Emerging Issues In Bacterial Resistance

3,076 views

Published on

Microbiology for the Clinician; Sinusitis; Otitis Media; AECB; PK/PD

Published in: Health & Medicine, Technology
2 Comments
3 Likes
Statistics
Notes
No Downloads
Views
Total views
3,076
On SlideShare
0
From Embeds
0
Number of Embeds
6
Actions
Shares
0
Downloads
0
Comments
2
Likes
3
Embeds 0
No embeds

No notes for slide

Emerging Issues In Bacterial Resistance

  1. 1. Microbiology for the Clinician
  2. 2. Classification of Bacteria  Morphology  Metabolic requirements  Cell wall – Gram-positive – Gram-negative Levinson and Jawetz, 1998.
  3. 3. Cell Wall  The cell walls of bacteria consist primarily of proteins, lipids, and mucopolysaccharides  Cell-wall contents and organization vary between gram-positive and gram-negative bacteria Levinson and Jawetz, 1998.
  4. 4. Gram-Positive Bacteria The peptidoglycan layer is composed of mucopolysaccharide Thick peptidoglycan chains cross-linked by short peptides Cell membrane Penicillin-binding protein (PBP) Levinson and Jawetz, 1998.
  5. 5. Penicillin-Binding Proteins  Penicillin-binding proteins are enzymes involved in cell-wall synthesis  One specific type is transpeptidase, which catalyzes the cross-linking of mucopolysaccharides Levinson and Jawetz, 1998.
  6. 6. Gram-Negative Bacteria Lipopolysaccharide, lipoprotein-phospholipid cell wall (hydrophobic) Porin channels Peptidoglycan Periplasmic space (Important site for degradation of antibiotics by drug-inactivating enzymes, such as PBP -lactamases) Levinson and Jawetz, 1998.
  7. 7. Minimum Inhibitory Concentration (MIC) MIC = 4.0 µg/mL 0.25 0.5 1.0 2.0 4.0 8.0 16 Antibiotic µg/mL µg/mL µg/mL µg/mL µg/mL µg/mL µg/mL Concentrations Known quantity of bacteria placed into each tube and observed 18 to 24 hours later
  8. 8. MIC  MIC is an in vitro measurement of antimicrobial activity  Environmental conditions at the site of infection, such as oxygen tension or pH, are radically different than they are in the test tube!  Example: pH at infection site can have a significant detrimental effect on macrolides Chambers and Sande, 1996; Carbon and Poole, 1999; File, 2000; Lynch and Martinez, 2000.
  9. 9. MIC Breakpoints  NCCLS established susceptibility guidelines (breakpoints) to interpret MICs  Four types of data are needed to determine breakpoints – Pharmacokinetic/pharmacodynamic (PK/PD) data – In vitro data – In vivo data – Clinical outcomes data  PK/PD data are needed for more clinically relevant breakpoints Lynch and Martinez, 2000; File, 2000; Chambers and Sande, 1996; Craig, 1998.
  10. 10. Bacterial Resistance: Mutations  Occur in previously susceptible cells  May occur in gene encoding target protein, transport protein, etc  Single-step mutation may lead to high resistance or may need several steps for mutation Levinson and Jawetz, 1998; Chambers and Sande, 1996.
  11. 11. Bacterial Resistance: Transduction  Occurs by intervention of virus that contains bacterial DNA incorporated within its protein coat  Particularly important among Staphylococcus aureus, in which the virus may carry plasmids (autonomously replicating pieces of extrachromosomal DNA) Chambers and Sande, 1996.
  12. 12. Bacterial Resistance: Transformation  Method of transferring genetic material by incorporation of free DNA into the bacteria  Important for PCN resistance in pneumococci  Foreign DNA—possibly from a related Streptococcus species—incorporated into the gene for PBP Chambers and Sande, 1996; Mandell and Petri, 1996.
  13. 13. Bacterial Resistance: Conjugation  Passage of genes from cell to cell by direct contact  Important mechanism for spread of antibiotic resistance  Mainly among gram-negative bacteria Chambers and Sande, 1996.
  14. 14. -Lactams: Mechanisms of Resistance     Susceptible Resistant -Lactamases Penicillin-binding proteins
  15. 15. -Lactams: Changes in PBP Site Penicillin-binding proteins          PBP (Susceptible) PBP (Low-level resistance) PBP (High-level resistance)
  16. 16. Macrolides: Mechanisms of Resistance M M M M M Bacterium M M Drug efflux M Susceptible Resistant Esterases Ribosome
  17. 17. Quinolones: Mechanisms of Action Inhibit DNA topoisomerases required to supercoil DNA
  18. 18. Quinolones: Mechanisms of Resistance F O Bacterium Susceptible Resistant Drug efflux Prevention of Topoisomerases influx
  19. 19. Careful Use of Antibiotics  Bacteria have a remarkable ability to develop resistance to antibiotics  Physicians need to understand the etiology of the specific infection being treated and choose the appropriate antibiotic based upon sound microbiologic principles  Increasing antibiotic resistance threatens success of antibiotic treatment for common infections  Antibiotic overuse drives the spread of resistance CDC, 2000a,b.
  20. 20. Types of Resistance  Streptococcus pneumoniae – Quinolones: alterations in DNA gyrase (gyrA and gyrB genes); topoisomerase IV (parC and parE genes) – Chloramphenicol: acetyltransferase alteration of molecule (cat gene) – Tetracycline: “ribosomal protection” (tetM and tetO genes) – Trimethoprim/sulfamethoxazole substituted in dihydrofolate reductase File and Slama, 2000; Lynch and Martinez, 2000; Corso et al, 1998; Luna and Roberts, 1998.
  21. 21. Macrolide Resistance in S pneumoniae  Efflux mechanism (mefE gene) – Moderate degree of resistance – Does not affect clindamycin  Target modification – Ribosomal methylase (erm gene) – High-level resistance – Cross-resistance to clindamycin  In the United States, mef is twice as common as erm  In most parts of the world, the erm gene is more common Lynch and Martinez, 2000; Nishijima et al, 1999; File, 2000.
