Bugs and Drugs: Update on Antimicrobial Therapy

1. KCNPNM 2014 Conference Bugs and Drugs: Update on Antimicrobial Therapy

2. Objectives • Compare and contrast the antimicrobial drug classes • Understand the types of antimicrobial drug resistance that can occur • Create treatment plans for which antimicrobial therapy can be managed successfully • Related prudent use of antimicrobial therapy to quality metrics

3. Introduction • The modern age of antibiotic therapeutics was launched in the 1930s with sulfonamides and the 1940s with penicillin • Since then, many antibiotic drugs have been developed, most aimed at the treatment of bacterial infections • These drugs have played an important role in the dramatic decrease in morbidity and mortality due to infectious diseases • While the absolute number of antibiotic drugs is large, there are few unique antibiotic targets

4. Nine Factors to Consider When Selecting an Antibiotic • Spectrum of coverage • Patterns of resistance • Evidence or track record for the specified infection • Achievable serum, tissue, or body fluid concentration (e.g. cerebrospinal fluid, urine) • Allergy • Toxicity • Formulation (IV vs. PO); if PO assess bioavailability • Adherence/convenience (e.g. 2x/day vs. 6x/day) • Cost

5. Principles of Antibiotic Therapy Directed Therapy (15%) • Infection well defined • Narrow spectrum • One, seldom two drugs • Evidence usually stronger • Less adverse reactions • Less expensive Empiric Therapy (85%) • Infection not well defined (“best guess”) • Broad spectrum • Multiple drugs • Evidence usually only 2 randomized controlled trials • More adverse reactions • More expensive

6. Why So Much Empiric Therapy? • Need for prompt therapy with certain infections • Life or limb threatening infection • Mortality increases with delay in these cases • Cultures difficult to do to provide microbiologic definition (i.e. pneumonia, sinusitis, cellulitis) • Negative cultures • Provider Beliefs • Fear of error or missing something • Not believing culture data available • “Patient is really sick, they should have ‘more’ antibiotics” • Myth of “double coverage” for gram-negatives e.g. pseudomonas • “They got better on drug X, Y, and Z so I will just continue those”

7. To Increase Directed Therapy for Inpatients: • Define the infection 3 ways • Anatomically, microbiologically, pathophysiologically • Obtain cultures before starting antibiotics • Use imaging, rapid diagnostics and special procedures early in the course of infection • Have the courage to make a diagnosis • Do not rely solely on “response to therapy” to guide therapeutic decisions; follow recommended guidelines • If empiric therapy is started, reassess at 48-72 hours • Move to directed therapy (de-escalation or streamlining)

8. To Increase use of Directed Therapy for Outpatients: • Define the infection 3 ways • Anatomically, microbiologically, pathophysiologically • Obtain cultures before starting antibiotics • Often difficult in outpatients (acute otitis media, sinusitis, community-acquired pneumonia) • Narrow therapy often with good supporting evidence • Amoxicillin/clavulanate for AOM, sinusitis and CAP • Penicillin for Group A Streptococcal pharyngitis • Clindamycin or trimethoprim/sulfamethoxazole for simple cellulitis • Trimethoprim/sulfamethoxazole or ciprofloxicin for cystitis

9. Is An Infection Present?

10. Signs and Symptoms • Increase in WBCs and a “left shift” • Fever • Pain and Inflammation • Hemodynamic changes • Neurologic changes • Gram stain

11. Overview • Colonization • Where bacteria are supposed to reside • Bacteria are present but no signs and symptoms of infection • Infection • Where bacteria invade • Bacteria are present and have often migrated to different organs to cause systemic infection • Most likely to occur • The intrinsic virulence of the particular organism • The immune status of the host • The quantity or load of the initial innoculant

12. Treat Bacterial Infection, not Colonization • Many patients become colonized with potentially pathogenic bacteria but are not infected • Asymptomatic bacteriuria or foley catheter colonization • Tracheostomy colonization in chronic respiratory failure • Chronic wounds and decubiti • Lower extremity stasis ulcers • Chronic bronchitis • Can be difficult to differentiate • Presence of WBCs not always indicative of infection • Fever may be due to another reason, not the positive culture

