Antimicrobial Agents - General Considerations 2 - PDF

Antimicrobial agents- General Considerations 2 Dr Suprava Das  Learning Outcomes At the end of the lectures the students should be able to: Explain the following terms with examples: chemotherapy, antibiotic, antimicrobial agent (AMA), broad spectrum AMA, narrow spectrum AMA...

Antimicrobial agents- General Considerations 2 Dr Suprava Das  Learning Outcomes At the end of the lectures the students should be able to: Explain the following terms with examples: chemotherapy, antibiotic, antimicrobial agent (AMA), broad spectrum AMA, narrow spectrum AMA, bactericidal and bacteriostatic, empiric therapy, definitive therapy and chemoprophylaxis *** Show the sites of action of various antimicrobial agents using a diagram of a bacterial cell. *** Explain the mechanism of action of antimicrobials at various sites. *** Explain the principles of antimicrobial drug dosing. *** Explain the rationale for combination antimicrobial therapy. *** Explain the disadvantages of antimicrobial combinations. *** Manipal University College Malaysia (MUCM) 2  Learning Outcomes List the general principles of antimicrobial prophylaxis. *** Explain superinfection, its prevention and treatment. *** Explain following factors affecting the choice of an AMA: Local host factors, impaired host defense, spectrum of antimicrobial activity and sensitivity of organism. *** Explain the principles of approach to empiric therapy. *** List factors determining duration of antimicrobial therapy. *** List the factors leading to failure of antimicrobial therapy. *** Manipal University College Malaysia 3  Chemoprophylaxis Administration of antimicrobial agents to prevent infection or to prevent development of disease in persons who are already infected. The ideal time to initiate therapy is before the organism enters the body or before the development of signs and symptoms of the disease.  Characteristics of an ideal chemoprophylactic agent: Should be effective Should be specific to common possible pathogens Should achieve plasma concentration above minimum inhibitory concentration (MIC) Should be least toxic Should be used for short duration Manipal University College Malaysia 4  Good Chemoprophylactic Agent Manipal University College Malaysia 5  Indications for Chemoprophylaxis To prevent endocarditis in patients with heart valve lesions before undergoing surgery To prevent involvement of heart (carditis) in patients with history of rheumatic fever, may require years of treatment To prevent infection in patients undergoing organ transplantation To prevent opportunistic infection in immunocompromised patients Prior to surgical procedures to prevent wound infection after surgery To prevent infection in patients with burns To prevent tuberculosis in contacts Pre-treating of patients undergoing dental extractions who have implanted prosthetic devices such as artificial heart valves prevents infection Pre-treating mother with zidovudine protects the foetus incase of HIV infected pregnant woman. Manipal University College Malaysia 6  Indications for Chemoprophylaxis Manipal University College Malaysia 7  Antimicrobial Drug Combination It is the simultaneous use of two or more antimicrobial agents for the treatment of certain infections.  Advantages of Antimicrobial Combinations: In case of mixed bacterial infection: Intrabdominal, pulmonary, hepatic, pelvic and brain infections etc. are due to both aerobic and anaerobic organisms and they require antimicrobial combination therapy. In severe infections when the etiology is not known i.e., suspected cases of bacterial meningitis To increase antibacterial activity in the treatment of specific infections for synergistic effect i.e., in case of bacterial endocarditis, in P.jiroveci infection To prevent the emergence of resistant organisms in TB, leprosy, HIV To reduce duration of therapy i.e., TB and leprosy To reduce adverse effects Manipal University College Malaysia 8 Antimicrobial Drug Combination  Disadvantages: Increased toxicity : vancomycin + tobramycin produce exaggerated kidney failure as both are nephrotoxic Increased cost Decreased antibacterial activity due to improper combination i.e., combination of bactericidal with bacteriostatic Increased chance of superinfection Irrational combination may lead to development of resistance Manipal University College Malaysia 9 Factors Affecting Choice of AMA Patient factors: Drug factors: Age Route of administration History of allergy Spectrum of antimicrobial activity Genetic abnormalities Selection of Bactericidal/bacteriostatic an Pregnancy appropriate PK & PD consideration Host defense AMA Cost of AMA depends on Hepatic dysfunction Renal dysfunction Organism related factor Presence of pus/FB Clinical diagnosis: empirical therapy Resistance to AMA Manipal University College Malaysia 10 Superinfection Superinfection (Opportunistic infections)- is the appearance of a new infection during chemotherapy of another infection. It occurs due to alterations in normal microbial flora of upper respiratory, intestinal & genitourinary tract, permitting growth of opportunistic organisms, especially fungi or resistant bacteria. The principal organisms are Candida albicans & pseudomonas. The drugs like clindamycin, tetracyclines, aminoglycosides, ampicillin, cotrimoxazole may cause superinfection with Clostridium difficile leading to pseudomembranous enterocolitis. metronidazole and vancomycin are the drugs of choice to treat this infection. This is common in immunocompromised conditions i.e., diabetes, malignancy, AIDS and during prolonged corticosteroid therapy The broader the spectrum of activity of the AMA, the greater the incidence of Manipal University College Malaysia 11 superinfection.  Factors Determining Duration Antimicrobial Therapy Some information is already available about the duration of treatment of some infections: Tuberculosis, gonorrhea, syphilis, streptococcal pharyngitis etc. The duration also depends on the clinical outcome i.e., improvement in patient’s clinical condition Follow up laboratory investigation like culture report demonstrating eradication of the organism Manipal University College Malaysia 12 Failure of Antimicrobial Therapy The failure of treatment by AMA may be due to : 1. Improper selection of drug, dose, route of administration and duration of treatment 2. Delay in initiation of treatment 3. Failure to take necessary adjuvant measures like drainage of abscess, removal of foreign body, control of diabetes 4. Treating viral infections with antibiotics, fever due to malignancy etc. 5. Poor host defence. Manipal University College Malaysia 13  Bacterial Resistance to AMA Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not stop their growth. Multidrug resistant bacteria causing nosocomial infections / hospital acquired infections is the most serious consequence of indiscriminate use of antibiotics. E.g. TB, Staphylococcal infections etc. Indiscriminate use of antibiotics in human and veterinary medicine has resulted in the growth of resistant strains. Antibiotic resistance results in increase in morbidity & mortality among patients raising the health care costs.  Bacterial Resistance to AMA Resistance may be innate or acquired Mechanisms of drug resistance - 1. Due to altered targets in microbes: E.g. alteration in the target enzyme, DNA gyrase resulted in resistance to fluoroquinolones. 2. Inactivation of the drug by microbial enzymes E.g. βlactamases by staphylococci & gonococci destroy βlactam antibiotics. 3. Decreased accumulation of the drug by the microbe E.g. - Resistance to tetracycline by bacteroides is due to efflux of the drug from the bacterium. Bacterial resistance can be prevented or reduced by: 1. Follow rational drug therapy by ensuring that right patient gets right drug for right indication in right dose for right duration, by right route. 2. Avoid indiscriminate use in human and veterinary practice & in food industry. 3. Restrict AMA (Antimicrobial agent) combinations only for appropriate indications. E.g. Tuberculosis, leprosy 4. Monitor resistance pattern in a hospital / community and recommend AMA appropriately. 5. Restrict the use of newest AMA so long as the current AMA are effective. Frame and implement ‘Antibiotic policy’.