  22. 22. Resistance: Summary  Rates of resistance to non–-lactam antimicrobials – Higher in penicillin-resistant strains of S pneumoniae  Macrolides – Efflux pump alteration (mediated by mefE gene) – Ribosomal methylase target modification (mediated by erm AM gene) – Spontaneous mutations – Extended-duration macrolides drove clindamycin resistance – Additional studies needed to determine whether in vitro resistance translates into clinical failures Lynch and Martinez, 2000; File, 2000.
  23. 23. Resistance: Summary (cont’d)  Tetracyclines – Resistance has increased worldwide – Prevalence of resistance highly variable  TMP/SMX – Resistance has increased worldwide – Increase in tandem with increase in penicillin resistance Lynch and Martinez, 2000.
  24. 24. Resistance: Summary (cont’d)  Fluoroquinolones – Alterations in DNA gyrase (gyrA and gyrB) – Alterations in topoisomerase IV (parC and parE) – Overzealous use may drive resistance Lynch and Martinez, 2000; File, 2000; Hooper, 2000.
  25. 25. Pharmacokinetic/Pharmacodynamic Principles for Antibiotics
  26. 26. Factors That Determine the Relationship Between Prescribed Drug Dosage and Drug Effect PRESCRIBED DOSE  Formulation (palatability)  Patient compliance  Medication errors ADMINISTERED DOSE  Rate and extent of absorption  Body size and composition  Distribution in body fluids  Binding in plasma and tissues  Rate of metabolism and elimination CONCENTRATION – Physiological variables AT LOCUS – Pathological factors OF ACTION – Genetic factors – Interaction with other drugs – Development of tolerance  Drug-receptor interaction  Functional state INTENSITY OF EFFECT  Placebo effects Nies and Spielberg, 1996.
  27. 27. Success of Drug Therapy  Dependent on integration of drug’s pharmacokinetic (PK) and pharmacodynamic (PD) profiles  PK describes overall disposition profile – Absorption, distribution, metabolism, excretion  PD describes relation between drug concentration and effect Craig, 1998; Nies and Spielberg, 1996; File, 2000.
  28. 28. MIC As a Determinant of Antimicrobial Activity  Determined at a specific point in time  Dependent on inoculum size  Dependent on media composition  Results observed after 18 to 24 hours do not reflect differences in drug’s pharmacokinetics  Contribution of host defenses not addressed  No albumin-free drug Guglielmo, 1995; Chambers and Sande, 1996.
  29. 29. Patterns of Antimicrobial Activity: Time-Dependent Concentration With Minimal to Moderate Persistent Effect  Antibiotic activity dependent on amount of time drug concentration exceeds pathogen MIC – Time-dependent bacterial killing (T >MIC) – Minimal to moderate persistent effect (postantibiotic) – Goal of dosing regimen to maintain drug concentration above pathogen MIC for greatest amount of time – Penicillins, cephalosporins, carbapenems, monobactams, clindamycin, macrolides Craig, 1998.
  30. 30. Patterns of Antimicrobial Activity of Antibiotics: Concentration Dependent  Antibiotic activity dependent on drug concentration relative to MIC – Concentration-dependent bacterial killing (peak or AUC/MIC) – Goal of dosing regimen to obtain greatest drug concentration relative to pathogen MIC – Aminoglycosides, fluoroquinolones Craig, 1998; File and Slama, 2000; File, 2000.
  31. 31. Patterns of Antimicrobial Activity: Time-Dependent Concentration With Prolonged Persistent Effect  Antibiotic activity dependent on amount of time drug concentration exceeds pathogen MIC – Prolonged, persistent postantibiotic effects – Goal of dosing regimen to obtain greatest drug concentration – PK/PD parameters: peak or AUC/MIC – Tetracyclines, azithromycin, vancomycin Craig, 1998; File, 2000.
  32. 32. Relationship Among Three Pharmacodynamic Parameters When Applying to β-lactams and Most Macrolides A B C Log10 CFU/lung at 24 hours Log10 CFU/lung at 24 hours Log10 CFU/lung at 24 hours 10 10 10 R2=94% 9 9 9 8 8 8 7 7 7 6 6 6 5 5 5 0.1 1 10 100 1,000 10,000 3 10 30 100 300 1,000 3,000 0 20 40 60 80 100 Peak MIC ratio AUC/MIC ratio at 24 hours Time above MIC (%) Craig, 1998.
  33. 33. PK/PD Parameters: Fluoroquinolones  AUC/MIC is the PK/PD parameter that best correlates with efficacy for fluoroquinolones  24-hr AUC/MIC ratio for unbound drug in plasma needs to reach about 25 for efficacy in immunocompetent animal infection models Craig, 1998; File and Slama, 2000.
  34. 34. PK/PD Parameters: Macrolides*  Time above MIC is the important parameter for determining efficacy of the macrolides  Macrolides should provide unbound drug levels in serum that exceed the MICs of strains of S pneumoniae for at least 50% of the dosing interval  Macrolides do not provide unbound drug levels that exceed the MICs of H influenzae * Azalides not included. Craig, 1998; File and Slama, 2000; File 2000; Carbon and Poole, 1999.
  35. 35. Conclusions  Defining optimal dose regimens for antibiotics has been elusive – Lack of incentives–safety, cost, compliance – Current clinical/economic pressures mandate definition  Target-concentration strategy challenged – Poor relationships between level and effect – Invalid relationships Craig, 1998; File, 2000.
  36. 36. Conclusions (cont’d)  Successful antibiotic therapy requires PK/PD integration – Accounts for drug-pathogen dynamics – Permits development of optimal dose regimens – Permits comparisons of different regimens – Imperative for cost-efficient drug development/utilization Craig, 1998; File, 2000.
  37. 37. Selection for Bacterial Resistance
  38. 38. Selective Pressure of Antibiotics  Exposure of both pathogens (at site of infection) as well as normal flora with antibiotic administration  Provides a selective advantage for any resistant mutants that occur  In vitro studies performed with new and commonly used antimicrobial agents Cole and Nadler, 1999; Pankuch et al, 1998; Davies et al, 1999.
