Describe the aminoglycosides and macrolides with their mechanisms, uses and toxicity.

Aminoglycosides — Mechanism and Properties

• Drugs — gentamicin, amikacin, tobramycin, netilmicin, streptomycin, kanamycin, neomycin
• Entry into the bacterium requires oxygen-dependent active transport, so they are inactive against anaerobes and work poorly in the acidic, anaerobic environment of an abscess
• Highly polar, so not absorbed orally — neomycin is given orally precisely because it stays in the gut, for bowel preparation and hepatic encephalopathy
• Do not cross the blood–brain barrier; excreted unchanged by glomerular filtration, so the dose must be adjusted to renal function
• Concentration-dependent killing with a marked post-antibiotic effect — the basis of once-daily dosing
• Synergy with beta-lactams and vancomycin, which damage the wall and let the aminoglycoside in — exploited in enterococcal and streptococcal endocarditis

Uses and Toxicity of Aminoglycosides

• Serious gram-negative infection — septicaemia, complicated urinary infection, hospital-acquired pneumonia, usually with a beta-lactam
• Endocarditis — with penicillin or vancomycin for synergy
• Streptomycin — second-line antitubercular; plague, tularaemia, brucellosis (with doxycycline)
• Amikacin — resistant to most aminoglycoside-modifying enzymes, so it is reserved for gentamicin-resistant organisms and for multidrug-resistant tuberculosis
• Topical neomycin; oral neomycin for gut decontamination

• Once-daily dosing is both more effective and less toxic, which sounds contradictory until the pharmacodynamics are separated.
• Killing tracks the peak concentration
• toxicity tracks the trough, because uptake into hair cells and tubular cells is saturable and depends on sustained exposure. One large dose gives a high peak and a long low trough — maximising the first and minimising the second.

Macrolides

• Uses — the alternative to penicillin in penicillin-allergic patients; atypical pneumonia (Mycoplasma, Legionella, Chlamydia); whooping cough; diphtheria carriers; Campylobacter; chlamydial urethritis and trachoma (single-dose azithromycin); H. Pylori; and MAC prophylaxis in HIV
• Adverse effects — gastrointestinal upset (erythromycin), QT prolongation and torsades, cholestatic hepatitis with erythromycin estolate, reversible ototoxicity at high dose, and numerous interactions through CYP3A4 inhibition — with statins (rhabdomyolysis), warfarin, carbamazepine, ciclosporin and theophylline
• Azithromycin is the macrolide of choice where interactions matter, and its single-dose regimens greatly aid adherence in trachoma and sexually transmitted infection programmes

Other Protein Synthesis Inhibitors

• Most protein synthesis inhibitors are bacteriostatic — the aminoglycosides are the notable exception, being bactericidal, which is why they are used in endocarditis where killing is required

Applied Aspects

• Monitor aminoglycosides by trough level (and peak where conventional dosing is used); check renal function before and during treatment, and hearing if treatment exceeds a few days
• Limit aminoglycoside courses to the shortest necessary, usually under 7 days; most toxicity relates to duration
• Never give an aminoglycoside for an abscess without drainage — it cannot work in that environment
• Avoid aminoglycosides in myasthenia gravis and in pregnancy
• Streptomycin-induced deafness is a significant and preventable disability in India, where it has been widely used for tuberculosis; audiometry and careful dosing matter
• Erythromycin with a statin risks rhabdomyolysis; azithromycin is the safer choice, or the statin is withheld for the course
• Azithromycin is invaluable in mass treatment programmes — a single dose treats trachoma and chlamydial infection, which makes directly observed therapy feasible on a population scale
• Aminoglycoside resistance is largely enzymatic, and amikacin resists most of these enzymes, which is why it is held in reserve rather than used first
• Check for concurrent nephrotoxins — contrast, NSAIDs, vancomycin, amphotericin — before starting an aminoglycoside, since the risks compound
• Ask about hearing and balance at every review, since early high-frequency loss is not noticed by the patient and vestibular damage may present only as unsteadiness in the dark
• Macrolides prolong the QT interval, and the risk is compounded by other QT-prolonging drugs and by hypokalaemia — a review of the drug chart before prescribing is worthwhile
• Erythromycin is used therapeutically as a prokinetic in gastroparesis and to clear the stomach before endoscopy in upper gastrointestinal bleeding, exploiting the motilin agonism that is otherwise a side effect
• Aminoglycosides remain valuable despite their toxicity — they are cheap, bactericidal and retain activity against many resistant gram-negatives; used for a short course with monitoring, the risk is acceptable
• Do not give an aminoglycoside as sole therapy for endocarditis; the synergy with a beta-lactam or vancomycin is the point, and neither works well alone
• Azithromycin resistance is rising in typhoid and gonorrhoea, both of which are common in India, so local sensitivity data must guide use rather than habit
• Reduce the aminoglycoside dose interval rather than the dose in renal impairment, preserving the high peak that gives efficacy while allowing a longer low trough
• Clarithromycin resistance now limits standard H. Pylori triple therapy in much of India, and quadruple or bismuth-based regimens are increasingly needed
• Neomycin is too toxic for systemic use and is confined to topical application and oral gut decontamination, where its lack of absorption is the point