13. Treat Bacterial Infection, not ColonizationExample: Asymptomatic Bacteriuria • ≥105 colony forming units is often used as a diagnostic criteria for a positive urine culture • It does NOT prove infection; it is just a number to state that the culture is unlikely due to contamination • Pyuria also is not predictive on its own • It is the presence of symptoms ANDpyuriaANDbacteriuria that denotes infection

14. Do Not Treat Sterile Inflammation or Abnormal Imaging Without InfectionExample: Community-Acquired Pneumonia (CAP) • CAP: often a difficult diagnosis • X-rays can be difficult to interpret. Infiltrates may be due to non-infectious causes. • Examples: • Atelectasis • Malignancy • Hemorrhage • Pulmonary edema

15. Do not Treat Viral Infections with Antibiotics • Acute bronchitis • Common colds • Sinusitis with symptoms less than 7 days • Sinusitis not localized to the maxillary sinuses • Pharyngitis not due to Group A Streptococcus spp. Gonzales R, et al. Annals of Intern Med 2001;134:479 Gonzales R, et al. Annals of Intern Med 2001;134:400 Gonzales R, et al. Annals of Intern Med 2001;134:521

16. Culture and Sensitivity • Final identification of pathogen and effectiveness of antibiotics • May not give appropriate information • Patient previously taking antibiotics • Culture not obtained properly • Contamination • Not time sensitive

17. Key Terms • MIC= Minimal inhibitoryconcentration. Lowest concentration of antimicrobial that inhibits growth of bacteria. Commonly used in clinical lab • MBC= Minimal bactericidal concentration. Concentration of an antimicrobial that kills bacteria. Used clinically only in special circumstances • Breakpoint = The MIC that is used to designate between susceptible and resistant. Arbitrarily set by the laboratory

18. Breakpoint Susceptibility • Susceptible – pathogens with the lowest MICs and are most likely to be eradicated with antibiotic therapy • Intermediate - ?? – Treatment may be successful if the antibiotic is used in higher doses or if the antibiotic has good penetration into the infection site • Resistant– significantly higher MICs that will cause a less than optimal clinical outcome even if higher doses of the antibiotic are used

19. Concept of Breakpoint to Determine Susceptibility EXAMPLE:Susceptibility testing for a single isolate of Pseudomonas aeruginosa -Breakpoint for intermediate resistance for meropenem is 4 and for piperacillin/tazobactam (pip/tazo) 32 -Pip/tazo is the better choice between the two -Ciprofloxacin is a poor choice even though the MIC is lowest of the three

20. Resistance

21. Introduction • Since the first use of antibiotics in the 1930s and 1940s, bacteria quickly adapted and developed mechanisms to escape their effects • Over the following decades, new antibiotics were developed to overcome resistance • Since the 1990s, new antibiotic development has fallen sharply while bacterial resistance continues to increase • Antibiotic resistance is responsible for countless human deaths and billions of dollars in healthcare expenses • 70% of bacteria that cause healthcare-acquired infections are resistant to common antibiotics

22. Antibiotic Use Leads to Antibiotic Resistance Inpatient Agriculture Outpatient

23. Clearing Up Misconceptions • Misconception: Antibiotics are no longer effective because people who have taken the medication have developed a tolerance to the drug • Truth: People do NOT develop a tolerance to drugs; the reason drugs no longer work is because the bacteria is no longer killed by the drug because they have become resistant to the effects

24. Factors that Promote Resistance • Exposure to antibiotics • Prolonged courses • Use of incorrect antibiotic • Sub-therapeutic doses • Treatment of viral infections • Introduction of resistant organisms from outside the population • Transfers from outside facilities • Long-term care facilities are primary reservoirs of antimicrobial resistance • Food sources (BSE, VRE, Hepatitis A, GI bugs) • Mobile society (SARS) • Tissue culture passage effect • Spread from patient to patient (hand hygiene) • Animal to human spread - agriculture

25. Reasons for Antibiotic Overuse : Conclusions from Eight Focus Groups Patient Concerns Want clear explanation Green nasal discharge Need to return to work Physician Concerns Patient expects antibiotic Diagnostic uncertainty Time pressure Antibiotic Prescription Barden L.S. Clin Pediatr 1998;37:665

