1. Antibiotic Therapy-1 -Lecture Objectives Introduction Antibiotics-Targets, Problems of Resistance, Administration, Tissue Distribution Sulfonamides & Cotrimoxazole Fluoroquinolones

2. Lecture Outcomes At the end of this lecture, you should be able to: –Discuss the Targets, Problems of Resistance, Administration, Tissue Distribution of Antibiotics –Describe the pharmacological actions & uses of Sulfonamides & Cotrimoxazole –Describe the pharmacological actions & uses of Fluoroquinolones

3. Antibiotic Therapy-Terminology Chemotherapy: –Use of chemical compounds in the treatment of infectious diseases so as to inhibit or destroy offending organisms without damaging host tissues Bactericidal agent: –A chemotherapeutic agent destroying/killing the offending organism Bacteriostatic agent: –A chemotherapeutic agent inhibiting the growth/multiplication of offending organism

4. Antibiotic Therapy-Terminology Antibiotic: –A naturally occurring substance produced by a microbe that in small amounts inhibits or kills other microbes Antibacterial: –A natural, semi-synthetic or synthetic substance that inhibits bacteria Antimicrobial: –A natural, semi-synthetic or synthetic substance that inhibits microbes

5. Antibiotic Therapy-General Principles Selective toxicity: –Essential property of antimicrobial drug that equips it for systemic use in treating infections is selective toxicity –Drug must inhibit microorganism at lower concentrations than those that produce toxic effects in humans –No antibiotic is completely safe

6. Antibiotic Therapy-General Principles Broad and Narrow spectrum antimicrobials: –Broad spectrum antibiotics inhibit wide range of bacteria –Narrow spectrum antibiotics inhibit narrow range of bacteria –Broad spectrum desirable if infecting organism not yet identified –Narrow spectrum preferable when organism has been identified

7. Antibiotic Therapy-General Principles Bactericidal or bacteriostatic action: –Bactericidal antibiotics kill bacteria –Bacteriostatic antibiotics arrest/inhibit bacterial growth –Bacteriostatic antibiotics may work as well as bactericidal antibiotics if they sufficiently arrest the bacterial growth to enable the immune system to eliminate the bacteria

8. Antibiotic Therapy-General Principles Combinations of antibiotics: –Some antibiotics work better together - than alone –Combining 2 or more drugs may be required to prevent the emergence of resistance e.g. tuberculosis –Combinations should not be given when 1 drug would suffice, e.g. Antagonistic effects Inability to adjust 1 drug concentration

9. http://worldbestonlinepharmacy.com/?wm=17750&tr=8030&search=antibiotic

13. Resistance to Antibacterial Agents Antibiotic resistance either arises as a result of innate consequences or is acquired from other sources Bacteria acquire resistance by: –Mutation: spontaneous single or multiple changes in bacterial DNA –Addition of new DNA: usually via plasmids, which can transfer genes from one bacterium to another –Transposons: short, specialised sequences of DNA that can insert into plasmids or bacterial chromosomes

14. Mechanisms of Antibacterial Resistance Antibiotic inactivation –Bacteria acquire genes encoding enzymes that inactivate antibiotics Examples include: –  -lactamases –Aminoglycoside - modifying enzymes –Chloramphenicol acetyl transferase

15. Mechanisms of Antibacterial Resistance Structurally modified antibiotic target site, resulting in: –Reduced antibiotic binding –Formation of a new metabolic pathway preventing metabolism of the antibiotic

16. http://scienceaid.co.uk/biology/micro/antibiotics.html Antibiotic Resistance Antibiotic resistance arises as a result of natural selection. Since bacteria reproduce rapidly, resistance can arise quickly. Those antibiotics resistant will remain after treatment and can continue to divide.natural selection An example of antibiotic resistance can be seen with Penicillin, some bacteria can produce an enzyme called Penicillinase which breaks down Penicillin before it can take effect. Other mechanisms of resistance include the evolution of a capsule that is resistant to antibiotic, and cell membranes becoming less permeable to antibiotic. Bacteria can spread resistance genes between each other by bacterial conjugation where two cells join by their pilli and exchange plasmids which often contain genes for antibiotic resistance.

17. Sulfonamides Classification (duration of action) –I. Those employed for systemic infections Short-acting(4-8 h): Sulfafurazone (Sulfisoxazole/Sulfamethizole Intermediate-acting(8-12h): Sulfadiazine/ Sulfamethoxazole/Sulfamoxole Long-acting(~7-9 days): Sulfamethoxypyridazine/Sulfadoxine

18. Sulfonamides Classification (duration of action) –II. Those employed orally for treatment of ulcerative colitis Sulfasalazine(Salicylazosulfapyridine) –III.Those employed topically Sulfacetamide sodium/Mafenide sodium/ Silver sulfadiazine

19. Sulfonamides Antimicrobial spectrum –Effective against a variety of Gram +ve & -ve bacteria, Nocardia, Chlamydia trachomatis, & some protozoa –Some enteric bacteria such as E. coli, Klebsiella, Salmonella, Shigella, & enterobacter are inhibited

20. Sulfonamides Mechanism of action: –Susceptible microorganisms require extra cellular PABA in order to form DHFA, an essential step in the production of purines & synthesis of nucleic acids –Sulfonamides are structural analogs of PABA that competitively inhibit Folate synthase –Prevention of conversion of PABA to DHFA

21. Sulfonamides Mechanism of action: –Mainly bacteriostatic –Occasionally, in very high concentrations particularly in the urinary tract, they may act as bactericidal compounds

