Lincosamide, Glycopeptides & UTI

Clindamycin. a potent lincosamide antibiotic is similar in
mechanism of action (inhibits protein synthesis
by binding to 50S ribosome) and spectrum of
activity to erythromycin.
Oral absorption of clindamycin is good. It
penetrates into most skeletal and soft tissues,
but not in brain and CSF; accumulates in neutrophils
and macrophages. It is largely metabolized and
metabolites are excreted in urine and bile. The
t½ is 3 hr.
Vancomycin is a glycopeptide antibiotic discovered in 1956
as a penicillin substitute which assumed special
significance due to efficacy against MRSA,
Strep. viridans, Enterococcus and Cl. difficile.
Bactericidal action is exerted on gram-positive
cocci, Neisseria, Clostridia and diphtheroids.
However, in hospitals where it has been
extensively used for surgical prophylaxis, etc.
URINARY ANTISEPTICS
Some orally administered AMAs attain antibacterial
concentration only in urine, with little or
no systemic antibacterial effect. Like many other
drugs, they are concentrated in the kidney tubules,
and are useful mainly in lower urinary tract
infection. They have been called urinary
antiseptics because this may be considered as
a form of local therapy. Nitrofurantoin and
methenamine are two such agents; infrequently
used now. Nalidixic acid can also
be considered to be a urinary antiseptic.

1. LINCOSAMIDES GLYCOPEPTIDES & URINARY TRACT INFECTION 28 January 2018 1 VINAY GUPTA DEPT OF PHARMACOLOGY UP UNIVERSITY OF MEDICAL SCIENCES, SAIFAI, ETAWAH (UP) INDIA

2. 1 4 5 3 3 2 Modes of Antimicrobial Action of AMAs

3. LINCOSAMIDES 28 January 2018 3

4. Lincomycin Clindamycin Pirlimycin MOA : Similar to Macrolides . Binds with 23 rd portion of 50 S ribosome subunit of bacterial ribosome & prevents protein synthesis. Lincosamides don't interfere with protein synthesis in humans. LINCOSAMIDE BACTERIOSTATIC

5. Its first Lincosamide AB Absorbed Orally Eliminated in faeces through bile. Colitis is more common in comparison to Clindamycin . Dose: 500 mg Orally 600 mg (iv/ im ) 6-8 hourly LINCOMYCIN No More in Use

6. Clindamycin palmitate – Clindamycin Clindamycin phosphate – Clindamycin Strains resistant to macrolides are may be sensitive to clinda as clinda is not a substrate for macrolides efflux mechanism resistance. Resistance in Clinda may occur d/t alternation in metabolism & also d/t methylation of bacterial RNA + nt in 50 S ribosomal subunit of Bacteroides fragilis. CLINDAMYCIN

7. Strains resistant to macrolides are may be sensitive to clinda as clinda is not a substrate for macrolides efflux mechanism resistance. Resistance in Clinda may occur d/t alternation in metabolism & also d/t methylation of bacterial RNA + nt in 50 S ribosomal subunit of Bacteroides fragilis. CLINDAMYCIN

8. Oral absorption is Good. Absorption is not affected by presence of Food. Plasma t1/2 is 3 hrs Plasma protein binding is > 90% Distribution - PKa CLINDAMYCIN

9. About 10% of drug excreted unchanged in Urine. It undergoes intrahepatic circulation & the metabolites are excreted in urine, bile & faeces. Dose reduction is required in case of hepatic dysfunction. PKa CLINDAMYCIN

10. Sensitive Anaerobic Bact. MSSA Therapeutic Uses - CLINDAMYCIN Resistant Gm – ve Bacilli MRSA Effective for infections caused by- Bacteroides fragilis Bact. melanenogenicus Clost . perfringens Fusobacterium Peptostreptococcus

11. Therapeutic Uses - CLINDAMYCIN as an alternative drug for bacterial endocarditis . 1 % cream – Acne vulgaris . with Primaquine – Pneumosystis with Pyrimethamine – Encephalitis ( Toxoplasma gondii ) with Quinine/ Artesunate – Maleria with Aminoglycosides / Cephalosporins – non sexually transmitted infection of genital tract of females.