  39. 39. Study Objectives  The objective of Pankuch et al was to – Study in vitro selection of resistance to 4 -lactams and azithromycin by subculturing 10 strains of Streptococcus pneumoniae in media with subinhibitory concentrations of antibiotics Pankuch et al, 1998.
  40. 40. Study Objectives (cont’d)  The objective of Davies et al was to – Examine the development of resistance by exposing 10 strains of S pneumoniae to subinhibitory concentrations of antibiotics – Determine mutations in parC, parE, gyrA, gyrB associated with quinolone resistance – Determine if the mutations possessed a quinolone efflux mechanism by comparing MICs in the presence and absence of reserpine, a known efflux pump inhibitor Davies et al, 1999.
  41. 41. Methods  MICs of parent strains determined  Strains passaged daily for 50 days in subinhibitory concentrations of antibiotics or until MIC increased fourfold  Strains then passaged daily for 10 days on antibiotic- free media and MICs determined  Parent and derived strains serotyped and compared by pulse-field gel electrophoresis  Mutant and parent strains tested for known resistance mechanisms to macrolides and quinolones Pankuch et al, 1998; Davies et al, 1999.
  42. 42. Antibiotics Tested: Study 1  Amoxicillin  Amoxicillin/clavulanate  Cefaclor  Cefuroxime  Azithromycin Pankuch et al, 1998.
  43. 43. Results: MICs (g/mL) of Pneumococcal Parent  Mutant Strains S pneumoniae Strain Amoxicillin Amox/Clav Cefaclor Cefuroxime Azithromycin 1 Pen-S -* - 0.5 4 0.060.25 0.03 8 2 Pen-S - - 0.5 2 0.030.25 - 3 Pen-S - - 0.5 2 0.06 0.5 0.03 >256 4 Pen-S - - - 0.030.12 0.03 0.5 5 Pen-S - 0.008 0.12 - 0.06 0.5 0.03 2 6 Pen-S - - - 0.030.12 0.03 32 7 Pen-I - - - - - 8 Pen-I - - - - 0.12 32 9 Pen-I - - 0.5  2 - 4  16 10 Pen-I - - - - 2  16 * Symbol (-) indicates no increase in MIC was detected. Pankuch et al, 1998.
  44. 44. Results: No. of Passages Needed to Establish Resistance S pneumoniae Strain Amoxicillin Amox/Clav Cefaclor Cefuroxime Azithromycin 1 Pen-S -* - 24 24 31 2 Pen-S - - 28 39 - 3 Pen-S - - 35 28 32 4 Pen-S - - - 44 45 5 Pen-S - 41 - 38 37 6 Pen-S - - - 28 17 7 Pen-I - - - - - 8 Pen-I - - - - 13 9 Pen-I - - 19 - 7 10 Pen-I - - 42 - 7 * Symbol (-) indicates no increase in MIC was detected. Pankuch et al, 1998.
  45. 45. Antibiotics Tested: Study 2  Amoxicillin/clavulanate  Ciprofloxacin  Grepafloxacin  Levofloxacin  Sparfloxacin  Trovafloxacin Davies et al, 1999.
  46. 46. Results: MICs (g/mL) of Pneumococcal Parent Mutant Strains S pneumoniae Strain Amox/Clav Cipro Grepa Levo Spar Trova 1 Pen-S -* 2 32 0.25  2 1  4 0.25  2 0.12  8 2 Pen-S - - 0.25  2 1  8 0.25  4 - 3 Pen-S 0.015 0.06 2 16 0.25  8 1>  32 0.25  4 0.12  1 4 Pen-S - 1 8 0.12  4 0.5  8 0.25  1 0.06  1 5 Pen-S - 0.5  4 0.12  0.5 0.5  4 0.12  1 0.06  0.25 6 Pen-S - 0.5  4 0.12  1 0.5  4 0.25  4 0.12  2 7 Pen-S - 0.5  8 0.06  0.5 1  8 0.12  1 0.06  0.25 8 Pen-S - 4 32 0.12  2 1  8 0.25  16 0.12  4 9 Pen-I - 1 8 0.12  0.5 0.5  16 0.12  1 0.12  2 10 Pen-I - 1  16 0.12  1 1  4 0.12  0.5 0.12  1 * Symbol (-) indicates no increase in MIC was detected. Davies et al, 1999.
  47. 47. Results: No. of Passages Needed to Establish Resistance S pneumoniae Strain Amox/Clav Cipro Grepa Levo Spar Trova 1 Pen-S -* 8 12 21 8 6 2 Pen-S - 8 14 49 20 - 3 Pen-S 24 8 5 20 16 7 4 Pen-S - 12 9 19 10 15 5 Pen-S - 12 23 24 25 - 6 Pen-S - 7 8 14 9 28 7 Pen-S - 9 5 46 9 5 8 Pen-S - 10 5 18 8 6 9 Pen-I - 10 18 22 26 28 10 Pen-I - 7 9 15 12 26 * Symbol (-) indicates no increase in MIC was detected. Davies et al, 1999.
  48. 48. Results: Development of Resistance in Quinolones vs Amoxicillin/Clavulanate  Sequential subculture in subinhibitory concentrations of all quinolones led to substantially increased MICs  Sequential subculture in subinhibitory concentrations of amoxicillin/clavulanate did not select for resistance  Demonstrates need for cautious and judicious use of broad-spectrum quinolones Davies et al, 1999.
  49. 49. Conclusions  In vitro selection of resistant mutants occurs readily with many agents, including cephalosporins, macrolides, and fluoroquinolones  Resistant mutants were not selected with amoxicillin and amoxicillin/clavulanate  Resistant mutants selected with fluoroquinolones had the same or similar changes in DNA gyrases seen in wild-type resistant strains Pankuch et al, 1998; Davies et al, 1999.
  50. 50. Conclusions (cont’d)  Antibiotic overuse likely drives the spread of resistance  Prevalence of S pneumoniae with reduced susceptibility to quinolones is increasing in Canada and Hong Kong  As with any antibiotic, judicious use of quinolones is the key to decreasing the spread of resistance CDC, 2000a,b,c; Hooper, 2000; 1998a,b; Chen, 1999; Ho et al, 1999; Peterson and Sahm, 1999.
