1. dr. Dina Fauzia, SpFK Bagian Farmakologi dan Terapi Fakultas Kedokteran Universitas Riau Januari 2012

2.  Antimicrobial agents are the most commonly used and misused of all drugs.  The inevitable consequence  emergence of antibiotic-resistant pathogens.  Reducing inappropriate AM use is thought to be the best way to control resistance.  Over prescribing remains widespread:  patients demand,  time pressure on clinician,  diagnostic uncertainty

3. 3  Lack of new antimicrobial agents developed in recent years.  Unnecessary financial burden to the patients.  Scarcity of objective information on appropriate use of antimicrobial agents.

4.  If the microorganism is considered to be susceptible to the antibiotic when the drug concentration at the site of infection inhibit ( bacteriostatic effect) or kill ( bactericidal effect ) the the microorganism.  Inhibitory or bactericidal concentration cannot be achieved safely, then the microorganism is considered resistance to the drug.

5. 5  Successful AM therapy depends on concentration of AMA at the site of infection  must be sufficient to inhibit the growth of microorganism  must remain below toxic level  in this condition, microorganism is considered susceptible to AMA.  If host defenses are intact and active, bacteriostatic agent may be sufficient.  If host defenses are impaired, a bactericidal effect is required

6. 6  The emergence of bacterial resistance to AMA is a very serious development that threatens the end of antibiotic era.  For an antibiotic to be effective, it must reach its target, bind to it, and interfere with its function.  Mechanism of bacterial resistance to an antimicrobial agent falls into three general categories: (1) the drug does not reach its target; (2) drug is not active; (3) the target is altered

7.  Most antimicrobial agents and their metabolite are eliminated primarily by the kidneys.  One must be particularly careful when using aminoglycosides, vancomycin, and fluocytocine in patients with impaired renal function.  For AM that are metabolized or excreted by the liver, dosage must be reduced in patient with hepatic failure.  Oral administration is preferred, but parenteral AM is recommended in in seriously ill patients

8. 8  Four options of AM therapy:  Empirical, experimental, definitive, prophylaxis.  Empirical th/ is widely utilized, and is potential for abuse.  Whenever initiate empirical therapy, cultures of the presumed site of infection should be taken prior to the institution of AM therapy.  The location of the infection may usually the choice of drug and the route of administration

9. 9  Considerations in selecting an AMA :  Whether it is even indicated:  Use “educated guess” or  Culture and sensitivity test, if appropriate  In cases of symptoms are present but are not life- threatening, it is better to postpone the AM Th/ until the D/ is obvious. Example: FUO

10. 10  Optimal and judicious selection of AM requires:  clinical judgment  detailed knowledge of pharmacological and microbiological factors  knowledge of the most likely infecting microorganisms and their susceptibility to AMA.  The most practical method for immediate identification of bacteria is examination of the infected secretion or body fluids with Gram’s stain.

11. 11  In many situations, identification of morphology of the infecting organism is not adequate to arrive at specific bacteriological diagnosis  Broad spectrum AM is then indicated,  Culture of the presumed site of infection and blood, should be taken prior to the institution of drug therapy.  For definitive therapy, once an organism has been isolated and results of susceptibility tests are known, the regimen should be changed to specific and narrow spectrum AMA

12. 12  If a sensitivity test indicates that a pathogen is sensitive to some antibiotics, it does not mean all these agents are equally effective in clinical setting.  If 2 antibiotics are equally safe and effective, choose the one with narrower antibacterial spectrum.  Generic antibiotics are not of low quality but their price is much more affordable.

13. 13  Do not use obsolete antibiotics  A new generation antibiotic is not always superior to its older generations  A slightly more potent antibiotic shown in vitro, is not necessarily associated with better clinical efficacy

14. 14 INDICATIONS  Severe infection in which the cause is unknown. Prolong use should be avoided, because toxicity, superinfection, and selection of multiple drug resistant may result.  Polymicrobial infection  To have synergistic effect in specific infection (endocarditis, Ps aeruginosa infection, H influenza infection).  To prevent the emergence of resistant microorganism (in TBC, H pylori infection)

15. 15 DISADVENTAGES  Increase risk of toxicity  Selection of multiple-drug resistant microorganisms  Eradication of normal host flora with subsequent superinfection.  Increase cost to patients  Possibility of antagonistic effect.

