram-negative only)
• Last resort for multi-drug resistant Gram-negative infections (Pseudomonas, Acinetobacter, carbapenem-resistant Enterobacteriaceae)
• Nephrotoxic (dose-limiting); neurotoxic
• Dosing based on ideal body weight; loading dose recommended for severe infections
• Monitor renal function and colistin levels (where available)
• In South Africa, colistin is reserved for extreme cases; resistance is emerging

Antituberculous Drugs

TB is a critical public health issue in South Africa (one of the top 30 high-burden countries globally).

First-line TB treatment (drug-susceptible TB):

Drug	Abbreviation	Mechanism	Key Adverse Effects
Isoniazid (INH)	H	Inhibits mycolic acid synthesis	Hepatotoxicity; peripheral neuropathy (prevent with pyridoxine B6); drug-induced lupus
Rifampicin (RIF)	R	Inhibits RNA polymerase	Hepatotoxicity; orange body fluids; potent CYP450 inducer (warfarin, ART, many drugs)
Pyrazinamide (PZA)	Z	Unknown (acidic environment)	Hepatotoxicity; hyperuricaemia; arthralgia
Ethambutol (EMB)	E	Inhibits arabinosyl transferase (cell wall)	Optic neuritis (red-green colour blindness); rare in children at standard doses

Standard regimen (intensive phase): 2HRZE (or HRZE) Continuation phase: 4HR (or 6H in some protocols)

Fixed-dose combinations (FDCs) used in South Africa:

• Rifafix, Rimstar (quadruple FDC: HRZE) for intensive phase
• Rifampicin-isoniazid (RH) for continuation phase

Drug-resistant TB:

• Rifampicin resistance (RR-TB) tested by GeneXpert MTB/RIF
• MDR-TB: resistant to INH + RIF (at minimum)
• Pre-extensively drug-resistant (pre-XDR): MDR + fluoroquinolone resistance
• XDR-TB: MDR + fluoroquinolone resistance + injectables (kanamycin, amikacin)
• Treatment: longer (9–24 months); newer drugs (bedaquiline, delamanid, linezolid, clofazimine)

Bedaquiline (Sirturo):

• Diarylquinoline; inhibits mycobacterial ATP synthase
• Approved for MDR-TB and XDR-TB in South Africa
• SAHPRA conditional registration; included in NTCP (National Tuberculosis Programme) guidelines
• Significant cardiotoxicity (QT prolongation); requires ECG monitoring

Monitoring during TB treatment:

• LFTs (baseline, then monthly)
• Visual acuity and colour vision (ethambutol — baseline and monthly)
• Serum uric acid (pyrazinamide — baseline and if symptomatic)
• Sputum for acid-fast bacilli (AFB) at 2 months, 5 months, end of treatment
• Weight (dose adjustments as weight changes, especially in children)

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Antifungal Therapy

Fungal Classification

Type	Examples	Cell Wall	Cell Membrane
Yeasts	Candida, Cryptococcus	β-glucan	Ergosterol
Moulds	Aspergillus, Mucor, Rhizopus	β-glucan	Ergosterol
Dimorphic fungi	Histoplasma, Blastomyces	β-glucan	Ergosterol
Dermatophytes	Trichophyton, Microsporum	β-glucan	Ergosterol

Antifungal Drug Classes

Polyenes — Amphotericin B and its formulations:

• Binds ergosterol → forms pores in fungal cell membrane → cell death
• Broad spectrum (Candida, Cryptococcus, Aspergillus, Mucorales)
• Amphotericin B deoxycholate: nephrotoxicity (dose-limiting); infusion reactions (fever, chills, hypotension)
• Liposomal amphotericin B (L-AmB): less nephrotoxic; equally effective; preferred in SA for serious fungal infections in patients with or at risk of renal impairment
• Azoles: first-line for many fungal infections; better safety profile

Azoles — Inhibition of lanosterol 14-α-demethylase (ergosterol synthesis):

Drug	Notes
Fluconazole	Fungistatic; Candida (including C. albicans, C. glabrata dose-dependent, C. krusei intrinsically resistant), Cryptococcus; excellent CNS penetration; CYP2C9/CYP2C19/CYP3A4 inhibitor
Itraconazole	Aspergillus, Histoplasma, Blastomyces, Sporotrichosis, onychomycosis; requires acidic environment for absorption (avoid with PPIs/antacids); CYP3A4 inhibitor
Voriconazole	Aspergillus (drug of choice), other filamentous fungi; CYP2C9/2C19/3A4 substrate and inhibitor; visual disturbances (common); hepatotoxicity; many drug interactions
Posaconazole	Broadest azole; Aspergillus, Mucorales, Candida; prophylaxis in immunocompromised; CYP3A4 inhibitor; better tolerated than itraconazole