12. 600 – 1200 mg/ day 1200 – 2400 mg/day * *(in severe cases by IV route, in 4 divided dose) CLINDAMYCIN DOSE -

13. Pseudomembranous colitis d/t Clost . difficile - Hypersensitivity Reactions - Liver enzymes - Thrembophlebitis - CLINDAMYCIN ADVERSE EFFECTS - Safe in Pregnancy & Children's

14. Active only against GM + ve bact. MOA same as Clinda Preferably used for treatment of Mastitis. PIRLIMYCIN

15. GLYCOPEPTIDES 28 January 2018 15

16. Inhibitors of Cell wall synthesis bactericidal for all susceptible bacteria except Enterococci Only active against Gm + ve bact. Except Flavobacterium all Gm – ve bact including pseudomonas & mycobacterium are resistant. GLYCOPEPTIDES BACTERICIDAL Gm + ve

17. Tricyclic glycopeptide Obtained from Streptococcus orientalis in 1956 Its not susceptible to any of the Beeta - lactamases . Inhibits cell wall synthesis Bactericidal VANCOMYCIN

18. has high affinity & binds with D- alanyl - D- alanine dipeptide terminus of nascent peptidoglycon & prevents its release. Elongation of peptidoglycon or polymerization is inhibited d/t inhibition of transglycosylase , so the further step of cross linking is not possible, leading to cell damage. MOA - VANCOMYCIN

19. Resistant to Enterococci Resistance is d/t alteration of dipeptide from D- alanyl - D- alanine to D- alanyl - D- lactate OR to D- alanyl - D- serine. RESISTANCE - VANCOMYCIN Vancomycin + Aminoglycosides

20. Oral absorption is poor bt used orally in case of Pseudomembranous colitis. also used orally for Staphylococcal enterocolitis . water soluble. t1/2 is 6 hr, used at 6 hourly. Distribution – body fluids Reaches to CNS 90% of drug is excreted unchanged through kidneys. PKa - VANCOMYCIN Only IV No IM

21. Sensitive for- Streptococcal bact. like- S. pyogenes S. pneumoniae S. viridans MRSA MRSE Corynebacterium Clostridium spp. ( difficile ) THERAPEUTIC USES - VANCOMYCIN Gm + ve Only

22. It should be only used for serious nosocomial infections where other agents are not effective. It can be used in pts allergic to penicillins or cephalosporins & also for surgical prophylaxis for MRSA infections. its drug of choice for MRSA like- Pneumonia Endocarditis Soft tissue abscess Osteomyelitis THERAPEUTIC USES - VANCOMYCIN

23. Vancomycin + Cefotaxime / Ceftriaxone / Rifampicin – for treatment of penicillin resistant Pneumococcal meningitis caused by Streptococcus pneumoniae . also used for vascular catheter infections d/t Gm + ve organism. Drug of choice for Pseudomembranus colitis caused by Clost . difficile THERAPEUTIC USES - VANCOMYCIN

24. Glycopeptide Active against both MSSA & MRSA its more active against Enterococci than Vanco & also active against VRE . t1/2 is long – 100 hrs , OD Highly bounded with plasma proteins TICOPLANIN Both IV & IM

25. Skin Rashes Pain & Phlebitis- Rapid IV infusion / higher doses – Ototoxicity – Nephrotoxicity - RESISTANCE- VANCOMYCIN

26. Used for Osteomylitis d/t MSSA & MRSA . equally effective as Vanco for Pseudomembranus colitis caused by Clost . difficile with Gentamicin – Enterococcal Endocarditis . Dose: 400 mg im /iv / day Loading dose 200 mg im /iv / day Maintenance dose TICOPLANIN

27. Lypo-glycopeptide . effective against VRSA . t1/2 – 8 hr Indicated for complicated skin & soft tissue infections as/as hospital acquired infections & ventilator associated bacterial pneumonia d/t S. aureus. TELAVANCIN

28. Lipo-glycopeptide . effective against MRSA & VRE t1/2 is too long – 6-11 Days used once in a week Drug is still under evaluation. DALBAVANCIN

29. URINARY TRACT INFECTION 28 January 2018 29

30. Bacteriuria Pyuria Bact may + nt in distal urethra as transient flora, most of which are derived from faecal flora. Types of UTI- UTI Lower UTI Uretheritis Cystitis Prostatitis Upper UTI Acute Pyelitis Acute Pyelonephritis

31. GENDER- Shorter length of urethra Sexual intercourse 2) Pregnancy 3) Obstruction to flow of urine 4) Neurogenic bladder 5) upward reflux of urine 6) Genetic factors UTI Predisposing Factors-

