Principles of Antibiotic Therapy by Ahmed A.pptx

Principles of Antibiotic Therapy by Ahmed

1. Principles of Antibiotic Therapy Prof Ahmed A MBBS, LLB, FWACS, FICS, FACS DEPARTMENT OF SURGREY ABU/ABUTH ZARIA, NIGERIA

2. INTRODUCTION In the past, infection was one of the major obstacles to safe surgery Problems of infection became more noticeable when the problems posed by hemostasis and anesthesia were controlled in the 18 th and mid-19 th centuries In the latter half of the 19 th century, with the gradual acceptance of the pioneer work of Louis Pasteur, Joseph Lister and Von Bergmann, the principles of microbial infection in surgery were laid down

3. . Si r A l exan d er Fleming ushered in the antibiotic era with th e di sco v ery of penicillin in 1928 The term antibiotic was first used in 1942 by Waksman S et al to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms This definition excluded substances that kill bacteria but that are not produced by microorganisms ( eg . gastric juice) It also excluded synthetic antibacterial compounds such as the sulfonamides In current usage, the term "antibiotic" is applied to include both the natural and synthetic products

4. (1) Enhancing infection prevention and control measures Prevention is better than cure Use of evidence-based infection prevention and control interventions to: prevent healthcare associated infections to prevent transmission of infections when they occur Infection prevention and control programs  and antimicrobial stewardship through interdependent and coordinated multi disciplinary approach reduce the need for antibiotics therapy

5. (2) Controlling source of infection Appropriate source control is fundamental in the management of surgical infections Intra-abdominal infections and soft tissues infections are the sites where a source control is more feasible and more impactful Source control encompasses all measures undertaken to eliminate the source of infection reduce the bacterial inoculum; correct anatomic derangements and restore normal physiology

6. Source control Drainage of abscesses Drainage of infected fluid collections Debridement of necrotic or infected tissues Definitive control of the source of contamination.  Operative intervention is the most reliable therapeutic strategy for managing surgical infections Non-operative interventional procedures Source control also :reduce duration of antibiotic therapy reduce risk of antibiotic resistance

7. Antibiotics should be used after an infection has been recognized or when there is a high risk for infection (3) Identification of site if infection and the Infective Organism History taking Physical examination Laboratory investigations Other investigations

8. History Taking Duration and pattern of fever Associated symptoms /Systemic review History of treatment Underlying diseases and Medication Occupation Travelling Illness in the family Vaccination and Prophylasis Disease outbreak Food consumption

9. Physical Examination to identify site of Infection General examination Temperature; Pallor; Jaundice; Dehydration; LN Chest examination RR; Pleural collection; Abscess; other Abdomino -pelvic examination Peritonitis; Sub-phrenic/Pelvic Abscess; other Soft tissue Other

10. Laboratory Investigation to identify the Infectious Agents Staining techniques A rapid assessment of the nature of the pathogen on the basis of the staining characteristics Identify the presence and morphologic features of microorganisms in body fluids that are normally sterile Gram Stain AFB Stain Modified AFB Stain Wright Stain India Ink Preparation Fresh Smear / KOH Preparation

11. Identification of the infective Organisms Microbial Factors Antibiotic susceptibility Appropriate specimen collection and transport Appropriate culture medium and Incubation Disk diffusion susceptibility testing (MCS) Minimal Inhibitory concentration (MIC) the lowest antibiotic concentration that prevents visible growth of an organism after 24 hours of incubation Minimal Bactericidal concentration (MBC) the lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight incubation Antibacterial Resistance Imaging investigations Abdomino -pelvic Ultrasound; CT Scan; Other

12. (4) Selecting the appropriate antibiotics (a)EMPIRICAL THERAPY Ideally, the antibiotic used to treat an infection is selected after the organism has been identified and its drug susceptibility established Critically ill and emergency patients require immediate treatment (identification of pathogens and antibiotic susceptibility takes ≥48h) Therefore, timing and selection of antibiotics is crucial Choice of empirical antibiotic regimen depends on: presumed pathogens and risk factors for resistance clinical patient’s severity presumed or identified source of infection. Clinicians starting empiric therapy should know the local epidemiology

13. Host Factors Underlying diseases Drug allergy Pregnancy/Breast feeding Age Genetic or Metabolic abnormalities Sites of infection Immune status Hepatic and renal function

14. Antimicrobial Factors Spectrum Mechanisms of action Pharmacokinetic Pharmacodynamics Drug interaction Side effect Drug monitoring

15. (b) TARGETED THERAPY Reassessing treatment when culture results are available is essential The results of microbiological testing may provide the opportunity to alter therapeutic strategy leading to the adaptation of targeted antimicrobial treatment expand antimicrobial regimen if the initial choice was too narrow de-escalation of antimicrobial therapy if the empirical regimen was too broad

