Antimicrobial Regimen selection and drug of choice

lecture

1. Antimicrobial Regimen Selection

2. Introduction In many infections, the pathogen causes disease not in the whole body, but in specific organs. Within an infected organ only specific pathological compartments may be infected. Antibiotics are often administered orally or parenteral, far away from these sites of infection. Therefore , in choosing an antimicrobial agent for therapy, a crucial consideration is whether the drug can penetrate to the site of infection.

3. Changing antimicrobial therapy based on the subsequent available culture results and antibacterial susceptibilities may not reduce the excess risk of hospital mortality associated with inappropriate initial antibiotic treatment Therefore, selection of initial appropriate therapy (i.e., getting antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections.

4. Crude hospital mortality from four clinical studies for patients receiving either appropriate or inappropriate initial antimicrobial therapy for hospital-acquired infections in the intensive care unit setting.

5. Most inappropriate antimicrobial treatment of hospital-acquired infections appears to be the result of bacteria resistant to the prescribed antimicrobial agents Antibiotic-resistant gram-positive bacteria such as MRSA Similarly, some antibiotic-resistant gram-negative bacteria explain the excess attributable mortality observed with infections due to these pathogens as well.

6. inappropriate antimicrobial treatment are associated with prolonged hospitalization and increased health care costs relative to antibioticsensitive bacterial infections The overall national costs of antimicrobial resistance have been estimated to be between $100 million and $30 billion annually for the control and treatment of infections caused by antibiotic-resistant bacteria

7. Inappropriate antimicrobial treatment of serious infections in the hospital setting has been demonstrated to be an important determinant of hospital mortality Inappropriate antimicrobial treatment represents the use of antibiotics with poor or no in vitro activity against the identified microorganisms causing infection at the tissue site of infection.

8. Definition Appropriate antibiotic therapy It is the cornerstone of management in septic shock and in any serious infection requiring intensive care unit (ICU) care and has a great influence on hospital mortality. It is defined as an initial antimicrobial regimen that demonstrates in vitro activity against the isolated organisms responsible for the infection, whereas inappropriate antibiotic therapy is defined as an initial regimen demonstrating a lack of in vitro activity against the causative pathogens .

9. Selecting the most appropriate antimicrobial agents for the treatment of serious infections, clinicians must insure that antibiotic administration follows certain minimal requirements. These minimal requirements include proper dosing, interval administration, optimal duration of treatment, monitoring of drug levels when appropriate, and avoidance of unwanted drug interactions

10. The administration of inappropriate initial antibiotic therapy can lead to treatment failures and adverse outcomes. Similar associations between the administration of inappropriate initial antimicrobial therapy and greater mortality have been shown for bloodstream infections by Candida. Moreover , the importance of treating all pathogens associated with serious infection is further emphasized by a retrospective analysis of patients with severe sepsis and septic shock

11. The importance of early appropriate antibiotic selection was also demonstrated in a recent randomized trial among patients with Escherichia coli or Klebsiella pneumonia bloodstream infection and ceftriaxone resistance demonstrating that definitive treatment with piperacillin-tazobactam compared with meropenem resulted in greater 30-day mortality. This study also highlights the importance of early identification of antibiotic resistance to optimize antimicrobial prescription in order to improve patient outcomes

12. The number needed to treat with appropriate antimicrobial therapy to prevent one patient death was 4.0 (95% confidence interval [0.84-0.98]

13. The importance of selecting appropriate initial antimicrobial therapy has been emphasized in the most recent Surviving Sepsis Guidelines. The guidelines recommend that initial empiric anti-infective therapy include one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that the antibiotics penetrate, in adequate concentrations, into the tissues presumed to be the source of sepsis (grade 1B ).

14. This guideline urges clinicians to use the patient’s history (including drug intolerances), recent receipt of antibiotics, underlying disease, clinical syndrome, and susceptibility patterns of pathogens in the community and hospital and that have been previously documented to colonize or infect the patient when making decisions regarding initial antimicrobial regimen selection.

15. In addition to selecting an appropriate antimicrobial regimen, the timing of antibiotic delivery is an essential element in determining the outcome of critically ill patients with infection. Several studies have found strong relationships between delays in effective antimicrobial initiation and in-hospital mortality for serious infections, including ventilator-associated pneumonia (VAP) and septic shock.