Echinocandins — Caspofungin, micafungin, anidulafungin:

• Inhibits β-(1,3)-glucan synthase → disrupts fungal cell wall
• Fungicidal for Candida; fungistatic for Aspergillus
• IV only; no oral formulation
• Not metabolised by CYP enzymes (few drug interactions)
• Used for invasive candidiasis, aspergillosis when azoles contraindicated or failed
• Well tolerated; minimal nephrotoxicity

Flucytosine (5-FC):

• Converted to 5-fluorouracil (5-FU) by fungal cytosine deaminase → inhibits DNA/RNA synthesis
• Used in combination with amphotericin B for cryptococcal meningitis (synergistic)
• Monitor levels; narrow therapeutic range (50–100 mg/L)
• Bone marrow suppression at high levels

South African context for antifungals:

• Cryptococcal meningitis is a major opportunistic infection in advanced HIV/AIDS; treatment: amphotericin B + flucytosine (induction), then fluconazole (consolidation/maintenance)
• South African guidelines (NACM (National AIDS and STI Indicator) and HIV guidelines): flucytosine and liposomal amphotericin B are registered for this indication
• Voriconazole registered for invasive aspergillosis
• Availability of newer antifungals (isavuconazole, posaconazole) in public sector may be limited

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Antiviral Therapy

HIV Antiretroviral Therapy (ART)

South Africa has the largest ART programme in the world. Pharmacists working in HIV care must know the major drug classes, interactions, and adverse effects.

NRTIs (Nucleoside/Nucleotide Reverse Transcriptase Inhibitors):

• Tenofovir disoproxil fumarate (TDF) — first-line backbone; nephrotoxicity and bone density effects
• Tenofovir alafenamide (TAF) — less nephrotoxic and bone effects; weight gain; caution with hepatitis B
• Emtricitabine (FTC) — similar to 3TC; once-daily formulation
• Lamivudine (3TC) — well tolerated; hepatitis B co-treatment
• Zidovudine (AZT) — anaemia; GI intolerance; rarely used first-line now
• Abacavir (ABC) — hypersensitivity reaction (HLA-B*5701 testing required); cardiovascular risk

NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors):

• Efavirenz — first-line; CNS effects (vivid dreams, dizziness); teratogenicity (avoid in pregnancy); CYP2B6/CYP3A4 substrate and inducer
• Nevirapine — hepatotoxicity; severe rash (SJS); used less now
• Etravirine — second-line; many drug interactions (CYP2C9/2C19/3A4)
• Rilpivirine — first-line in some regimens; only for patients with CD4 >200 and viral load <100,000; food requirement; avoid with PPIs

Integrase Inhibitors (INSTIs):

• Dolutegravir — first-line; generally well tolerated; INSTI associated weight gain (metabolic effects); CYP3A4 not involved; good option for TB co-treatment (interacts with rifampicin — dolutegravir dose increase)
• Raltegravir — second-line; IV and PO;较少 drug interactions

Protease Inhibitors (PIs) — Ritonavir or cobicistat as boosters:

• Atazanavir/ritonavir — jaundice (unconjugated hyperbilirubinaemia); stone formation; CYP3A4 inhibitor
• Lopinavir/ritonavir (Kaletra) — GI intolerance; metabolic effects; limited use now due to better alternatives
• Darunavir/ritonavir — preferred PI; once or twice daily; CYP3A4 inhibitor

CCR5 Antagonist:

• Maraviroc — for R5-tropic HIV only; requires tropism testing; CYP3A4 substrate; drug interactions with rifampicin

First-line SA public sector regimen (according to NTCP):

• TDF + 3TC (or FTC) + Efavirenz (or dolutegravir in updated protocols)

ART and TB interactions:

• Rifampicin induces CYP3A4 and CYP2B6 → reduces PI and NNRTI levels
• Lopinavir/ritonavir: double dose (Kaletra 2 tabs BD instead of 1 tab BD) with rifampicin
• Dolutegravir: 50 mg BD (instead of 50 mg daily) with rifampicin
• NRTIs (tenofovir, 3TC): generally not affected by rifampicin

Hepatitis B and C Antivirals

Hepatitis B:

• Tenofovir (TDF or TAF) — first-line; long-term treatment
• Entecavir — first-line; CYP3A4 not significantly involved; resistance selection if not taken consistently

Hepatitis C:

• Direct-acting antivirals (DAAs): Sofosbuvir, ledipasvir, velpatasvir, glecaprevir/pibrentasvir, elbasvir/grazoprevir, voxilaprevir
• Cure rates >95% in most populations
• Expensive; access in South Africa public sector limited but improving
• Ribavirin (for some genotypes); teratogenic
• Drug interactions: sofosbuvir and others (CYP and transporter interactions)

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Antimicrobial Stewardship

Antimicrobial stewardship (ASP) refers to coordinated interventions designed to improve and measure the appropriate use of antimicrobials by promoting the selection of the optimal drug regimen, dose, duration, and route of administration.