  51. 51. Emerging Patterns of Resistance in Key Respiratory Tract Pathogens
  52. 52. Bacterial Pathogens in Community-Acquired Respiratory Tract Infections Prevalence (%) Infection S pneumoniae H influenzae M catarrhalis Acute sinusitis 42 29 22 Acute otitis media 42 38 17 Acute exacerbations 15 32 13 of chronic bronchitis Community-acquired 20-60 3-10 — pneumonia Zeckel et al, 1992; Hoberman et al, 1996; Bartlett and Mundy, 1995.
  53. 53. MIC Interpretation  MICs can be interpreted according to breakpoint cutoffs (for a particular agent) as susceptible, intermediate, or resistant  MIC breakpoints are based on – In vitro MIC data – In vivo animal model data – Pharmacokinetic/pharmacodynamic (PK/PD) data – Clinical outcomes data NCCLS, 2000; Guglielmo, 1995; Craig, 1998; File 2000.
  54. 54. Penicillin-Resistant S pneumoniae: United States (1979–1998) 50 Penicillin-resistant (%) 40 33% 29% 30 Resistant (>2.0 µg/mL) Intermediate (0.12 to 1.0 µg/mL) 20 18% 10 16% 0 1990-91 1981 1998 1987 1997 1988-89 1992-93 1986 1979 1980 1983 1985 1994-95 1982 1984 Year Doern, 1995; Jacobs et al, 1999.
  55. 55. S pneumoniae: US Surveillance 1997 (N=1476) and 1998 (N=1760) NCCLS Susceptible Susceptible (%) Antibiotic Breakpoints 1997 1998 (µg/mL) Amoxicillin 2 94 90 Cefuroxime 1 63 65 Azithromycin 0.5 70 68 Amox/clav 2/1 94 90 Jacobs et al, 1999; NCCLS, 2000.
  56. 56. H influenzae: MICs for Amoxicillin/Clavulanate  1997 US Surveillance Study reported that 41.6% of H influenzae strains were -lactamase positive  Amoxicillin/clavulanate at NCCLS breakpoint of 4/2 g/mL is active against >99% of all strains of H influenzae Jacobs et al, 1999; NCCLS, 2000.
  57. 57. Prevalence of -Lactamase–Producing, Ampicillin- Resistant, Nontypable H influenzae in the United States -lactamase–producing isolates 40 Ampicillin-resistant (%) 30 42% 37% 20 10 0 1983-841 19862 1987-883 1992-934 19935 1994-956 19977 19988 No. of centers 22 30 15 19 5 187 8 16 No. of isolates 2200 2054 564 890 5750 2278 1676 1919 1Doern et al, 1986; 2Doern et al, 1988; 3Jorgensen et al, 1990; 4Barry et al, 1994; 5Rittenhouse et al, 1995; 6Jones et al, 1997; 7Jacobs et al, 1999; 8Jacobs et al, 1999a.
  58. 58. H influenzae: MICs for Macrolides/Azalides  Mean MIC90s of H influenzae are relatively high (4 to 16 g/mL)  Macrolides have low in vitro activity against H influenzae  Concentrations of macrolides and azalides in extracellular tissue fluids — where H influenzae is located — are low  H influenzae is the most prevalent pathogen in chronic bronchitis and is a key pathogen in other RTIs Carbon and Poole, 1999; File, 2000; Jacobs et al, 1999.
  59. 59. Activity of Fluoroquinolones Against H influenzae MIC50 MIC90 MIC Breakpoint Antimicrobial (µg/mL) (µg/mL) (µg/mL) Ciprofloxacin 0.015 0.015 1 Levofloxacin 0.03 0.03 2 Gemifloxacin (SB 265805) 0.008 0.015 Kelly et al, 1998; NCCLS, 2000.
  60. 60. M catarrhalis: MICs for Amoxicillin and Amoxicillin/Clavulanate 50 No. of strains 25 Amoxicillin Amox/clavulanate 0 0.12 0.25 0.5 1 2 4 8 16 32 MIC (µg/mL) Jacobs et al, 1999a.
  61. 61. 1997 Study Summary: S pneumoniae (1476 Strains)  50% Not susceptible to penicillin  18% Pen-I, 33% Pen-R  94% Amox-, amox/clav- susceptible – At NCCLS breakpoints  30% Macrolide-resistant  No quinolone resistance Jacobs et al,1999.
  62. 62. 1997 Study Summary: H influenzae (1676 Strains)  42% -Lactamase-positive  No amox/clav-resistant strains  One BLNAR strain  No BLPACR strains  One quinolone-resistant strain Jacobs et al, 1999.
  63. 63. Agents Active Against 1998 US Surveillance Isolates Applying NCCLS January 2000 Breakpoints (%) S pneumoniae H influenzae M catarrhalis* Antimicrobial (N=1760) (N=1919) (N=204) Amoxicillin 90 —† —† Amox/clav 90 >99 >99 Cefuroxime 65 98 99 Cefprozil 67 86 89 Cefixime —† >99 >99 Cefaclor 46 82 95 Loracarbef 60 90 90 Clarithromycin 68 73 >99 Azithromycin 68 97 >99 *There are no current breakpoints for M catarrhalis: breakpoints for H influenzae have been applied. †No breakpoints available. Jacobs et al, 1999a.
  64. 64. Pathogens and Susceptibility: Conclusions  -Lactam resistance continues to increase in S pneumoniae  -Lactamase production 40% in H influenzae  Macrolide/azalide resistance is high (~30%) in S pneumoniae  Macrolides/azalides have limited activity against H influenzae Jacobs, 1999.
  65. 65. Choosing the Right Antibiotic: Conclusions  Based on NCCLS breakpoints,* the only oral -lactam, macrolide, or azalide that is effective against >90% of current strains of the three key respiratory pathogens is amoxicillin/clavulanate  Newer fluoroquinolones are currently active against the three key respiratory pathogens, but development of resistance is likely with overuse *The H influenzae susceptible breakpoint of 4 g/mL was applied to M catarrhalis because no NCCLS breakpoints are currently available. Jacobs et al, 1999; NCCLS, 2000; Davies et al, 1999; Hooper, 2000; Chen et al, 1999.
