Emerging Issues In Bacterial Resistance

Microbiology
for the Clinician

Classification of Bacteria

 Morphology
 Metabolic requirements
 Cell wall
– Gram-positive
– Gram-negative

Levinson and Jawetz, 1998.

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


Gram-Positive Bacteria
The peptidoglycan
layer is composed of
mucopolysaccharide
Thick peptidoglycan chains cross-linked
by short peptides

Cell membrane
Penicillin-binding
protein (PBP)


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


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)

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

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.

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.

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.

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.

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.

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.

-Lactams: Mechanisms of Resistance



 

Susceptible Resistant
-Lactamases
Penicillin-binding proteins

-Lactams: Changes in PBP Site

Penicillin-binding proteins

        

PBP (Susceptible) PBP (Low-level resistance) PBP (High-level resistance)

Macrolides: Mechanisms of Resistance

M
M M

M M
Bacterium
M M
Drug efflux M
Esterases Ribosome

Quinolones: Mechanisms of Action

Inhibit DNA
topoisomerases
required to
supercoil DNA

Quinolones: Mechanisms of Resistance
F

O

Bacterium

Drug efflux Prevention of Topoisomerases
influx

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.

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.

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.

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.

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.

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.

Pharmacokinetic/Pharmacodynamic
Principles for Antibiotics

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.

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.

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.

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.

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.

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.

Relationship Among Three Pharmacodynamic Parameters
When Applying to β-lactams and Most Macrolides

A B C

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.

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.

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.

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.

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.

Selection for
Bacterial Resistance

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.

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.

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.

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.

Antibiotics Tested: Study 1

 Amoxicillin
 Amoxicillin/clavulanate
 Cefaclor
 Cefuroxime
 Azithromycin


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.

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

Antibiotics Tested: Study 2

 Ciprofloxacin
 Grepafloxacin
 Levofloxacin
 Sparfloxacin
 Trovafloxacin

Davies et al, 1999.

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

Davies et al, 1999.

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
Davies et al, 1999.

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.

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.

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.

Emerging Patterns of
Resistance in Key
Respiratory Tract Pathogens

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

Emerging Issues Regarding Bacterial
Resistance and Clinical Efficacy in
Respiratory Tract Infections:
Recommendations and
Treatment Guidelines

Otitis Media

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

†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.

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.
Dagan et al, 2000.

Total Adverse Experiences
30
27 P=NS
A/C*
25 AZ†
22

20

% 15

10

5

0
32/118 26/120
Dagan et al, 2000.

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)

Recommendations and Treatment
Guidelines

AECB

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.

Schema of COPD
CHRONIC EMPHYSEMA
BRONCHITIS (Red)
(Blue)

COPD

AIRFLOW
OBSTRUCTION

ATS
ASTHMA (Yellow)

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.

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.

Prevention of Respiratory Tract
Infections

 Cessation of smoking
 Influenza immunization
 Pneumococcal immunization

Canadian Medical Association, 1994; Bartlett, 1997.

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.

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.

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.

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.

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.

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.

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.

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.

Common Pathogens in AECB (cont’d)
 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.

Common Pathogens in AECB (cont’d)


 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.

Recommendations and
Treatment Guidelines

Sinusitis

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.

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.

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.

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.

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.

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.

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.

Rhinoscopic Examination for RS
Structural Problems
 Deviated nasal septum
 Enlarged turbinates

Mucosal Problems
 Hyperemia
 Edema
 Crusting
 Pus
 Polyps

Hadley and Schaefer, 1997.

General Management Goals
 Management goals for RS
– Reduce tissue edema
– Facilitate drainage
– Control infection

American Academy of Otolaryngology, 2000; Low et al, 1997.

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.

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.

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.

Recommended Antibiotics
 Amoxicillin Cover S pneumoniae and
 Trimethoprim–sulfamethoxazole non-β-lactamase-
producing H influenzae

 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.

 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

Emerging Issues In Bacterial Resistance

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