16. TARGETED THERAPY Main focus of antimicrobial therapy is selective targeted therapy in order to avoid toxicity to the host and to avoid emergence of resistance This is achieved by understanding the PK/PD parameters of antimicrobials such as bactericidal and static nature, spectrum of activity, host factors, and biology of the organism Choose the most sensitive , least toxic , least expensive combination that will achieve desirable tissue concentrations and are unlikely to jeopardise the microbial ecology

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18. (5) ROUTE OF ADMINISTRATION There are different routes of administration of antibiotics The oral route is appropriate for mild infections that can be treated on outpatient basis Some antibiotics, such as aminoglycosides and amphotericin B are poorly absorbed from the gastrointestinal tract (GIT) Parenteral administration is used for drugs that are poorly absorbed from the GIT and for treatment of patients with serious infections Where the site of infection is easily accessed, antibiotics may be given topically in the form of eye drops or ear drops

19. (6) Prescribing rational dosage Antibiotic dose should be established based on host factors and properties of the antibiotic agents Antibiotic pharmacodynamics integrates the relationship between organism susceptibility and patient pharmacokinetics Pharmacokinetics describes the processes of absorption, distribution, metabolism, and elimination and the resulting concentration-versus-time profile of an antibiotic agent The achievement of appropriate target site concentrations of antibiotics is essential to eradicate the relevant pathogen

20. Knowledge of PK and PD properties of antibiotics provides the rational for optimal dosing regimen in terms of the dose and the dosing interval Pharmacodynamic characteristics of antibiotic argents Time-dependent killing : Beta-lactams exhibit time-dependent activity and exert optimal bactericidal activity when drug concentrations are maintained above the MIC Therefore, it is important that the serum concentration exceeds the MIC for appropriate duration of the dosing interval Higher frequency dosing, prolonged infusions and continuous infusions have been used to achieve this effect

21. Concentration-dependent killing Aminoglycosides exhibit concentration-dependent activity and should be administered in a once daily pattern in order to achieve high peak plasma concentration Peak serum concentration and not the time the concentration remains above the MIC, is more closely associated with efficacy of bactericidal activity This extended interval dosing strategy reduces the renal cortex exposure to aminoglycosides and reduces the risk of nephrotoxicity

22. Post-antibiotic effect Post-antibiotic effect (PAE)is a persistent suppression of microbial growth after levels of antibiotic have fallen below the MIC Antimicrobial drugs exhibiting a long PAE ( eg aminoglycosides and fluoroquinolones ) often require only one dose per day, particularly against gram negative bacteria

23. Loading dose/volume of distribution In patients with severe sepsis or septic shock, administering an optimal first dose is very important This optimal first dose is described as a loading and is calculated from the volume of distribution ( Vd ) of the drug and the desired plasma concentration. The Vd of hydrophilic agents in patients with septic shock may be altered by changes in the permeability of the microvascular endothelium resulting in lower than expected plasma concentrations Resulting in sub-optimal achievement of antibiotic levels on the first day of therapy In the setting of altered Vd , loading doses or higher overall daily dose is required for optimal drug concentration at the site of infection

24. Pharmacokinetics of Antibiotic Agents Absorption Consider extent and rate of absorption via route of administration Consider drug interaction and food effect Distribution to the site of infection Volume of distribution ( Vd ) Water soluble drug, small Vd ? high serum conc. Lipophilic drug, large Vd ? extensively distributed in body fluid and tissue Vascular supply Distribution to the site of infection Protein binding Local factor at site of infection pH, dense population of organism, foreign body Metabolism Mainly in liver Active vs. Inactive metabolites Route of metabolism esp. CYP P450 system Route of elimination kidney, liver Rate of elimination T1/2

25. (7) Duration of antibiotic therapy Duration should be long enough to prevent relapse yet not excessive, as it can increase side effects and resistance Antibiotic therapy may be prolonged in immunosuppression or ongoing infections Too brief or prolonged therapy my lead to development of resistant strains Patients with intra-abdominal infections who have signs of sepsis beyond 5- 7 days of treatment require diagnostic investigation to determine: Ongoing uncontrolled source of infection Antimicrobial treatment failure ; Other

26. Chemotherapeutic Spectrum Clinically important bacteria are organized into eight groups based on Gram stain, morphology, biochemical or other characteristics Antibiotic acting on a single or a limited group of micro-organisms are said to have a narrow spectrum eg Isoniazid Extended spectrum antibiotics that are modified to be effective against gram-positive and a significant number of gram-negative bacteria eg Ampicillin Broad-spectrum antibiotics such as tetracycline, fluoroquinolones and carbapenems affect a wide variety of microbial species