  66. 66. Conclusions  -Lactams – Resistance continues to increase in S pneumoniae – -Lactamase production in H influenzae is 40%  Macrolides – Resistance high (30%) in S pneumoniae – Limited activity against H influenzae  Fluoroquinolones – Currently active against H influenzae, S pneumoniae, and M catarrhalis – Concern about resistance with overuse Jacobs et al, 1999; Lynch and Martinez; 2000, File 2000; File and Slama, 2000; Hooper, 2000
  67. 67. Emerging Issues Regarding Bacterial Resistance and Clinical Efficacy in Respiratory Tract Infections: Recommendations and Treatment Guidelines Otitis Media
  68. 68. Otitis Media  Acute otitis media (AOM): inflammation of the middle ear accompanied by fluid and signs and symptoms of ear infection  Otitis media with effusion (OME): fluid in the middle ear without signs or symptoms of ear infection Always use pneumatic otoscopy or tympanometry to confirm middle ear effusion (MEF) Klein, 1995; Otitis Media Guideline Panel, 1994; American Academy of Pediatrics, 1994; CDC, 2000; CHMC, 1999.
  69. 69. Risk Factors for Recurrent Otitis Media  Male gender  Sibling history of recurrent otitis media (OM)  Early occurrence of OM  Bottle-feeding rather than breast-feeding  Lower socioeconomic group  Attendance at group child-care facility  Exposure to smoke in the household Klein, 1995; Otitis Media Guideline Panel, 1994; Bluestone and Klein, 1995; Harrison and Belhorn, 1991.
  70. 70. Risk Factors for Recurrent Otitis Media (cont’d)  Race and ethnicity – Native Americans, Alaskan and Canadian Eskimos, and Australian Aborigines have a very high incidence and severity of OM  Children with craniofacial abnormalities, such as cleft palate and Down’s syndrome Klein, 1995; Otitis Media Guideline Panel, 1994; Bluestone and Klein, 1995; Harrison and Belhorn, 1991.
  71. 71. Otitis Media in the United States  Overall incidence of OM rising – Age of onset becoming earlier and number of otitis-prone cases increasing – Office visits rose from 9.9 million in 1975 to 24.5 million in 1990  Most frequent diagnosis in office practice for children <15 years of age – By 3 years of age between 67% and 75% of children have had one or more episodes of AOM – Highest incidence of AOM occurs between 6 and 24 months of age – Most frequent reason for administering antibiotics to children  Annual cost – Medical and surgical treatment of between $3 and $4 billion dollars – Median costs and lost wages amount to $5 billion dollars per year Klein, 1995; CDC, 1999; NIDCD, 2000; Gates, 1996; Block et al, 1999; Berman et al, 1997; Berman, 1995.
  72. 72. Prevention of OM  Vaccinations – Pneumococcal – Haemophilus influenzae (type b)  Breast feeding  Promote ventilation and frequent hand washing at child care facilities  Smoking cessation Wadwa and Feigin, 1999; Klein, 1995; Otitis Media Guideline Panel, 1994; Zenni et al, 1995; Bluestone and Klein, 1995, American Academy of Pediatrics, 1997.
  73. 73. Pathophysiology  Middle ear cavity normally sterile and filled with air  During swallowing, air enters middle ear through eustachian tube  If normal ventilation of middle ear cavity does not occur, negative pressure builds up as the air is absorbed  Effusion of fluid into middle ear may occur  Bacteria from the nasopharynx may be drawn into the middle ear Klein, 1995; NIDCD, 2000.
  74. 74. Pathophysiology (cont’d)  Eustachian tube may malfunction because of – Obstruction from inflammation of the tube itself or from hypertrophied nasopharyngeal lymphatic tissue – Mechanical factors, including diminished patency, poor muscular function, and increased tortuosity Klein, 1995; NIDCD, 2000.
  75. 75. Signs and Symptoms Specific Symptoms Nonspecific Symptoms  Ear discomfort or pain,  Fever may be severe  Vestibular disturbances  Fullness, pressure in the  Fever ear  Chills  In children, pulling at the  Irritability ear  Feeling of malaise  Drainage from the ear  Nausea, vomiting, and/or  Hearing loss in the affected diarrhea ear NIDCD, 2000; Berman, 1995.
  76. 76. Additional Signs and Symptoms  Sore throat  Neck pain  Nasal discharge  Nasal congestion  Joint pain  Headache  Ear noise or buzzing NIDCD, 2000; Berman, 1995; American Academy of Pediatrics, 2000.
  77. 77. Diagnosis  Always use pneumatic otoscopy or tympanometry to confirm MEF  No effusion: Not AOM or OME  Effusion with signs and symptoms of AOM: AOM  Effusion without signs and symptoms of AOM: OME CDC, 2000; Klein, 1995.
  78. 78. Otoscopic Examination  May show dullness, redness, air bubbles, or fluid behind the eardrum  Eardrum may bulge out or retract inward or have perforations  Presence of fluid in the middle ear determined by – Pneumatic otoscopy to assess mobility of the tympanic membrane – Tympanometry  Fluid may show blood, pus, and/or bacteria  Fluid or high negative pressure in the middle ear makes tympanic membrane less motile Klein, 1995; CDC, 2000; Berman, NIDCD, 2000.
  79. 79. Most Common Bacterial Pathogens in AOM*  Streptococcus pneumoniae – Larger proportion of cases than any other agent (40% to 50%) – Least likely of the major pathogens to resolve without treatment  H influenzae – 20% to 30%  M catarrhalis – 10% to 15% *Lessfrequent bacteria include: Group A streptococci, and Staphylococcus aureus; gram-negative enteric bacteria (in newborns, persons with depressed immune response, and in patients with suppurative complications of chronic OM). Barnett and Klein; 1995; Jacobs, 1998; Dowell et al, 1999; Klein, 1995; Hoberman et al, 1996; Bluestone and Klein, 1995.