16. A metaanalysis of randomized and observational studies evaluating the impact of goal-directed bundles on the outcomes of patients with septic shock found that timely antibiotic administration was statistically more common among patients receiving protocolized management of septic shock In-hospital mortality was 29.7% for the cohort as a whole, and there was a statistically significant increase in the probability of death associated with the number of hours of delay for the first antibiotic administration.

17. In addition to delivering timely appropriate antibiotic regimens, adequate drug concentrations at the site of infection are needed to optimize clinical outcome Empiric antibiotic courses of 7–8 days of treatment should suffice, unless specific infections are identified, such as bacteremia, fungemia , endocarditis, osteomyelitis, or meningitis, which would require longer treatment durations

18. De-escalation of Empiric Antibiotic Regimens Antimicrobial de-escalation is a clinical approach to empiric antibiotic therapy of serious infections that attempts to balance the need for appropriate initial therapy with the need to limit unnecessary antimicrobial exposure in order to curtail the emergence of resistance

19. Types and Goals of Antimicrobial Therapy Therapy can be prophylactic, preemptive, empirical, definitive , or suppressive .

20. Prophylactic Therapy The goal of prophylaxis is to prevent infection In some patients or to prevent development of a potentially dangerous disease in those who already have evidence of infection. The main principle behind prophylaxis is targeted therapy .

21. Prophylaxis in Immunosuppressed Patients Chemoprophylaxis for Surgical Procedures Prophylaxis in Patients at Risk of Infective Endocarditis Prophylaxis for Procedures on Infected Tissues Post-exposure Prophylaxis Rifampin administration to prevent meningococcal meningitis in people who are in close contact with a case, prevention of gonorrhea or syphilis after contact with an infected person, and macrolides after contact with confirmed cases of pertussis

22. Consider narrow-spectrum antibiotics targeted at the most important ( potential surgical site) infectious organisms and do not target all possible bacteria. Limit the duration of prophylaxis to be as short as the time in which maximum contamination is expected (e.g., during incisions and the surgical procedure) and do not prolong beyond this time. Apply PK/PD thinking , as described previously

23. Preemptive Therapy Delivery of therapy prior to development of symptoms aborts impending disease, and the therapy is for a short and defined duration. Thematopoietic stem cell transplants and after solid-organ transplantation Empirical Therapy in the Symptomatic Patient initiation of optimal empirical Antimicrobial therapy should rely on the clinical presentation and clinical experience. In addition, simple and rapid laboratory techniques are available for the examination of infected tissues.

24. The first consideration in selecting an antimicrobial is to determine if the drug is indicated. The diagnosis may be masked if therapy is started and appropriate cultures are not obtained. Antimicrobial agents are potentially toxic and may promote selection of resistant microorganisms. For some diseases, the risk in waiting a few days is low, and these patients can wait for microbiological evidence of infection without empirical treatment. If the risks of waiting are high, based either on the patient’s immune status or other known risk factors

25. Definitive Therapy With Known Pathogen Once a pathogen has been identified and susceptibility results are available, Therapy should be streamlined to a narrow targeted antibiotic. Monotherapy is preferred to decrease the risk of antimicrobial toxicity and selection of antimicrobial-resistant pathogen Proper antimicrobial doses and dose schedules are crucial to maximizing efficacy and minimizing toxicity . In addition , the duration of therapy should be as short as is necessary

26. There are special circumstances where evidence favors combination therapy : Preventing resistance to monotherapy Accelerating the rapidity of microbial kill Enhancing therapeutic efficacy by use of synergistic interactions or enhancing kill by a drug based on a mutation generated by resistance to another drug Reducing toxicity (i.e., when sufficient efficacy of a single antibacterial agent can be achieved only at doses that are toxic to the patient and a second drug is co-administered to permit lowering the dose of the first drug)

27. Post treatment Suppressive Therapy The infection is controlled but not completely eradicated by the initial round of antimicrobial treatment, and the immunological or anatomical defect that led to the original infection is still present . It is eventually discontinued if the patient’s immune system improves.