27. (8) Combination of antibiotic drugs Sometimes multiple drugs used in combination may be necessary Prevent antibiotic resistance/tolerance eg Anti-TB drugs, H.Pylori As narrow as possible, as broad as necessary Empiric antibiotic therapy in critically ill patients To treat Polymicrobial (mixed) bacterial infections To achieve a synergistic effect To decrease the toxicity of the most effective agent In addition to combining one antibiotic with another, antibiotics can be co-administered with resistance-modifying agents, eg β- lactam antibiotics in combination with β-lactamase inhibitors, such as clavulanic acid or sulbactam

28. . The effect may be additive, synergistic, or antagonistic. Additive effect: antibacterial action is the sum of the individual agents e.g. Bacitracin and polymyxin B or neomycin in topical preparations. Synergism: Antibiotic combination exceeds the algebraic sum of the effects of each drug acting separately. ≥4 -fold decrease in the MIC of each drug. e g Sulfonamide + trimethoprim Antagonism - Antibacterial effects of a drug combination is less than that for either drug alone. e.g. Sulfonamides + penicillins Jawetz's rule on antimicrobial combination Bactericidal + bactericidal: may be synergistic or additive Bacteriostatic + bacteriostatic: usually additive Bacteriostatic + bactericidal: it is antagonistic and should be avoided. Bactericidal drug kills only growing organisms Disadvantages: antagonism; toxicity; cost; selection of resistant strains

29. (9) Prophylactic antibiotic therapy Use of antibiotic where there is no evidence of infection but expected to be exposed to pathogens that constitutes a major risk of infection Antibiotic prophylaxis (AP) is one of the most important component of   perioperative infection prevention strategy Given to reduce risk of Surgical Site Infection and post-op infection Classification of surgical wound Clean ( ˂ 2% ); Cl - contaminated (6%); Contaminated (15%); Dirty (40%) Inappropriate use of AP may be associated with increases in antibiotic resistance and healthcare costs Ideal AP agent should be nontoxic, inexpensive and have activity against the common organisms that cause postoperative wound infection after a specific surgical procedure

30. Antibiotic Prophylasis Primary AP: Prevention of an initial infection Secondary AP: Prevention of the recurrence or reactivation of an infection Tertiary AP: Administered to prevent infection by eliminating a colonizing organism General indications Asplenic children Prevention of TB in close relatives of patient Prevent transmission of HIV from mother to fetus Prevention of streptococcal infections in patients with RHD Prevent infection following surgical procedures

31. Indication for Antibiotic Prophylasis Prevent wound infection where the likelihood of such infection is high e.g. clean- contaminated (risk 6%) and contaminated (risk 15%) Prevent infection where the likelihood of such infection is high e.g. the compromised host eg HIV infection, Diabetes Mellitus, Neutropenia Prevent infection where the likelihood though not high carries grave consequences should it occur e.g. surgery involving placement of prosthetic devices and implants; neurologic or cardiac surgery Given at the time of induction to ensure the MIC during skin incision

32. Complications of antibiotic therapy Hypersensitivity penicillin-urticarial; anaphylactic shock; rashes; fever Direct toxicity Hepato -toxicity; Nephto -toxicity; Neuro -toxicity Super infections Oral/Intestinal candidiasis; Staphylococcal Enterocolitis Pseudomembranous Enterocolitis Gastrointestinal symptoms Anorexia, Nausea, Vomiting, Metallic taste Other Granulocytopinia; Hemolytic anemia

33. Reasons for Antibiotic Treatment Failure Polymicrobial infection Errors in susceptibility testing Decreased activity at site of infection Chemical factor (pH and others) Antibiotic antagonism Other host factors Collection requiring drainage Necrotic tissue Foreign body Inadequate concentration of antibiotic at the site of infection Inadequate dosage Decreased absorption Increased elimination Poor delivery ( eg shock, vascular diseases) Necrotic tissue Impaired immune defenses Development of drug resistance

34. (10) Antibiotic Stewardship Program Educating staff with Evidence based knowledge Supporting surveillance of ABR and HAIs and monitoring of antibiotic consumption Multidisciplinary approach to therapy Local and international collaboration

35. Feature trend Phage therapy Phage injecting its genome into a bacterium. Viral replication and bacterial cell lysis will ensue Fecal microbiota transplants Transferring the full intestinal microbiota from a healthy human donor in the form of stool to patients with resistant C. difficile infection Antisense RNA-based treatments Inhibit bacterial replication and block resistant strains formation

36. Conclusion Antibiotic therapy is one of the principal factors that determine successful outcome in modern surgical practice Clinicians should always optimize antibiotic management to maximise clinical outcome and minimize selection and emergence of resistant pathogens Appropriate use of antimicrobials is an integral part of good clinical practice. Clinicians should be aware of their role and responsibility for maintaining the effectiveness of current and future antibiotics.

37. PRESCRIBE THE RIGHT ANTIBIOTIC FOR THE RIGHT PATIENT AT THE RIGHT TIME AT THE RIGHT DOSE AND FOR THE RIGHT DURATION