Protein Synthesis Inhibitors

Ribosomal targets

Selective toxicity. Bacteria translate on 70S ribosomes (30S plus 50S subunits); human cytoplasmic ribosomes are 80S (40S plus 60S). Mitochondrial ribosomes resemble bacterial ones, which explains some toxicities, such as linezolid lactic acidosis and chloramphenicol gray baby syndrome. Most ribosome-targeting drugs are bacteriostatic; aminoglycosides are the bactericidal exception.

Aminoglycosides

Mechanism. Gentamicin, tobramycin, amikacin, streptomycin and neomycin bind the 30S subunit, block formation of the initiation complex and cause misreading of mRNA. Misfolded proteins inserted into the membrane increase drug entry, and the cell dies. Killing is concentration-dependent with a long post-antibiotic effect, so a single large daily dose gives high peaks and near-zero troughs, which also limits toxicity.

Spectrum. Entry across the inner membrane uses oxygen-dependent active transport, so anaerobes such as B. fragilis are intrinsically resistant, and activity is poor in acidic, hypoxic abscesses. The targets are aerobic gram-negative rods; tobramycin and amikacin are the best against Pseudomonas. Streptomycin or gentamicin treats plague and tularemia, and streptomycin is a second-line TB drug. Oral neomycin is not absorbed and is used for bowel preparation and hepatic encephalopathy.

Synergy. A β-lactam or vancomycin damages the cell wall and lets the aminoglycoside reach the ribosome, converting two inhibitory drugs into a bactericidal pair. Ampicillin plus gentamicin is the classic regimen for enterococcal endocarditis; ampicillin plus ceftriaxone is an alternative for E. faecalis that spares the kidneys.

Kidneys and ears. Proximal tubular uptake causes nonoliguric acute tubular necrosis that is usually reversible. Hair-cell damage causes irreversible cochlear toxicity (high-frequency hearing loss first) and vestibular toxicity (ataxia, oscillopsia). Risk rises with loop diuretics, vancomycin, cisplatin, long courses and high troughs. Carriers of the mitochondrial 12S rRNA variant m.1555A>G can go deaf even at standard doses. Aminoglycosides cross the placenta and can cause congenital deafness.

Aminoglycosides reduce presynaptic acetylcholine release by competing with calcium. They can precipitate weakness or apnea in myasthenia gravis, with neuromuscular blocking agents, or after rapid infusion; calcium reverses the block.

Resistance. Plasmid-encoded modifying enzymes (acetyltransferases, adenylyltransferases and phosphotransferases) inactivate the drug. Amikacin resists most of these enzymes and is kept for resistant gram-negatives.

Tetracyclines

Mechanism and spectrum. Doxycycline, minocycline and tigecycline bind the 30S subunit and block aminoacyl-tRNA docking at the A site; they are bacteriostatic. Active uptake concentrates them inside cells, which suits intracellular organisms: Rickettsia (Rocky Mountain spotted fever), Ehrlichia and Anaplasma, Borrelia (Lyme disease), Chlamydia and Mycoplasma. They also treat CA-MRSA skin infections and acne. Resistance comes from efflux pumps and ribosomal protection proteins.

Tigecycline. This glycylcycline evades common tetracycline resistance and adds MRSA, VRE and ESBL organisms, but not Pseudomonas or Proteus. It is IV only and carries a warning for higher all-cause mortality.

Absorption and elimination. Calcium in dairy, magnesium and aluminum antacids, and iron supplements chelate tetracyclines in the gut, so doses are separated by hours. Doxycycline is eliminated mainly in feces and needs no renal adjustment; older tetracyclines accumulate in renal failure.