28. Role for adjunctive therapies, such as intravenous immunoglobulin G (IVIG) pooled from healthy adults or hyper immune globulin prepared from the blood of individuals with high titers of specific antibodies to select pathogens (e.g., cytomegalovirus, hepatitis B virus, rabies virus, vaccinia virus, Clostridium tetani , varicella-zoster virus, Clostridium botulinum toxin). Although the data suggesting efficacy are limited, IVIG is sometimes used for patients with suspected staphylococcal or streptococcal toxic shock syndrome.

29. CONFIRMING THE PRESENCE OF INFECTION FEVER It is defined as a controlled elevation of body temperature above the expected 37°C (98.6°F) (measured orally) and is a manifestation of many disease states other than infection . Many drugs have been identified as causes of fever . Drug-induced fever is defined as persistent fever in the absence of infection or other underlying condition. The fever must coincide temporally with the administration of the offending agent and disappear promptly upon its withdrawal, after which the temperature remains normal.

30. WHITE BLOOD CELL COUNT Most infections result in elevated white blood cell (WBC) counts (leukocytosis) because of the mobilization of granulocytes and/or lymphocytes to destroy invading microbes. Normal values for WBC counts are between 4000 and 10,000 cells/mm3 (4 × 109 and 10 × 109 /L).

31. Systematic Approach for Selection of Antimicrobials Confirm the presence of infection Careful history and physical examination Signs and symptoms Predisposing factors Identification of the pathogen Collection of infected material Stains Serologies Culture and sensitivity

32. Selection of presumptive therapy considering every infected site Host factors Drug factors Monitor therapeutic response Clinical assessment Laboratory tests Assessment of therapeutic failure

33. Bacterial infections are associated with elevated granulocyte counts (neutrophils and basophils), often with increased numbers of immature forms (band neutrophils) seen in peripheral blood smears. With infection, peripheral leukocyte counts may be high, but they are rarely higher than 30,000 to 40,000 cells/mm3 (30 × 109 /L to 40 × 109 /L ). Low neutrophil counts (neutropenia) after the onset of infection indicate an abnormal response and are generally associated with a poor prognosis for bacterial infection

34. Relative lymphocytosis, even with normal or slightly elevated total WBC counts, is generally associated with tuberculosis and viral or fungal infections . Many types of infections , however, may be accompanied by a completely normal WBC count and differential .

35. LOCAL SIGNS Pain and inflammation may accompany infection and are sometimes manifested by swelling , erythema, tenderness, and purulent drainage. Unfortunately , these signs may be apparent only if the infection is superficial or in a bone or joint.

36. The manifestations of inflammation with deep-seated infections such as meningitis, pneumonia , endocarditis, and urinary tract infection must be ascertained by examining tissues or fluids. For example, the presence of polymorphonuclear leukocytes ( neutrophils) in spinal fluid, lung secretions (sputum), and urine is highly suggestive of bacterial infection.

37. IDENTIFICATION OF THE PATHOGEN Identification and antimicrobial susceptibility of a suspected pathogen are the most important factors in determining the choice of antimicrobial therapy . Infected body materials must be sampled, if at all possible or practical, before the institution of antimicrobial therapy . A Gram stain of the material may reveal bacteria, or an acid-fast stain may detect mycobacteria or actinomycetes . Premature use of antimicrobials can suppress the growth of pathogens that might result in false-negative culture results or alterations in the cellular and chemical composition of infected fluids.

38. Blood cultures should be performed in the acutely ill, febrile patient. Infected materials produced by the patient ( eg , blood, sputum, urine, stool, and wound or sinus drainage) and less accessible fluids or tissues are obtained when needed to assess localized signs or symptoms. Abscesses and cellulitic areas should also be aspirated. • After a positive Gram stain, culture results, or both are obtained, the clinician must be cautious in determining whether the organism recovered is a true pathogen, a contaminant, or a part of the normal flora. Cultures of specimens from purportedly infected sites that are obtained by sampling from or through contaminated areas might contain significant numbers of the normal flora.