Core Elements of ASP

1. Leadership commitment — institutional support and resources
2. Accountability — designated ASP team (pharmacist + infectious diseases physician + microbiologist)
3. Pharmacy expertise — clinical pharmacist with ID training
4. Tracking — monitoring of antimicrobial use and outcomes
5. Action — specific stewardship interventions (formulary restriction, pre-authorisation, de-escalation, IV-to-oral switch, dose optimisation)
6. Reporting — feedback to prescribers on antimicrobial use patterns and resistance

Key Stewardship Interventions

Intervention	Description
Formulary restriction	Limit access to certain broad-spectrum or high-risk antibiotics
Pre-authorisation	Require ID/pharmacy approval before dispensing restricted antibiotics
De-escalation	Narrow spectrum based on culture and susceptibility results
IV-to-oral switch	Switch from IV to oral formulation when clinically appropriate
Dose optimisation	TDM-guided dosing; alternative dosing regimens (extended infusion for piperacillin-tazobactam)
Duration optimisation	Shorter courses where evidence supports (CAP 5–7 days, cellulitis 5–7 days, pyelonephritis 7–14 days)

ASP in South Africa

SA Antibiotic Stewardship Programme (SAABSP):

• National initiative to promote rational antibiotic use -指引 hospital ASPs
• Point prevalence surveys (SAPS — South African Point Prevalence Survey)
• Resistance surveillance through NICD (National Institute for Communicable Diseases)

Pharmacist role in ASP:

• Daily review of restricted antibiotic prescriptions
• Intervention documentation
• Education to junior doctors and nurses
• Antimicrobial formulary management
• Surveillance of resistance patterns
• Patient counselling on antibiotic adherence

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SAPC Examination Focus Areas

High-yield topics for the SAPC exam:

1. β-lactam mechanisms and spectrum — penicillin-binding proteins, transpeptidation inhibition
2. Antibiotic resistance mechanisms — β-lactamases, MRSA (mecA gene), ESBL producers, VRE
3. Aminoglycoside TDM — peak/trough targets, nephrotoxicity monitoring, once-daily dosing
4. Fluoroquinolone adverse effects — tendinopathy, QT prolongation, C. difficile, photosensitivity
5. Vancomycin TDM — trough targets, nephrotoxicity
6. Co-trimoxazole — TMP-SMX spectrum, PCP prophylaxis, hyperkalaemia, SJS in HIV
7. First-line TB drugs — INH, RIF, PZA, EMB: mechanisms, adverse effects, monitoring
8. ART drug classes — NRTIs, NNRTIs, PIs, INSTIs: mechanisms, major adverse effects, interactions
9. Rifampicin as enzyme inducer — interactions with warfarin, ART, anticonvulsants
10. Antifungal classes — polyenes, azoles, echinocandins; azole interactions (CYP3A4)
11. Cryptococcal meningitis treatment — amphotericin + flucytosine, then fluconazole consolidation
12. Empiric vs directed therapy — narrowing spectrum based on culture results
13. Antimicrobial stewardship — pharmacist’s role, de-escalation, IV-to-oral switch
14. Penicillin allergy and cross-reactivity — cephalosporin use in penicillin-allergic patients

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Summary of Key Concepts

• Antimicrobial selection must account for likely pathogens, local resistance patterns, patient factors, and infection severity
• Understanding spectrum of activity is essential for appropriate empiric and directed therapy
• Resistance mechanisms include enzymatic inactivation, target alteration, reduced permeability, and efflux
• TDM is essential for aminoglycosides, vancomycin, and some antifungals (flucytosine)
• β-lactams are bactericidal by inhibiting cell wall synthesis; glycopeptides work similarly but are only effective against Gram-positives
• TB management in South Africa uses first-line HRZE; MDR/XDR-TB requires newer agents (bedaquiline)
• ART in South Africa is predominantly NRTI backbone + NNRTI or INSTI; rifampicin interactions require dose adjustments
• Cryptococcal meningitis treatment involves amphotericin B + flucytosine
• Antimicrobial stewardship is a core hospital pharmacy function; pharmacists must lead de-escalation, IV-to-oral switching, and monitoring
• Adverse effects of antibiotics (tendinopathy with fluoroquinolones, C. difficile with broad spectrum, SJS with co-trimoxazole in HIV) are commonly examined