32. Asymptomatic Symptomatic Increased frequency of micturation dysuria suprapubic pain fever with rigors enlarged prostate in male – more susceptible. UTI Clinical Features-

33. Gm – ve Bacilli E. coli 70-80% acute infection 50% hospital acquired Klebsella Protius Psuedomonas Schigela Enterobactor Aerobactor UTI Causative Organism- Gm + ve Cocci Enterococci Streptococci Staphylococci 95% 5% Miscll . M. tuberculosis Citrobacter Salmonellae Candida albicans

34. - Antibiotics which specifically act at urinary tract Methenamine Nitrofurantoin Nalidixic acid They r mainly used for prophylactic purpose. Show remarkable potency in suitable pH of urine. UTI URINARY ANTISEPTICS

35. Hexa Methylene tetramine / Hexamine Its a Pro drug. Acids used are Mandelic acid Hippuric acid Ascorbic acid URINARY ANTISEPTICS METHENAMINE METHENAMINE FORMALDEHYDE Acidic pH Decomposition + Ammonia BACTERIOSTATIC

36. Favorable urinary pH- UTI ACIDIC Cloxacillin Tetracycline Nitrofuratoin Methenamine ALKALINE Cephalosporin Cotrimoxazole Aminoglycosides Fluroquinolones No effect Chloramphenicol Ampicillin

37. GIT discomfort / gastritis with dose > 2gm/day. Higher dose > 3gm/day for longer duration may cause – Painful micturation Albuminuria Haematuria Increased frequency of micturation Side Effects - URINARY ANTISEPTICS METHENAMINE

38. Highly useful against E. coli, Staph. aureus, Staph. epidermidis & other Gm – Ve bact. Protius vulgaris is resistant , produces Ammonia which raises pH of urine. Psuedomonas are resistant . Not effective for Upper UTI as drug is eliminated before converting to Formaldihyde . Not useful for tt of acute UTI. Mainly used for prophylaxis of resistance, chronic recurrent UTI including post catheterization or Instrumentation. URINARY ANTISEPTICS METHENAMINE

39. Absorbed orally. Enteric coated preparation preferred (20% of drug decomposed). pH – 5 (20% drug decomposed). Urine pH – 6, Urine output – 1.5 Ltr , Dose -2 gm Dose 0.5 – 1 gm QID with fluid restriction. PKa - URINARY ANTISEPTICS METHENAMINE

40. Used for both therapeutic & prophylaxis purpose in Lower UTI. During course of treatment, Resistance does not develop easily in susceptible bact. Bacteriostatic but at higher c/n may exert Bactericidal effect, especially in acidic pH URINARY ANTISEPTICS NITROFURANTOIN BACTERIOSTATIC C/N BACTERICIDAL

41. Active against E. coli & Enterococci Many Gm – ve bact are susceptible. Duration of treatment should not exceed > 2 weeks. Antagonizes activity of Nalidixic acid which is a Bactericidal UA drug Resistant for – Protius Psuedomonas Klebsella Enterobacter URINARY ANTISEPTICS NITROFURANTOIN

42. Absorbed orally. about 40% excreted unchanged in urine. undergo rapid hepatic metabolism. t1/2 is < 1 Hr, hence therapeutic antibacterial concentration is not achieved in plasma. Dose: 50 – 100 mg TDS/QID for 5-10 days URINARY ANTISEPTICS NITROFURANTOIN PKa -

43. GIT upset, Anorexia Haemolysis may occur in persons with G-6-PD deficiency. Colour of urine turns brown on exposure to air. Acute pulmonary toxicity may occur in elderly. Polyneuropathy may occur on prolonged treatment in impaired renal function patients. Probenecid decreases its action by inhibiting renal tubular secreations . URINARY ANTISEPTICS NITROFURANTOIN S/E- NO to Pregnancy Neonates Renal impaired

44. Non Fluorinated Quinolones . Acts by inhibiting bacterial DNA gyrase . Absorbed orally, excreted in Urine, t1/2 – 8 Hrs Active against Gm – ve like E. coli Protius Klebsella Enterobacter Shigella but not Pseudomonas URINARY ANTISEPTICS NALIDIXIC ACID NO to Infants Neonates BACTERICIDAL

45. To be continued.....

46. UTI I

47. UTI I Warning!