NEGATIVE NEGATIVE Lack of bacterial Spread of R R Lack of - - PowerPoint PPT Presentation

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Increase in in Increase bacterial R R bacterial NEGATIVE NEGATIVE Lack of bacterial Spread of R R Lack of bacterial Spread of eradication clones eradication clones SPIRAL SPIRAL Recolonization by Recolonization by R

SLIDE 1

NEGATIVE NEGATIVE SPIRAL SPIRAL

Increase Increase in in bacterial bacterial R R

Lack of bacterial Lack of bacterial eradication eradication Spread of Spread of R R clones clones Recolonization by Recolonization by R R microorganisms microorganisms

SLIDE 2

Clinical relevance of Clinical relevance of in in vitro vitro data data Macrolides Macrolides

Which are the breakpoints in Europe?
Effect of methodology used
Effect of incubation atmosphere
Lack of reproducibility among labs.
Data for antimicrobial without published

interpretative criteria

Differences in resistance mechanisms

SLIDE 3

Macrolides breakpoints proposed by Macrolides breakpoints proposed by different organizations for different organizations for Streptococcus spp Streptococcus spp

S R S R S R S R Erythromycin

≤ ≤ ≤ ≤ 0.5 >2 ≤ ≤ ≤ ≤ 0.25 >1 ≤ ≤ ≤ ≤ 1 >8 ≤ ≤ ≤ ≤ 0.5 >1

Clarithromycin

≤ ≤ ≤ ≤ 0.5 >2 ≤ ≤ ≤ ≤ 0.25 >1 ≤ ≤ ≤ ≤ 1 >8 ≤ ≤ ≤ ≤ 0.5 >1

Azithromycin

≤ ≤ ≤ ≤ 0.5 >2 ≤ ≤ ≤ ≤ 0.25 >2 ≤ ≤ ≤ ≤ 1 >8 ≤ ≤ ≤ ≤ 1 >2

Mensura NCCLS SFM BSAC Modified from Perea E. Int J Antimicrob Agents. 2001

SLIDE 4

% of agreement (± ± ± ± 1 dilution) among different susceptibility methods

E/BD E/AD AD/BD

S. pneumoniae

Erythromycin 58% 75% 65% Azithromycin 0% 0% 9%

H. influenzae

Erythromycin 65% 75% 70% Azithromycin 33% 42% 42%

CO2/Ambient E: e-test; AD: agar dilution; BD: broth dilution Bolstrom et al. ICAAC. 1996

SLIDE 5

How should resistance limit the use

f macrolides (evidence-based?)
Streptococcus pneumoniae
Streptococcus pyogenes
Haemophilus influenzae
Campylobacter spp
Others?

SLIDE 6

10 20 30 40 50 60 70 20 40 60 80

Isolates non susceptible to penicillin (%) Isolates non susc. to erythromycin (%)

ESGARS

Antibiotic resistance in Streptococcus pneumoniae

Cornaglia et al.

SLIDE 7

1 2 3 4 5 6 7

France Portugal Luxembourg Greece Ireland Austria Sweden Netherlands

Macrolides - lincos.

∆∆∆ / 1,000 ∆∆∆ / 1,000 ∆∆∆ / 1,000 ∆∆∆ / 1,000 ινηαβιταντσ ινηαβιταντσ ινηαβιταντσ ινηαβιταντσ / δαψ / δαψ / δαψ / δαψ

Outpatient antibiotic sales Outpatient antibiotic sales in 1997 in the in 1997 in the E.U. E.U.

(Cars et al., 2001)

SLIDE 8

Macrolide resistance Macrolide resistance in in S.

S. pneumoniae

pneumoniae Phenotype Phenotype distribution distribution

Country MLSB (ermAM) M (mef E) Spain1 98.4% 1-3% USA2 <25% >75%

1 Baquero F et al. Antimicrob Agents Chemother. 1999 2 Sutcliffe J et al. Antimicrob Agents Chemother 1996.

Whitney et al. NEJM 2000

SLIDE 9

Macrolides and S. pneumoniae Lack of correlation in vitro/in vivo

Different mechanism of resistance
Relation between mechanism of R and

bacterial eradication

Redefinition of susceptibility and

resistance:

– Moving breakpoints to reflect 2 mechanisms – Use of a surrogate such as clindamycin

SLIDE 10

MIC Strains 0.25 0.5 1 2 8 1 15 15 2 52 51 1 4 53 53 8 68 68 16 23 22 1 32 6 5 1 64 85 1 1 83

Characterization of 302 erythromycin-R

S. pneumoniae isolates

Doern et al. Emerging Infect Dis. 1999

Erythromycin Clindamycin MICs

SLIDE 11

Pneumococcal macrolide resistance: myth or reality?

Provide the clinicians MIC data
Compare MICs with in vivo pharmacokinetics

and pharmocodinamics

Provide MICs of different macrolides

(erythromycin and azalides)

Review MIC breakpoints according to site of

infection

New clinical breakpoints for intravenous

formulations.

Amsdem GW. J Antimicrob Chemother. 1999

SLIDE 12

no data available < 5% 5 - 15% 16-25% > 25%

Incidence of macrolide resistance in S.pyogenes

(G.Cornaglia and P.Huovinen, 12th ECCMID, Berlin, 1999) ESGARS

SLIDE 13

Macrolide resistance Macrolide resistance in in S.

S. pyogenes

pyogenes. . Clinical Clinical significance significance?: No ?: No

Macrolide treatment of pharyngitis accounts

for a low proportion of the overall use

Pharyngitis by S. pyogenes is a mild, self

limiting disease

The prevalent phenotypes are endowed with

low resistance level (M) versus high tissue concentration

C16 macrolides and ketolides may still be

effective.

SLIDE 14

Macrolide resistance Macrolide resistance in in S.

S. pyogenes

pyogenes. . Clinical Clinical significance significance?: ?: Yes Yes

Increase in severe infections: necrotising

fasciitis, STSS

Role of low level resistance
Role of C16 macrolides and ketolides.
In vitro susceptibility and outcome of infection
Spread of macrolide resistance to other species

(S. pneumoniae, S. viridans)

SLIDE 15

Otitis media Otitis media caused by caused by H. H. influenzae influenzae

Bacterial failure with azithromycin: 71%

(similar to placebo). Dagan et al. K102. ICAAC 1997

New infections by H. influenzae: 15%. Dagan

et al. Antimicrob Agents Chemother. 2000.

Bacterial eradication: 33% azithromycin vs

87% amox/Clav. Craig et al. Ped Infect Dis J. 1996

SLIDE 16

Macrolide R in Campylobacter spp from human origin

Country

C. jejuni
C. coli

Both Austria 0.7 5.5 <1-1.4 Denmark 14.0 0-4 Finland

<1-3

France 1.1 12.2 3.5 Hungary

Italy

1.2-6 16-68.4 7.8-11.6 Spain 0-11 0-35 3.2-7.3 Sweden 6.4 11.1 7.3 U.K. 1 13 1.8 Mutation at 23S rRNA Almost 100% MLSB phenotype Engberg et al. Emerging Infect Dis. 2001