  80. 80. Management of AOM  Nasal sprays, nose drops, oral decongestants, or, occasionally, oral antihistamines to reduce congestion  Ear drops to relieve pain  Over-the-counter antipyretic and analgesic medications (such as oral acetaminophen or ibuprofen) to reduce fever and discomfort  Aspirin should not be given to children during a viral upper respiratory infection because of link with Reye's syndrome  Antibiotics if bacterial infection is present Klein, 1995.
  81. 81. Management of AOM (cont’d)  Oral corticosteroids may occasionally be prescribed to reduce inflammation  Myringotomy (surgical cutting of the eardrum) may occasionally be needed to relieve pressure and allow drainage. – This may or may not also involve placement of drainage tubes in the ear.  Surgery to remove the adenoids may prevent them from blocking the eustachian tube Klein, 1995.
  82. 82. Intracellular vs Extracellular Drugs in Middle Ear Fluid MEF with cells MEF without cells Concentrations Concentrations in MEF (g/ml) in MEF (g/ml) 16 Ceftibuten 16 Ceftibuten Cefixime Cefixime 14 14 Azithromycin Azithromycin 12 12 10 10 8 8 6 6 4 4 2 2 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Time (h) Time (h) Scaglione, 1997.
  83. 83. Clinical vs Bacteriologic Outcome of 123 Children With Acute Otitis Media P <.001 Failure 2 (3%) Failure 21 (37%) Cure Cure 36 (63%) 64 (97%) Cx result Cx (+) Cx (-) on day 4-5 n = 57 n = 66 Dagan et al, 1998.
  84. 84. AOM Double-Tap Study: Amoxicillin/Clavulanate* vs Azithromycin† Methodology Preliminary visit On-therapy End of Follow-up Tympanocentesis visit therapy visit visit therapy initiated Tympanocentesis (Days 12-14) (Days 22-28) (Day 1) (Days 4-6) Interim visit (optional) Patient’s condition is not improving or is worsening Study design: randomized, single-blind (investigator-blind), multicenter. Patients were 6-48 months old with protocol-defined AOM *Amoxicillin/clavulanate: 45/6.4 mg/kg/d ql2 x 10d w/food. †Azithromycin:10 mg/kg as single dose on day 1 followed by 5 mg/kg/d on days 2-5 w/o food. Dagan et al, 2000.
  85. 85. AOM Double-Tap Study: Amoxicillin/Clavulanate* vs Azithromycin† Clinical Success on Days 12 - 14 P=.023 P=.01 P=NS P=NS 100 A/C* 91 90 86 86 AZ† 80 80 75 70 68 70 65 60 % 50 40 30 20 10 0 60/70 51/73 30/33 22/34 18/21 16/20 12/16 13/19 All Patients H influenzae S pneumoniae Other Pathogens *Amoxicillin/clavulanate: 45/6.4 mg/kg/d ql2 x 10d w/food. †Azithromycin: 10 mg/kg as single dose on day 1 followed by 5 mg/kg/d on days 2-5 w/o food. Dagan et al, 2000.
  86. 86. AOM Double-Tap Study: Amoxicillin/Clavulanate* vs Azithromycin† Bacteriologic eradication on Days 4-6 100 P=.0001 P=NS P=.001 90 90 87 A/C* 83 80 AZ† 68 70 60 49 % 50 39 40 30 20 10 0 26/30 13/33 18/20 13/19 54/65 35/71 H influenzae S pneumoniae All Pathogens *Amoxicillin/clavulanate: 45/6.4 mg/kg/d ql2 x 10d w/food. †Azithromycin: 10 mg/kg as single dose on day 1 followed by 5 mg/kg/d on days 2-5 w/o food. Dagan et al, 2000.
  87. 87. AOM Double-Tap Study: Amoxicillin/Clavulanate* vs Azithromycin† Total Adverse Experiences 30 27 P=NS A/C* 25 AZ† 22 20 % 15 10 5 0 32/118 26/120 *Amoxicillin/clavulanate: 45/6.4 mg/kg/d ql2 x 10d w/food. †Azithromycin: 10 mg/kg as single dose on day 1 followed by 5 mg/kg/d on days 2-5 w/o food. Dagan et al, 2000.
  88. 88. CDC DRSP TWG Treatment Algorithm Antibiotic Therapy Within Prior Month for AOM? NO YES • Amoxicillin Amoxicillin • Amoxicillin/clavulanate • Cefuroxime axetil Clinical Failure on Day 3 • Amoxicillin/clavulanate • Ceftriaxone IM (up to 3 injections) • Cefuroxime axetil • Clindamycin (for S pneumoniae only) • Ceftriaxone IM (up to 3 injections) • Tympanocentesis (for culture)
  89. 89. Emerging Issues Regarding Bacterial Resistance and Clinical Efficacy in Respiratory Tract Infections: Recommendations and Treatment Guidelines AECB
  90. 90. Bronchitis  Inflammation of the bronchi, usually caused by infection  May be acute or chronic  Chronic bronchitis defined as cough and sputum production for at least 3 consecutive months in 2 consecutive years  Chronic bronchitis frequently complicated by acute episodes known as acute exacerbations of chronic bronchitis (AECB)  AECB defined in terms of clinical presentation, including increased cough, increased sputum volume and purulence, and dyspnea American Thoracic Society, 1995; American Lung Association, 2000; Ball et al, 1994; FDA, 1997.
  91. 91. Schema of COPD CHRONIC EMPHYSEMA BRONCHITIS (Red) (Blue) COPD AIRFLOW OBSTRUCTION ATS ASTHMA (Yellow)
  92. 92. Significance of Bronchitis in the United States  Over 14 million people – More women than men suffer from chronic bronchitis – 10.9 million affected Americans under age 45  American Lung Association ranks chronic bronchitis among the top 9 most prevalent conditions in the United States  3,000 deaths in 1996  16.3 million courses of outpatient antimicrobial therapy were prescribed for bronchitis in 1992 CDC, 2000; American Lung Association, 2000.