22. Sulfonamides Resistance to sulfonamides –Prominent bacteria developing resistance are Staph. aureus, Strep. pyogenes, Pneumococci, Meningococci, Gonococci, E. coli, Shigella, etc. –May be chromosomally mediated or transferred by ‘R’ factors –Resistant (mutant) strains either: Overproduce PABA, or Synthesize Folate synthase enzyme with low affinity for sulfonamides

23. Sulfonamides Therapeutic Uses –Important therapeutic uses are: Urinary Tract Infections: Sulfisoxazole/ Sulfamethoxazole Acute Bacillary Dysentery Meningococcal Meningitis

24. Sulfonamides Therapeutic Uses Ulcerative Colitis Sulfasalazine (Salicylazosulfapyridine) Acute Toxoplasmosis: Sulfadiazine + Pyrimethamine (first-line therapy) Malaria: Sulfadoxine + Pyrimethamine Bacterial conjunctivitis/adjunctive therapy for trachoma: sulfacetamide sodium ophthalmic solution. Prevention of bacterial colonization & infection of burn wounds: Mafenide sodium/Silver sulfadiazine

25. Sulfonamides Adverse Reactions: –Fever/skin rashes/exfoliative dermatitis/photosensitivity /urticaria/nausea/vomiting /diarrhea/crystalluria/hematuria /Steven-Johnson syndrome/ stomatitis/conjunctivitis/arthritis /hematopoietic disturbances (hemolytic or aplastic anemia, granulocytopenia, etc.)

26. Cotrimoxazole (Sulfamethoxazole + Trimethoprim) Salient Features: –Fixed-dose combination of sulfamethoxazole (SMX) + Trimethoprim (TMP) in the ratio of 5:1 –TMP, a trimethoxybenzylpyrimidine, inhibits bacterial dihydrofolic acid reductase(DHFAR) ~50,000 times more efficiently than mammalian DHFR –DHFAR’s convert DHFA to THFA, a step leading to purine & consequently DNA synthesis

27. Cotrimoxazole (Sulfamethoxazole+ Trimethoprim) Salient Features: –TMP given together with sulfonamides (e.g., SMX), produces sequential metabolic blockade resulting in marked enhancement (synergism) of the activity of both drugs –SMX alone has bacteriostatic activity –SMX+TMP combination often is bactericidal

28. Cotrimoxazole(Sulfamethoxazole+ Trimethoprim) Therapeutic uses: –Urinary Tract Infections- uncomplicated cases respond rapidly –Respiratory Tract Infections –Enteric Fever: SMX(800 mg) + TMP (160mg) bd for 14 days Drug of choice is ciprofloxacin –Bacterial Diarrheas & Dysentery –Chancroid –Granuloma inguinale –Prophylaxis & treatment of Pneumocystis carinii pneumonia

29. Cotrimoxazole(Sulfamethoxazole+ Trimethoprim) Advantages: –Broad-spectrum antibacterial drug –Relatively safe & well-tolerated –Highly cost-effective in many common infections in practice Adverse Effects: –May cause all untoward reactions associated with sulfonamides –Trimethoprim causes megaloblastic anemia, leukopenia & granulocytopenia

30. Fluoroquinolones Classification: –First generation: Norfloxacin/Ciprofloxacin/Ofloxacin/ Pefloxacin –Second generation: Gatifloxacin/Grepafloxacin/Levofloxacin/ Lomefloxacin/Moxifloxacin/Sparfloxacin/ Trovafloxacin

31. Fluoroquinolones Antimicrobial Spectrum: –Relatively broad spectrum of action against variety of Gram +ve & -ve bacteria –Excellent activity against Enterobacteriaceae (E. coli / Klebsiella / Proteus mirabilis) including many organisms resistant to penicillins/ cephalosporins / aminoglycosides –Highly effective against Shigella species, Salmonella

32. Fluoroquinolones Antimicrobial Spectrum(contd.): –Also possess activity against Mycobacterium tuberculosis, H. influenzae, B. catarrhalis, Neisseria (including penicillinase-producing gonococci) –High activity against Streptococci (including Streptococcus pneumoniae)

33. Fluoroquinolones Mechanism of action: –Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) & topoisomerase IV

34. Fluoroquinolones Resistance to Fluoroquinolones (FQ’s): –During FQ therapy, resistant mutants emerge with frequency of ~ 1 in 10 7 - 10 8 (especially staphylococci, pseudomonas & serratia) –Point mutations in quinolone binding region of target enzyme (amino acid substitution in A subunit of gyrase) –Changes in microbial drug permeability

35. Fluoroquinolones Therapeutic Uses (Ciprofloxacin): –Urinary Tract Infections –Gonorrhea –Chancroid –Bacterial gastroenteritis –Typhoid –Bone, soft tissue, gynecological & wound infections –Respiratory infections –Tuberculosis –Gram negative septicemias –Meningitis, etc.

36. Fluoroquinolones Adverse Effects: –Extremely well-tolerated –Most common effects are nausea, vomiting, diarrhea, headache, dizziness, insomnia, skin rash, abnormal liver function tests –Acute hepatitis & hepatic failure (Trovafloxacin), photosensitivity(Lomefloxacin, Pefloxacin), QTc interval prolongation(Grepafloxacin, Moxifloxacin, Sparfloxacin, Gatifloxacin)

37. Fluoroquinolones Adverse Effects: –Damage growing cartilage & cause arthropathy –Tendinitis Contraindications: –Pregnancy

38. http://www.fastbleep.com/medical-notes/other/21/50/336 http://www.gustrength.com/health:antibiotic-resistance-questions-and- answers http://scienceaid.co.uk/biology/micro/antibiotics.html