26. “As long as we expose bacteria to antibiotics, they will evolve resistance to them. The more exposure…the more rapidly resistance will occur” (National Institute of Allergy and Infectious Diseases, 2014)

27. Antibiotic Use Leads to Antibiotic Resistance • Resistant bacteria or their genetic determinates are selected when colonizing or infecting bacteria are exposed to antibiotics • Resistant bacteria can then be transmitted between patients • Highest risk patients: • Immunocompromised • Hospitalized • Invasive devices (central venous catheters)

28. Antibiotic Mechanism of Action Linezolid Daptomycin Linezolid Daptomycin Daptomycin Daptomycin Daptomycin Daptomycin

29. Mechanisms Of Antibiotic Resistance Decreased Permeability Alteration in Target Molecule Can be related back to how the antibiotic works Bacteria are capable of becoming resistant through several mechanisms One or many mechanisms may exist in an organism Multidrug-resistant bacteria often have multiple mechanisms Genes encoding resistance may exist on plasmid or chromosome

30. Mechanisms of Resistance Antibiotic Degrading Enzymes • Sulfonation, phosphorylation, or esterifictation • Especially a problem for aminoglycosides • β-lactamases • Simple, extended spectrum β-lactamases (ESBL), cephalosporinases, carbapenemases • Confer resistance to some, many, or all beta-lactam antibiotics • May be encoded on chromosome or plasmid • More potent in gram-negative bacteria • Examples: S. aureus, H. influenzae, N. gonorrhoeae, E. coli, Klebsiella sp., Enterobacter sp., Serratia sp., other enteric bacteria, anaerobes

31. Extended Spectrum -lactamases -lactamases capable of hydrolysing extended spectrum cephalosporins, penicillins, and aztreonam Most often associated with E. coli and Klebsiella pneumoniae but spreading to other bacteria Usually plasmid mediated Aminoglycoside, ciprofloxacin and trimethoprim-sulfamethoxazole resistance often encoded on same plasmid Has become a significant resistance determinate in acute and long-term care facility enteric pathogens

32. Class A Carbapenemases Most common in Klebsiella pneumoniae (KPC) Also seen in E. coli, Enterobacter, Citrobacter, Salmonella, Serratia, Pseudomonas and Proteus spp. Very often with multiple other drug resistance mechanisms, resistance profile similar to ESBL but also carbapenem resistant Became problem in New York City first in 2002-2003 and is being increasingly recognized in Mid-Atlantic US. Spreading across species to other gram-negatives and enterobacteriaceae Emerging in long-term care facilities

33. Multidrug Resistant Gram-Negative Organisms • Development of resistance to multiple antimicrobial classes severely limits treatment options and the incidence of resistance is rising • Proportion of isolates resistant to three antibiotic classes ranged from 10 to 60% for different gram-negative bacteria, while some are resistant to four antibiotic classes

34. Multidrug Resistant Gram-Negative Organisms • Widespread use of cephalosporins and beta-lactam combination antibiotics has led to extended-spectrum beta-lactamases (ESBLs), which are resistant to both classes • Carbapenems have been the only effective agents for ESBLs • Emergence of carbapenemases, such as Klebsiellapneumoniaecarbapenemase (KPCs) are threatening carbapenems as the antibiotics of last resort • Significant issue for many military personnel due to the high amount of Acinetobacter in the desert • NO NEW ANTIBIOTICS ON THE HORIZON!!!

35. Mechanisms of Resistance Decreased Permeability • Pseudomonas spp. • Affects many antibiotics including carbapenems Efflux Pumps • Pseudomonas spp. (multiple antibiotics) • Tetracyclines • Macrolides

36. Mechanisms of Resistance Target Alteration • DNA gyrase • Fluoroquinolones • Many gram-negatives, S. pneumoniae • Penicillin-binding protein • Methicillin-resistant S. aureus (MRSA) • Penicillin-resistant S. pneumoniae • Gram positive cell wall • Vancomycin • Enterococcus spp.