  93. 93. Differential Diagnosis of AECB  Aspiration of foreign body  Cardiac-related problems (arrhythmias, CHF)  Gastroesophageal reflux disease (GERD)  Pulmonary embolism  Pneumothorax, pleural effusion  Infection, bacterial or viral  Pneumonia, bronchitis, bronchiectasis, asthma  Metabolic disease  Low PO2/low K  Drugs, eg, angiotensin-converting enzyme (ACE) inhibitors, sedatives Canadian Medical Association, 1994; Bartlett, 1997; Irwin et al, 2000; Ducolon’e et al, 1987; Crausaz and Favez, 1988; Veterans Health Administration, 2000.
  94. 94. Prevention of Respiratory Tract Infections  Cessation of smoking  Influenza immunization  Pneumococcal immunization Canadian Medical Association, 1994; Bartlett, 1997.
  95. 95. AECB: Signs and Symptoms Symptoms Patients (%)  Dyspnea* 90  Cough 82  Sputum production* 69  Sputum purulence* 60 Fever 29 Average exacerbations 2.56/yr * Cardinal symptoms for Anthonisen’s classification of AECB: Type 1 exacerbation includes all three symptoms; Type 2 includes two symptoms; and Type 3 includes only one symptom. Adapted from Anthonisen et al, 1987.
  96. 96. Potential Benefits of Antibiotic Therapy for AECB Short-term Long-term  Duration of symptoms Possibly prevent progressive airway damage Avoid hospitalizations Prolong time between May return to work earlier exacerbations Prevent the progression Prevent secondary bacterial of airway infection to colonization and infection pneumonia after documented viral infection Niederman, 1996; Chodosh, 1999; Niederman, 2000.
  97. 97. Bacterial Colonization: Stable Chronic Bronchitis vs AECB  40 outpatients with stable chronic bronchitis: bronchoscopy sampling  29 outpatients with AECB  Positive bacterial cultures (103 CFU/mL) obtained from – 25% of outpatients with stable chronic bronchitis – 52% of outpatients with AECB  Positive bacterial cultures (>104 CFU/mL) obtained from – 5% of outpatients with stable chronic bronchitis – 24% of outpatients with AECB Monso et al, 1995.
  98. 98. Relationship Between Disease Severity and Respiratory Pathogens n=112 Patients with AECB 64 60 S pneumoniae, S aureus H influenzae, M catarrhalis Total isolates from sputum 50 47 Enterobacteriaceae, Pseudomonas spp, others* 40 40 33 30 (%) 30 27 23 23 20 13 10 0 50 35 to <50 <35 FEV1 (% predicted) * Other pathogens included Serratia marcescens, Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli, Citrobacter spp, and S maltophilia Eller et al, 1998.
  99. 99. Desirable Attributes of an AECB Agent  Activity against most likely organisms: H influenzae, S pneumoniae, M catarrhalis  Resistant to destruction by -lactamase  Good penetration into sputum and bronchial and lung tissue  High sputum MIC ratio against target organisms Niederman, 1996.
  100. 100. Bronchitis Categories Bronchitis Categories Clinical Characteristics  Acute tracheobronchitis  No underlying airway disease  “Simple” AECB  <4 exacerbations/year No comorbid illness FEV1> 50%  “Complicated” AECB  >4 exacerbations/year  FEV1 < 50%  Comorbid illness*  *At risk for Pseudomonas infection  Severe lung damage Frequent prior antibiotic therapy Chronic corticosteroids Recent hospitalization * Comorbid illness: CAD, CHF. Niederman, 1996; Canadian Medical Association, 1994; Grossman, 1997; Ball et al, 2000.
  101. 101. Therapy for AECB Bronchitis Categories Probable Pathogen Oral Therapy Acute tracheobronchitis Viral Symptomatic (no underlying airway Mycoplasma Doxycycline disease) Clarithromycin Azithromycin Fluoroquinolones “Simple” AECB H influenzae Amoxicillin/clavulanate M catarrhalis New macrolides S pneumoniae New cephalosporins “Complicated” AECB As per uncomplicated Fluoroquinolones Gram-negative pathogens Amoxicillin/clavulanate At risk for Pseudomonas Pseudomonas Ciprofloxacin infection Bartlett, 1997; Felmingham et al, 1999, Grossman, 1997; Sethi, 1999; Niederman, 1996; Canadian Medical Association, 1994.
  102. 102. Antimicrobials Most Active Against Common Pathogens in AECB Pathogens Antimicrobials H influenzae Amoxicillin/clavulanate, 2nd or 3rd generation cephalosporins (eg, – Resistance to ampicillin and ceftriaxone), doxycycline, amoxicillin related to –lactamase levofloxacin, ciprofloxacin, production azithromycin, TMP/SMX – Resistance to –lactam antibiotics due to alterations in PBPs (rare) Felmingham et al, 1999; Geddes, 1997; Grossman, 1997; Bartlett et al, 1998; Bartlett, 1997; Jacobs et al, 1999; Sethi, 1999; Thornsberry et al, 1997; Niederman, 1996; Richter et al, 1999; File and Slama, 2000; Eller et al, 1998; Canadian Medical Association, 1994; Chodosh, 1999.
  103. 103. Antimicrobials Most Active Against Common Pathogens in AECB (cont’d) Pathogens Antimicrobials  S pneumoniae Penicillin G or V, – Resistance to –lactam antibiotics amoxicillin ± clavulanate, due to altered penicillin-binding ceftriaxone, other proteins (PBPs) cephalosporins, macrolides, doxycycline, – Multidrug resistance due to various levofloxacin, clindamycin, mechanisms azithromycin, clindamycin – Macrolide resistance due to various mechanisms – Macrolide resistance due to altered ribosomes and increased efflux – Tetracycline resistance due to presence of tetM gene Felmingham et al, 1999; Geddes, 1997; Grossman, 1997; Bartlett et al, 1998; Bartlett, 1997; Jacobs et al, 1999; Sethi, 1999; Thornsberry et al, 1997; Niederman, 1996; File and Slama, 2000; Eller et al, 1998; Canadian Medical Association, 1994; Chodosh, 1999.