39. SELECTION OF PRESUMPTIVE THERAPY A variety of factors must be considered to select rational antimicrobial therapy for a given clinical situation. These include the severity and acuity of the disease , local epidemiology and antibiogram , patient history, host factors, factors related to the drugs used, and the necessity for using multiple agents. Choice of antimicrobial is influenced by local antimicrobial susceptibility data rather than information published by other institutions or national compilations.

40. The drugs of choice for the treatment of most pathogens are compiled from a variety of sources and are intended as guidelines rather than specific rules for antimicrobial use Important considerations when selecting empiric antimicrobial therapy include : Prior knowledge of colonization or infections, Previou antimicrobial use , The site of infection and the organisms most likely pathogens, And local antibiogram and resistance patterns for important pathogens.

41. HOST FACTORS When a patient for initial or empiric therapy is evaluated, the following factors should be considered: Allergy or history of adverse drug reactions. Age of patient . Pregnancy. Metabolic or genetic variation. Renal and hepatic function: Patients with diminished renal and/or hepatic function will accumulate certain drugs unless the dosage is adjusted. Concomitant drug therapy: Any concomitant therapy the patient is receiving may influence the selection of drug therapy, the dose, and monitoring. Concomitant disease states.

42. DRUG FACTORS Integration of both pharmacokinetic and pharmacodynamic properties of an agent is important when choosing antimicrobial therapy to ensure efficacy and prevent resistance Antibiotics may demonstrate concentration-dependent (aminoglycosides and fluoroquinolones ) or time-dependent ( β- lactams) bactericidal effects.

43. The importance of tissue penetration varies with the site of infection. The central nervous system (CNS) is one body site where the importance of antimicrobial penetration is relatively well defined, and correlations with clinical outcomes are established. Drugs that do not reach significant concentrations in CSF should either be avoided or instilled directly when treating meningitis.

44. Apart from the bloodstream, other body fluids in which drug concentration data are clinically relevant are cerebrospinal fluid, urine, synovial fluid, and peritoneal fluid . Pharmacokinetic parameters such as area under the drug concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved. For some agents, the ratio of AUC to MIC, peak-to-MIC ratio, or the time that the drug concentration is above the MIC (T > MIC) may predict efficacy.

45. The most important pharmacodynamic relationship for antimicrobials that display time-dependent bactericidal effects (such as penicillins and cephalosporins ) is the duration that drug concentrations exceed the MIC.

46. COMBINATION ANTIMICROBIAL THERAPY Combinations of antimicrobials are generally used to broaden the spectrum of coverage for empiric therapy, achieve synergistic activity against the infecting organism, and prevent the emergence of resistance. Increasing the coverage of antimicrobial therapy is generally necessary in mixed infections in which multiple organisms are likely to be present, such as intra-abdominal and female pelvic infections in which a variety of aerobic and anaerobic bacteria may produce disease . Combination antimicrobial therapy is also used in critically ill patients with presumed healthcare-associated infections in which an increased spectrum of activity is desirable

47. MONITORING THERAPEUTIC RESPONSE After antimicrobial therapy has been instituted, the patient must be monitored carefully for a therapeutic response. Culture and sensitivity reports from specimens sent to the microbiology laboratory must be reviewed and the therapy changed accordingly. Use of agents with the narrowest spectrum of activity against identified pathogens is recommended. Patient monitoring should include a variety of parameters, including WBC count, body temperature, signs and symptoms of infection, appetite, radiologic studies as appropriate, and determination of antimicrobial concentrations in body fluids.

48. As the patient improves, the route of antibiotic administration should be re-evaluated . Streamlining therapy from parenteral to oral (switch therapy) has become an accepted practice for many infections . Criteria favoring the switch to oral therapy include the following: Overall clinical improvement Lack of fever for 8–24 hours Decreased WBC A functioning gastrointestinal (GI) tract

49. FAILURE OF ANTIMICROBIAL THERAPY A variety of factors may be responsible for the apparent lack of response to therapy . It is possible that the disease is not infectious or nonbacterial in origin, or there is an undetected pathogen in a polymicrobial infection. Other factors include those directly related to drug selection, the host, or the pathogen . Laboratory error in identification and/or susceptibility testing errors are rare.

