Principles of Antimicrobial Therapy

Antimicrobial therapy means choosing a drug, dose, route and duration that delivers enough active drug at the site of infection to kill or arrest the pathogen, while limiting toxicity and the selection of resistance. The outcome depends on the host, the organism, the infected site and the drug together, so the same agent succeeds or fails depending on how well these are matched.

Mechanisms. Antibacterials act on cell wall synthesis (beta-lactams, glycopeptides), protein synthesis (macrolides, tetracyclines, aminoglycosides, oxazolidinones, lincosamides, chloramphenicol), nucleic acid synthesis or integrity (fluoroquinolones, rifamycins, nitroimidazoles), folate synthesis (sulphonamides, trimethoprim) and membrane integrity (polymyxins, daptomycin).

Bactericidal and bacteriostatic. The distinction depends on organism, inoculum and concentration, and seldom decides the choice. Bactericidal drugs are favoured where host defences cannot help: endocarditis, meningitis, neutropenia and infection of devices.

Pharmacodynamic patterns. Beta-lactams kill in a time-dependent way: the target is free drug concentration over the MIC for about 40 percent of the dosing interval for carbapenems, about 50 percent for penicillins and 60 to 70 percent for cephalosporins, with higher fractions in critical illness. Aminoglycosides and daptomycin kill in a concentration-dependent way (peak to MIC ratio of 8 to 10 or more for aminoglycosides). Fluoroquinolones, vancomycin, azithromycin and tetracyclines are driven by 24-hour AUC to MIC ratio (vancomycin about 400 or more).

Pharmacokinetics. Hydrophilic drugs (beta-lactams, aminoglycosides, glycopeptides) distribute in extracellular fluid and are cleared by the kidney. Lipophilic drugs (fluoroquinolones, macrolides, tetracyclines, linezolid, rifamycins, metronidazole) enter cells and tissue widely and are mostly metabolised. Tissue and compartment penetration (cerebrospinal fluid, bone, prostate, abscess, vegetation) often matters more than serum levels.

Antibacterial agents are grouped by structure and mechanism; each group differs in spectrum, tissue reach, route, toxicity and resistance liability.

Spectrum. Narrow-spectrum agents (benzylpenicillin, cloxacillin, nitrofurantoin) disturb the microbiome least. Broad-spectrum agents (piperacillin-tazobactam, carbapenems, fluoroquinolones, third generation cephalosporins) carry the highest risk of Clostridioides difficile infection and of selecting resistant Gram-negatives.

Oral availability. Amoxicillin, co-trimoxazole, doxycycline, metronidazole, clindamycin, linezolid, ciprofloxacin, levofloxacin and rifampicin reach serum levels close to intravenous dosing, which makes early oral switch safe. Oral cephalosporins, flucloxacillin and cloxacillin absorb less reliably and are not suited to deep-seated infection.

Toxicity profile. Each family has a characteristic dose-limiting effect: nephrotoxicity and ototoxicity (aminoglycosides, vancomycin at high exposure, polymyxins), tendon and CNS effects (fluoroquinolones), QT prolongation (macrolides, fluoroquinolones), marrow suppression (linezolid, chloramphenicol, co-trimoxazole), cholestasis (flucloxacillin, amoxicillin-clavulanate).

Before the first dose. Decide whether bacterial infection is likely. Take blood cultures (two sets) and cultures from the suspected source before antibiotics when this does not delay treatment. Give the first dose within 1 hour in septic shock or probable sepsis with organ dysfunction. Non-bacterial syndromes, asymptomatic bacteriuria (except in pregnancy and before urological procedures) and colonisation are not treated.

Empirical choice. Cover the likely organisms for the site, using local resistance data, severity, recent antibiotic exposure in the past 90 days, healthcare contact, travel, immune status and prior colonisation with resistant organisms. Source control (drainage, debridement, removal of infected devices) is part of therapy and often decides cure.

Dosing.