  104. 104. Antimicrobials Most Active Against Common Pathogens in AECB (cont’d) Pathogens Antimicrobials  M catarrhalis Amoxicillin/clavulanate, ceftriaxone, levofloxacin, – Resistance to ampicillin azithromycin, ciprofloxacin, and amoxicillin due to clarithromycin –lactamase production Felmingham et al, 1999; Geddes, 1997; Grossman, 1997; Bartlett et al, 1998; Bartlett, 1997; Jacobs et al, 1999; Sethi, 1999; Thornsberry et al, 1997; Niederman, 1996; Richter et al, 1999; File and Slama, 2000; Eller et al, 1998; Canadian Medical Association, 1994; Chodosh, 1999.
  105. 105. Emerging Issues Regarding Bacterial Resistance and Clinical Efficacy in Respiratory Tract Infections: Recommendations and Treatment Guidelines Sinusitis
  106. 106. Rhinosinusitis and Sinusitis  The terminology rhinosinusitis (RS) has been established to more accurately indicate that the inflammatory processes that cause sinusitis are associated with inflammation of the nasal passages  Rhinitis with nasal discharge and nasal obstruction typically precedes sinusitis – Sinusitis without rhinitis is rare – Mucous membranes of the nose and sinuses are contiguous Lanza and Kennedy, 1997.
  107. 107. Prevalence of Bacterial RS  Acute RS – 20 million episodes per year – Complication of URI in 0.5% to 2% of cases – Seasonal prevalence correlates with that of the common cold Adapted from CDC/National Center for Health Statistics, 1998; Bartlett, 1997; Gwaltney, 1996; Kaliner et al, 1997.
  108. 108. Pathophysiology of RS Viral URI Allergy Smoking Air Pollution Patient’s Mucociliary nasal/sinus Abnormalities mucosa & anatomy Immunodeficiency Trauma Gwaltney, 1996; Lanza and Kennedy, 1997; Hadley and Schaefer, 1997; American Academy of Otolaryngology, 2000; Benninger et al, 1997.
  109. 109. Pathophysiology of RS (cont’d) Normal gas exchange Decrease in pH leads to interrupted decreased ciliary activity Decreased O2 sat Environment Stagnation of secretions supports bacterial growth Ostium occluded Mucosal Further inflammation/edema inflammation and ciliary damage Gwaltney, 1996; Benninger et al, 1997.
  110. 110. Major Symptoms Associated With Diagnosis of RS  Nasal obstruction/blockage  Nasal discharge/pus/discolored postnasal drainage  Hyposmia/anosmia  Pus in nasal cavity  Facial pain/pressure*  Fever* * Must be accompanied by other nasal signs/symptoms. Adapted from Lanza and Kennedy, 1997; Hadley and Schaefer,1997.
  111. 111. Minor Symptoms Associated With Diagnosis of RS  Headache  Fever (all nonacute)  Halitosis  Fatigue  Dental pain  Cough  Ear pain/pressure/fullness Lanza and Kennedy, 1997; Hadley and Schaefer, 1997.
  112. 112. Consider Acute Bacterial RS  With prolonged nonspecific URI signs and symptoms – Rhinorrhea and cough without improvement for more than 10 to 14 days  More severe upper respiratory tract signs and symptoms – Fever >39°C (>102.2°F) – Facial swelling and pain  When a viral URI persists for 10 to 14 days  Or if after 5 or more days the symptoms of a viral URI become worse—rather than better You need to suspect acute bacterial rhinosinusitis CDC, 2000; American Academy of Otolaryngology, 2000.
  113. 113. Rhinoscopic Examination for RS Structural Problems  Deviated nasal septum  Enlarged turbinates Mucosal Problems  Hyperemia  Edema  Crusting  Pus  Polyps Hadley and Schaefer, 1997.
  114. 114. General Management Goals  Management goals for RS – Reduce tissue edema – Facilitate drainage – Control infection American Academy of Otolaryngology, 2000; Low et al, 1997.
  115. 115. Decongestants and Mucolytics  Decongestants reduce tissue edema and facilitate drainage by increasing ostial patency – Oxymetazoline (topical) – Pseudoephedrine – Phenylpropanolamine  Mucolytics thin secretions and facilitate drainage – Guaifenesin Low et al, 1997; Hadley and Schaefer, 1997.
  116. 116. Bacterial Causes of Acute Maxillary RS S pneumoniae (41%) H influenzae (35%) Other Strep spp (7%) Anaerobes (7%) M catarrhalis (4%) S aureus (3%) Other (4%) Adapted from Gwaltney, 1997.
  117. 117. CDC Recommendations on the Judicious Use of Antibiotics in Acute RS  Antibiotics should not be given for viral RS  Initial antibiotic treatment of acute bacterial RS should be a narrow-spectrum agent active against likely pathogens  Reasonable initial choices include amoxicillin or trimethoprim-sulfamethoxazole  Switch to broader coverage, such as amoxicillin/clavulanate, if patient is not improving after 96 hours CDC, 2000.
  118. 118. Recommended Antibiotics  Amoxicillin Cover S pneumoniae and  Trimethoprim–sulfamethoxazole non-β-lactamase- producing H influenzae  Amoxicillin/clavulanate  Azithromycin Cover S pneumoniae and H influenzae  Cefpodoxime  Cefprozil axetil Less active against S pneumoniae  Cefuroxime and H influenzae Use for PCN-allergic patient  Fluoroquinolones Not recommended 1st line Rx Not recommended for children CDC, 2000; Jacobs et al, 1999; Temple and Nahata, 2000.
  119. 119.  Augmentin® is contraindicated in patients with a history of allergic reactions to any penicillin or Augmentin®-associated cholestatic jaundice/hepatic dysfunction.  For susceptible strains of indicated organisms. Augmentin® is appropriate initial therapy when -lactamase–producing pathogens are suspected.  S. pneumoniae does not produce -lactamase and is therefore susceptible to amoxicillin alone. Empiric therapy with Augmentin® may be instituted when there is reason to believe the infection may involve -lactamase–producing pathogens. Once the results are known, therapy should be adjusted, if appropriate.  Please see complete prescribing information for warnings, precautions, adverse reactions, and dosage and administration. On Behalf of SmithKline Beecham, Thank You For Attending This Presentation

×