37. Mechanisms of Resistance Target Alteration (cont’d) • Ribosome • Tetracyclines • Macrolides • S. pneumoniae, Staphylococcus sp., N. gonorrhoeae, enteric gram-negative rods

38. Treatment Options for Common Infections

39. HA-MRSA • Patients have multiple risk factors • Usually involves various types of infection • Bacteremia • Intravenous lines • Pneumonia • Skin and soft tissue infections • Transmission is person to person • Growth rate is slow • Resistant to multiple antibiotics • Need to make sure that patient has an infection

40. Antibiotic Therapy for HA-MRSA • Usually resistant to multiple antibiotics • Resistant to penicillins and cephalosporins • May be resistant to clindamycin and trimethoprim-sulfamethoxazole • Drugs of choice include vancomycin, linezolid(Zyvox), daptomycin(Cubicin), or quinupristin-dalfopristin(Synercid)

41. CA-MRSA • Risk factors not clearly identified other than more likely in a younger patient • Des seem to be a correlation between sharing of close quarters • Transmission is person to person • Growth rate is fast • The prevalence factor is PVL (panton-valentine leukocidin) and two major clones have been identified - makes this strain more virulent • Resistant to beta-lactams, but sensitive to other agents

42. Antibiotic Therapy for CA-MRSA • When the infection is skin/ soft tissue, incision and drainage of area may be needed • Usually resistant to the beta-lactams (penicillin and cephalosporins) • Usually sensitive to clindamycin, trimethoprim-sulfamethoxazole, minocycline, doxycycline • May be beneficial to add Rifampin for synergistic effect • Also sensitive to vancomycin, daptomycin, and linezolid, although these agents are not first-line

43. Acute Pharyngitis • One of the four most common episodic clinic visit • May be viral or bacterial • 40% of children with pharyngitis have Group A Streptococcal pharyngitis • Most commonly affected ages of 5 to 12 years • Not usually seen in children under age 3 • Only 5-15% of adult cases of acute pharyngitis are caused by group A beta-hemolytic streptococcal (GABHS)

44. Acute Pharyngitis • Treatment • No antibiotics when viral! • Treatment with antibiotics usually last for 7 to 10 days • Penicillin • Amoxicillin or amoxicillin/ clavulanate • Second or third generation oral cephalosporin • Macrolide • Penicillin is recommended for initial treatment of GABHS • No resistance seen in the United States yet • Fluoroquinolones are NOT appropriate

45. Rhinosinusitis • Most cases are viral • Less than 10% are bacterial • Resolves in about 7 days • Bacterial - often atypicals • Double-sickening – symptoms last longer than 7 days • Nasal congestion • Cough - often worse at night due to drainage • Facial pain - above or below the eyes that worsens when patient leans forward • Toothache - if maxillary sinuses are involved • Headache • Purulent drainage, although nasal discharge alone is not a good predictor of a bacterial infection • Clear to yellow to green • High fever – 102 or higher

46. Pharmacologic Treatments • Regardless of whether the etiology is infectious, allergic, or irritant, treatment should focus on relieving obstruction and establishing drainage • Analgesics • Decongestants • Antihistamines • Corticosteroids • Mucolytics • Antibiotics

47. Antibiotics • Rhinosinusitis is the fifth most common diagnosis for which an antibiotic is prescribed • First need to be sure that the infection is bacterial – most are viral and not bacterial • Want to use antibiotics with good coverage of atypicals and gram-positive organisms, as well as good penetration into the sinus cavity • Usually need to treat for 10 to 14 days • If chronic sinusitis, may need to consider 3 to 4 weeks of antibiotics, especially if surgery may be required

48. Antibiotics • For milder infections • Penicillins, such as amoxicillin/clavulanate • Doxycycline • May not be as effective due to increasing resistance among pneumococci • Second or third generation cephalosporins • Macrolides • For more serious infections • Amoxicillin/ clavulanate (high dose) • Quinolone with antipneumococcal activity, such as levofloxacin • PQRS Measure

49. Treatment Options for OM • Studies have shown that the symptoms of OM spontaneously resolved in 80% of children at 2 to 7 days. (Otalgia – endpoint) • More likely to be bacterial if child has siblings or attends day care • Ibuprofen or acetaminophen are the best options for pain control • Analgesic ear drops can also provide symptomatic relief • Some controversy over the use of decongestants, although fluid accumulating behind the ear drum is often a contributing factor

50. Treatment Options for OM • Antibiotics • Amoxicillin or Amoxicillin/ clavulanate • Second or third generation cephalosporin • Macrolide • PQRS Measure