• Give a full first dose regardless of renal function. Loading doses are used for vancomycin (20 to 35 mg/kg actual body weight, maximum about 3 g), colistin and teicoplanin.
• In acute kidney injury, do not reduce beta-lactam doses in the first 24 to 48 hours of sepsis; reassess after that.
• In augmented renal clearance (creatinine clearance over 130 mL/min, common in young trauma and burns patients) beta-lactams are underdosed by usual regimens.
• In obesity, use actual weight for vancomycin loading, adjusted weight for aminoglycosides, and higher cefazolin prophylaxis doses (3 g at 120 kg or more).
• Extended or continuous infusion of piperacillin-tazobactam and meropenem improves target attainment in critical illness; the first dose is always given over 30 minutes.

Review at 48 to 72 hours. Stop if infection is excluded, narrow to the susceptible organism, switch to oral when the patient is afebrile or improving for 24 to 48 hours, haemodynamically stable, absorbing and without infection needing prolonged intravenous therapy (endovascular, CNS, undrained collections, some bone infections).

Duration. Shorter courses are as effective as long ones for most infections once source control is achieved.

Representative durations: uncomplicated cystitis 3 to 5 days; non-severe community pneumonia 3 to 5 days if clinically stable; cellulitis 5 days; Gram-negative bacteraemia from a controlled urinary or abdominal source 7 days; intra-abdominal infection after adequate source control about 4 days; uncomplicated Staphylococcus aureus bacteraemia at least 14 days from the first negative culture, and 4 to 6 weeks if complicated; pneumococcal meningitis 10 to 14 days; meningococcal meningitis 7 days.

Adverse effects. Common: gastrointestinal upset, rash, antibiotic-associated diarrhoea. Serious: anaphylaxis, severe cutaneous reactions, C. difficile colitis, organ toxicity specific to each family, and ecological harm through resistance.

Allergy. About 90 percent of patients labelled penicillin allergic are not allergic on testing. Clarify the reaction type, timing and treatment. Immediate (IgE) reactions and severe cutaneous reactions are avoided; benign remote rash or gastrointestinal intolerance does not exclude penicillins.

Monitoring.

• Renal function and electrolytes at baseline and at least every 2 to 3 days for aminoglycosides, glycopeptides and polymyxins.
• Therapeutic drug monitoring: vancomycin by AUC (target 400 to 600 mg.h/L) or trough 15 to 20 mg/L in older practice; gentamicin by a level at 6 to 14 hours after a once-daily dose or by pre-dose level under 1 mg/L.
• Full blood count and liver tests weekly in courses over 14 days.
• Clinical response, temperature, inflammatory markers and culture results at 48 to 72 hours.

Special groups.

• Pregnancy: penicillins, cephalosporins, azithromycin, erythromycin, clindamycin and metronidazole are acceptable. Tetracyclines, fluoroquinolones (unless essential), aminoglycosides (foetal ototoxicity), chloramphenicol near term and co-trimoxazole (first trimester folate antagonism, kernicterus at term) are avoided.
• Breastfeeding: penicillins, cephalosporins, macrolides and metronidazole are compatible; watch the infant for loose stools and thrush.
• Children: tetracyclines under 8 years are avoided except short doxycycline courses where needed; fluoroquinolones are restricted; ceftriaxone is avoided in neonates with jaundice or receiving calcium infusions; chloramphenicol is hazardous in neonates.
• Older adults: reduce doses for renal function, avoid fluoroquinolones where alternatives exist (tendon rupture, delirium, aortic risk).
• Region: in East Africa, high resistance to amoxicillin, co-trimoxazole and tetracyclines in many enteric and urinary isolates, ESBL carriage, over-the-counter sale, falsified or substandard products and limited culture services make syndromic empirical choice and local resistance data essential.

Referral and escalation. Involve microbiology or infectious diseases for S. aureus bacteraemia, endocarditis, CNS infection, bone and joint infection with implants, multidrug-resistant organisms, failure to improve at 72 hours, or unusual allergy history.