16. 16  The functional state of host defense mechanisms is a critical determinant of therapeutic effectiveness of AMAs. Both humoral and celular immunity are important.  In the immunocompetent host, halting the multiplication of microorganisms with a bacteriostatic agent is sufficient to cure the infection.  In immunocompromized host, a bactericidal agent is required (bacterial endocarditis, bacterial meningitis, infections in neutropenic patients, HIV/AIDS, uncontrolled DM, malnutrition, …)

17. 17 Local factors affect the AM activity.  Pus, can bind drugs or inhibit drug action. Low pH in infected sites and anaerobic condition can reduce AM activity, particularly aminoglycosides.  Foreign body markedly reduces the likelihood of successful AM therapy.  Prosthetic materials promotes a bacterial biofilm that impairs phagocytosis. Within the biofilm, bacterial density is high and bacterial growth is slow.  favor bacterial persistence  frequent relapses.

18. 18  Chemoprophylaxis is used to protect patients from invasion by specific microorganisms to which they are exposed. But it remains controversial in numerous situations.  Features of successful prophylaxis:  Aimed at a specific pathogen  The pathogen is highly sensitive to the prophylactic agent used.  Features of unsuccessful prophylaxis:  Aimed at any or all microorganism in the environment of a patient

19. 19  AMA must be present at wound site at the time of its closure. The drug must be given iv within 1 hour before incision and another one dose intra operatively for prolong procedure.  The AMA must be active against the most likely contaminating microorganisms.  AM must be present at the wound site at the time of its closure.

20. 20  The continued use of AMA after surgical procedure is unwarranted and potentially harmful.  Use beyond 24 hour is unnecessary.  Prophylaxis is justified in dirty and contaminated procedure.  In clean surgery, AMA should not be used routinely.

21. 21 Determined by:  The ability of the pathogens to resist host’s defense mechanism  Physical location of the pathogen  Potency of the AM agent  The frequency of development of resistance

22. 22  Poor antibacterial activity of a drug  Wrong route of administration or wrong dosage  The location of infection is inaccessible by the antimicrobial agent  Poor host ‘s defense mechanism  Premature discontinuation of treatment

23. 23  Serious toxicity necessitates discontinuation of therapy  Resistance of the microorganism  Superinfection  Foreign body or necrotic tissues  Patient’s incompliance

24. 24  Treatment of viral infections  Therapy of FUO which can mask an underlying infection, delay the diagnosis, prevent identification of the infectious pathogen by rendering culture negative.  Improper dosage, wrong frequency, excessive or subtherapeutic dose.  Inappropriate reliance on chemotherapy alone. Drainage, debridement, and removal of foreign body are important.

25. 25  AM for hospitalized patients is too often given in the absence of supporting microbiological data.  Bacterial culture and Gram stains frequently are not available; when available the results often are disregard of the selection and application of drug therapy.  Frequent use of drug combinations or drugs with broader spectra as a cover for diagnostic imprecision.  Routine dosage rather than individualized on the basis of clinical situation, microbiological information, and the pharmacological consideration.

26. 26  Past strategies  That narrow-spectrum agents be used.  That agents be used at the minimum doses possible based on clinical trial data.  That antibiotic be used for unnecessarily long period of treatment.  Net Results  Emergence of antimicrobial resistance

27. 27  Future strategies  Using more potent (not necessarily broader spectrum) antimicrobial agent  Using more appropriate (perhaps higher) doses and more appropriate (more frequent) dosing interval  Using antimicrobial for appropriate (possibly shorter) duration.  Net Results  Delaying, reducing or reversing the trends toward higher antimicrobial resistance rates

28. 28  Definition: appearance of bacteriological and clinical evidence of new infection during the AMT of a primary one.  Therapeutic doses of AMA alter the normal microbial population of intestinal, respiratory, and urinary tracts; as a result, some develop superinfection.  Microorganism responsible for the new infection can be drug-resistant strain of enterobacteriaceae, Pseudomonas, and Candida.  The broader the AM spectrum, and the longer the period of AM treatment, the greater is the possibility of superinfection produced by a typical drug-resistant microorganism.

29.  Antibiotics are substances produced by various species of microorganisms that suppress the growth of other microorganisms  The term antibiotics includes synthetic antimicrobial agents, such as sulfonamides and quinolones

30.  Classification has been based on chemical structure and mechanism of action: (1) inhibit of cell walls ( penicillins, cephalosporins ); (2) act on cell membrane leading leakage intracellular substances ( amphotericin B, polymixin ); (3) inhibit protein synthesis reversibly ( chloramphenicol, erythromycin); (4) alter protein synthesis leading to cell death (aminoglycosides ); (5) affect nucleic acid metabolism ( rifamycins ); (6) block essential enzymes ( sulfonamides, trimethoprim ).

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