Aminoglycosides

1. Aminoglycosides

2. Intro • Group of antibiotics used in the treatment of bacteria infections aerobic G-ve • Consists of 2 or more amino sugars and a hexose nucleus • Serious toxicity is a limiting factor for their application • Streptomycin was the first to be discovered in 1943 by Schatz, Bugie and Waksman

3. Other examples are: • Gentamicin* • Streptomycin • Amikacin • Neomycin • Netilmicin* • Tobramycin • Kanamycin • Paromomycin+ *Not from Streptomyce spp (from Actinomycetes spp) + Antiparasitic ( amoebiasis, cryptosporidiosis)

4. Families: • Determined by the type of amino sugar • Neomycin – there are 3 amino sugars attached to 2-deoxystreptamine e.g Neo B, Paromomycin • Kanamycin family – 2 amino sugars attached to 2 deoxystreptamine. E.gs amikacin*. Kanamycin A & B, tobramycin • *a semisynthetic derivative of kanamycin A and netilmicin is also semisynthetic

5. Aminoglycosides family • Gentamicin family- • Gent Ci, • Gent C1a and C2, • sisomicin and • Netilmicin (derivative of sisomicin) • Streptomycin family • Streptomycin and • dihydrostreptomycin. • Contains streptidine instead of deoxystreptamine

6. Spectrum of activity • Aerobic G-ve bacteria ( Citrobacter, Enterobacter, E. coli, proteus, Pseudomonas, Enterococci and Staph aureus *) • Lack activity against most anaerobic or facultative bacteria and activity against G+ve# organisms is limited * in combination # Strept pyogenes is highly resistant

7. Mechanism of Action • Bactericidal antibiotics • Penetration involves active transport • Inhibition of protein synthesis by binding to the 30S subunit of ribosomes • Causes misreading and premature termination of protein synthesis

8. Resistance- • May be plasmid mediated inactivation by microbial enzymes or failure of drug penetration • Synthesis of metabolizing enzymes • Mutation may alter ribosomal binding site for the aminoglycosides • Cross resistance with other aminoglycosides may occur

9. Absorption, Distribution and Elimination • Polar agents with poor oral absorption • Usual routes: IM or I.V • Cmax achieved within 30-90 of IM • Absorption increases in inflammation • No significant amount in breast milk • Plasma protein binding is minimal • Vd approximates 25% of lean body weight

10. Abs, Distr and Elimination • Penetration of CNS: 10-25% of plasma level • Accumulates in the perilymph and endolymph as well as renal cortex • Vd increases in – leukaemia • Clearance increases and T1/2 reduces in cystic fibrosis • T1/2 for most; 2-3 hours • Elimination is by glomerular filtration • Both haemo- and peritoneal dialysis remove aminoglycosides

11. Unwanted effects • Ototoxicity: netilmicin is reputed to be mildest on both Vest and Audi. Functions* • Nephrotoxicity# • Other neurotoxic effects – optic neuritis, peripheral neuritis, neuromuscular blockade • Others: angioedema, skin rash, blood dyscrasia, eosinophilia, fever, stomatitis, anaphylaxis *Neo/Amk/kan affect Audi more than others while Str/Gen tend to affect Vest fn more # Gen/Tob/Neo are relatively more nephrotoxic than the others NB: Nephrotoxic effects occurs in 5-10% of patients

12. Therapeutic drug monitoring Necessary in: • Patients with life threatening infections • Renal impairment • 24 hours into new regimen • Neonates • Samples usually taken just before and 30 minutes after a dose

13. Caution in: • Pregnancy • Myasthenia gravis (MG) • Renal impairment • Parkinson’s dx • 8th cranial nerve disease

14. Streptomycin • Usual dosage: 15-25 mg per Kg body wt IM Therapeutic applications in: • Bacterial endocarditis from enterococcal and group D Strep • Tularemia • Plague • Tuberculosis

15. Gentamicin • Inexpensive and reliable efficacy • Usual dose; 3-5 mg per Kg body wt in 3 divided doses daily • Therapeutic Applications: UTI, Pneumonia (nosocomial), Peritonitis, meningitis and sepsis

16. Tetracyclines

17. Tetracyclines • Broad spectrum antibiotics (incl: Legionella spp, Ureaplasma, Mycoplasma, chlamydia plasmodium and rickettsial infections) • Origin: Streptomyces spp • Examples: Chlortetracycline, demeclocyline, oxytetracycline, doxycline*, tetracycline*, minocycline* * semisynthetic

18. Mechanism of action: • Binding of the 30S subunit of ribosome, preventing the access of aminoacyl tRNA to the acceptor site on the mRNA-ribosome complex Resistance • Plasmid mediated decrease accumulation of the drug • Blockade of access by ribosome protecting protein • Enzymatic inactivation of TCN

19. ABS, DISTR and ELIMINATION • Most are incompletely absorbed when taken orally* • Abs occurs mainly in the stomach and upper small intestine • Fasting improves abs while presence of food or divalent cations reduce • Peak conc ~ 2-4 hr • T1/2: 6-12 hrs+ • Widely distributed (incl: RE cells in spleen, liver and bone marrow; also synovial and sinuses bone and dentine and prostate) *Chlortetracycline is worst; minocycline and doxy are best + half life of mino and doxy very long 16-18 hr