50. Failures Caused by Drug Selection Factors directly related to the drug selection include an inappropriate selection of drug, dosage, or route of administration . Malabsorption of a drug product due to GI disease ( eg , short-bowel syndrome) or a drug interaction ( eg , complexation of fluoroquinolones with multivalent cations resulting in reduced absorption) may lead to potentially subtherapeutic serum concentrations. Accelerated drug elimination is also a possible reason for failure and may occur in patients with cystic fibrosis or during pregnancy, when more rapid clearance or larger volumes of distribution may result in low serum concentrations, particularly for aminoglycosides.

51. A common cause of failure of therapy is poor penetration into the site of infection. This is especially true for the so-called privileged sites, such as the CNS, the eye, and the prostate gland

52. Failures Caused by Host Factors Patients who are immunosuppressed ( eg , granulocytopenia from chemotherapy and acquired immunodeficiency syndrome) may respond poorly to therapy because their own defenses are inadequate to eradicate the infection despite seemingly adequate drug regimens. Other host factors are related to the necessity for surgical drainage of abscesses or removal of foreign bodies and/or necrotic tissue. Results in persistent infection and, occasionally, bacteremia, despite adequate antimicrobial therapy.

53. Failures Caused by Microorganisms Factors related to the pathogen include the development of drug resistance during therapy. Primary resistance refers to the intrinsic resistance of the pathogens producing the infection. However, acquisition of resistance during treatment has become a major problem as well. The increase in resistance among pathogenic organisms is believed to be due, in large part, To continued overuse of antimicrobials in the community, as well as in hospitals, And the increasing prevalence of immunosuppressed patients receiving long-term suppressive antimicrobials for the prevention of infections.

54. Antimicrobial Stewardship Antimicrobial stewardship is an important concept that is pertinent to virtually every clinician. Its goals are to combat the emergence of resistance, improve clinical outcomes, and decrease healthcare costs OPTIMIZATION OF ANTIMICROBIAL THERAPY AVOIDANCE OF UNNECESSARY ANTIBIOTIC ADMINISTRATION

55. Antimicrobial Stewardship

56. Antimicrobial Stewardship Program Optimization of antimicrobial therapy Appropriate antimicrobial selection Timing of antibiotic administration Adequate dosing of antimicrobials and PK/PD considerations Duration of antibiotic treatment Augmented renal clearance Therapeutic drug monitoring

57. Optimization of appropriate antimicrobial therapy as part of an antimicrobial stewardship program

58. Avoidance of unnecessary antibiotic administration De-escalation of empiric antibiotic regimen Use of antibiotic resistance prediction tools Biomarker guidance of antimicrobial therapy Formalized antimicrobial stewardship programs Rapid microbiologic diagnostics Telemedicine driven stewardship Closed multidisciplinary ICU management Optimized infection control program

59. An algorithm for the use of antimicrobial therapy in critically ill patients attempting to balance the need for early appropriate therapy in infected patients with the need to avoid the unnecessary use of broad spectrum antibiotics

60. The Most Common Errors in Antibiotic Therapy Use of a broad-spectrum antibiotic when a narrow-spectrum agent would suffice Excessive duration of therapy Intravenous therapy when oral therapy would be equally effective Combination therapy when a single antibiotic would suffice Failure to change antibiotics when the antibiograms become available Failure to adjust the dosage in the case of decreased hepatic or renal function Outdated knowledge of antibiotic resistance and thus initial prescription of the wrong agent Assuming the worst case, i.e. routinely starting with single or combined antibiotics appropriate for pathogens such as Pseudomonas or methicillin-resistant staphylococci

61. Blood culture diagnosis: Suspicion of systemic and/or local infections (sepsis, meningitis , osteomyelitis, pneumonia, postoperative infections etc.) or pyrexia of unknown origin: one sample (for aerobic and anaerobic culture) from the first vein, one sample (for aerobic and anaerobic culture) from the second vein. Suspicion of bacterial endocarditis: three samples (for aerobic and anaerobic culture) from three different veins (within 3 h). Suspicion of intravenous catheter infection: one Isolator sample (for quantitative culture) from the intravenous catheter ; one Isolator sample and one sample for aerobic culture from a peripheral vein.

62. Important Infections and Their Microbiological Diagnosis

63. Any concern or questions Thanks