Toxicity. Binding to calcium in developing teeth and bone causes permanent yellow-brown staining, enamel hypoplasia and slowed bone growth. Short doxycycline courses do not stain teeth, so doxycycline remains first-line for suspected RMSF at any age. Other effects are phototoxic sunburn, pill esophagitis (take with a full glass of water and stay upright), pseudotumor cerebri (worse with isotretinoin) and GI upset. Minocycline adds vertigo, blue-gray skin pigmentation and drug-induced lupus. Degraded, expired tetracycline can cause Fanconi syndrome, and demeclocycline causes nephrogenic diabetes insipidus, which is exploited to treat SIADH.

Macrolides and clindamycin

Macrolide mechanism and uses. Azithromycin, clarithromycin and erythromycin bind 23S rRNA of the 50S subunit and block translocation. They treat atypical pneumonia (Mycoplasma, Chlamydophila, Legionella), chlamydia (azithromycin is used in pregnancy), pertussis treatment and prophylaxis, MAC (azithromycin prophylaxis; clarithromycin plus ethambutol treatment) and H. pylori (clarithromycin-based therapy). Resistance arises from erm methylation of 23S rRNA, which also blocks clindamycin, or mef efflux pumps.

Macrolide adverse effects. QT prolongation can cause torsades. Erythromycin stimulates motilin receptors, causing cramps and diarrhea, an effect used to treat gastroparesis. Erythromycin estolate can cause cholestatic hepatitis. Erythromycin or azithromycin in the first weeks of life raises the risk of infantile hypertrophic pyloric stenosis, which presents with nonbilious projectile vomiting.

CYP3A4 interactions. Erythromycin and clarithromycin (and the ketolide telithromycin) strongly inhibit CYP3A4 and P-glycoprotein, raising levels of statins (rhabdomyolysis), carbamazepine, theophylline, cyclosporine, tacrolimus, warfarin and digoxin. Azithromycin barely affects CYP3A4 and is the interaction-safe choice.

Clindamycin. It binds 23S rRNA at a site overlapping the macrolides and blocks translocation of the growing peptide. It covers gram-positive cocci, including many CA-MRSA strains, and oral anaerobes, which suits aspiration pneumonia, lung abscess and dental infections. Rising B. fragilis resistance limits it below the diaphragm, where metronidazole is preferred. It also treats bacterial vaginosis and, with quinine, malaria and babesiosis.

Toxin suppression. Because clindamycin halts protein synthesis regardless of growth phase, it is added to a β-lactam in necrotizing fasciitis and in streptococcal or staphylococcal toxic shock to shut down exotoxin and superantigen production; IVIG, not clindamycin, neutralizes toxin already circulating.

Clindamycin carries the highest classic risk of C. difficile colitis: watery diarrhea, fever and leukocytosis, with yellow-white pseudomembranes on colonoscopy.

Linezolid and chloramphenicol

Linezolid. This oxazolidinone binds 23S rRNA of the 50S subunit and prevents assembly of the 70S initiation complex, a step no other 50S-binding class targets. It treats MRSA (pneumonia, skin infections) and VRE, and its near-100% oral bioavailability allows an early IV-to-oral switch. Resistance arises from 23S rRNA point mutations or the transferable cfr methyltransferase.

Linezolid toxicity. Courses beyond about two weeks cause myelosuppression, especially thrombocytopenia; longer use causes optic and peripheral neuropathy and lactic acidosis from inhibition of mitochondrial ribosomes. As a weak monoamine oxidase inhibitor it can precipitate serotonin syndrome with SSRIs and hypertensive reactions with tyramine-rich foods.

Chloramphenicol. It binds the 50S subunit and inhibits peptidyltransferase. The spectrum is broad (meningitis pathogens, Rickettsia, anaerobes) and CSF penetration excellent, but toxicity restricts it mainly to resource-limited settings. It causes dose-related, reversible marrow suppression and, separately, a rare, dose-independent and often fatal aplastic anemia.

Gray baby syndrome: neonates, especially preterm, have low UDP-glucuronosyltransferase activity and immature renal excretion, so chloramphenicol accumulates and poisons mitochondria, causing vomiting, abdominal distension, ashen-gray cyanosis, hypotension and cardiovascular collapse.