20. Undergoes entero-hepatic cycling • Most tetracyclines are excreted in urine (doxicycline, an exception) • Clinical uses • Wide range of bacteria diseases+ • Ricketsial infections • Mycoplasma • Chlamydia + Use often precluded by resistance

21. Unwanted effects • GI upset including abd pain, nausea, vomiting diarrhea • Photosensitivity • Hepatotoxicity • Renal toxicity • Teeth and bone discolouration • Skin rashes • Pseudomembraneous colitis • Thrombophlebitis (IV) • Pseudo-tumour cerebri • Leukopenia, Thrombocytopenic purpura

22. Chloramphenicol

23. Chloramphenicol • Broad spectrum antibiotic (MIC for sensitive strains < 8 ug/ml) • Antimicrobial spectrum: Rickettsial, salmonella infections Mechanism • Inhibition of protein synthesis via 50S subunit of ribosome** Resistance • Plasmid mediated elaboration of inactivating enzymes (acetyl transferase) ** Other 50S: erythromycin Clindamycin

24. Chloramphenicol • Introduced to clinical practice in 1949 • Bacteriostatic • Fallen out favour in western countries cos it causes aplastic anaemia • Main use restricted as eye ointment/drops • Poorly dissolves in water requiring that IV is given as succinate ester. • The succinate ester is incompletely hydrolysed (70%); hence oral preferred to IV

25. Chloramphenicol • Usual oral dose = 50 mg per kg • IV usually 75 mg per kg • Drug level to be monitored in neonates to < 4 yrs old, elderly, renal impaired patients • Recommended peak level 15-25 mg/ml (sample taken 1 hr after dose) • Trough level < 15mg/kg (sample taken b4 next dose)

26. ABS DISTR EXCN • Well absorbed when given orally, (IM not advised as it is poorly absorbed) • Peak conc achieved within 2 hours • 60% of plasma found in CSF • T1/2 2 hours • 10% unchanged in urine, the rest is inactivated by glucuronidation in the liver

27. ADRs • Gray baby syndrome (consisting of: VDFlaccidityHypothermia Ashen-gray colour); Gray syndrome • Jarisch_Hexheimer reactions when used in brucellosis • Bone marrow suppression: • presents with low Hb; • does not predict Aplastic anaemia, • dose dependent (>20g) • Risk of leukaemia

28. ADRs • Bone marrow aplasia* • Not dose dependent • Unpredictable • commonest with oral (1:24000, least with eye preps (1: ~250000); • may begin weeks after stopping drug • Interactions: Phenytoin, phenobarb, Rifampicin, chlorpropamide, dicoumarol *Such effect unknown with Thiamphenicol (a methyl-sulphonyl analogue of Chloramphenicol)

29. The Quinolones

30. Intro • Group of broad spectrum antibiotics • Also known as DNA gyrase • Generally bactericidal • May be broadly divided into two groups • Fluoroquinolones • Other quinolones: Nalidixic acid, the oldest member, cinoxacin

31. Mechanism • Penetrates bacterial cell easily • Inhibition of DNA gyrase • (in eukaroytes is called Topoisomerase II) • Prevents DNA replication • Blocks transcription • Resistance results from: • Increased efflux of drug • Altered DNA gyrase binding site

32. Classes of quinolones • 4 generations (plus!) • Earlier generations have narrower spectrum • 1st generation: Nalidixic acid, cinoxacin, oxolinic acid • 2nd generation: ciprofoxacin, enoxacin, ofloxacin, norfloxacin • 3rd : sparfloxacin, levofloxacin • 4th : gatifloxacin, sitafloxacin

33. ADME • General good absorption profile • Achieves peak plasma conc. 1-3 hrs • Food may reduce rate but not extent of absorption • Bioavailability ranges from 50-90% • Kidneys involved in excretion

34. Clinical uses • UTI • Travellers’ diarrhoea • Bone, joint soft tissues infections • Respiratory infections esp. • Legionella spp • Mycoplasma • Mycobacterium spp infections • Other organisms: Chlamydia, Brucella

35. ADRs • Peripheral neuropathy • Tendonitis and tendon rupture can occur • Rhabdomyolysis • SJS • Pseudomembranous colitis • Prolongation of QT interval • Not recommended in pre-pubertal b’cos of tendency to cause arthropathy

36. The Macrolides

37. The macrolides • Many membered lactone ring plus deoxy sugar • Bacteriostatic antibiotics • Inhibits protein synthesis (50S) • Resistance is usually plasmid mediated reduced • Erythromycin • Azithromycin • Clarithromycin

38. macrolides • Spectrum of antibacterial activity • Mostly Gram +ve • Diphtheria • Mycoplasma • Legionella • Mycobacteria • Borrelia

39. Macrolides • Erythromycin base is susceptible to gastric acid inactivation • Thus, it is usually presented in enteric form • Poorly penetrates CNS but crosses placenta barrier • Plasma protein binding 70-90% • Half life is ~ 2 hours • Clinical uses include: Toxoplasmosis and cryptosporidiasis in HIV/AIDS • Chlamydia, mycoplasma, pertusis, tetanus, syphilis, H. pylori

40. Erythromycin ADRs • Hypersensitivity reactions • Cholestatic jaundice* • Cardiac arrhythmias • Transient hearing loss * Likened to hypersensitivity rxn. Starts ~10 days; GI disturbance; + fever; leukocytosis; eosinophilia; elevated liver enzymes • Interactions include inhibition of metabolism of: Digoxin, astemizole, carbamazepine, warfarin