Antonio Boccazzi
Clinica Pediatrica 2.a - Milano
DRUG RESISTANCE
Pharmacological aspects
• Minimize the time that suboptimal drug levels are
present by thoughful attention to dosing.
• Clinicians need to consider pharmacodynamic and
pharmacokinetic properties when choosing an antibiotic
therapy
• Choosing the right dose and dose interval may be
critical to achieving optimal clinical responses and
preventing the emergence of resistant pathogens.
J.J. Schentag, 1998; D.G. Burgess, 1999
Terapia empirica
Terapia ragionata
Terapia a casaccio
STA AUMENTANDO L’IMPORTANZA
DI MYCOPLASMA PN. ??
L’ESEMPIO DELL’ENCEFALITE
Mycoplasma Pneumoniae: The Most
Common Cause of Pediatric Encephalitis?
Posted 01/02/2008
William T. Basco, Jr, MD, FAAP
Author Information
Pediatric Encephalitis: What Is the Role of
Mycoplasma Pneumoniae?
Christie LJ, Honarmand S, Talkington DF, et al
Pediatrics. 2007;120:305-313
Abbiamo bisogno dei chinoloni
in pediatria ?
RESISTENZA DI S.PNEUMONIAE “PORTATO”
IN NASOFARINGE IN ITALIA
(242 ceppi – 2799 bambini)
PENICILLINA
100
80
60,4
56,3
60
40
MACROLIDE
52,1
44,6
25,9
7,6
20
5,9
9,1
0
<2
2-5
>5
totale
Marchisio et al, Emerg Infect Dis,2002
anni
Vaccino anti-pneumococco e modificazione
dell’etiologia di OMA
1992-98
Pre-vax SP
2000-2003
Post-vax SP
48%
31%
Pen-I
16%
13%
Pen-R
9%
6%
Vax-types
70%
36%
Vax-related types
8%
32%
41%
56%
56%
64%
S.pneumoniae
H.influenzae
B.la pos
Block S. Pediatr Infect Dis J sept. 04 pag.829
Vi sono novità nell’etiologia dell’OMA ?
1995-7
1998-2000
2001-03
(vax anti-SP)
Timpanocentesi
in OMA
persistente o
fallimenti
terapeutici
16.2%
16.1%
12.3%
*
MEF
48%
44%
31%
38%
43%
51%
*
***
SP
H.flu
*
Riduzione del 24% in 2001-03 vs altri periodi
Riduzione p=0.017
Incremento p=0.012
Incremento di SP Pen-S p=0.17
Casey and Pichichero, Pediatr Infect Dis J Sept 04, pag 824
IN ARRIVO
ALLARGAMENTO SIEROTIPI
DI SP
VAX ANTI-H.FLU non
CAPSULATO
Pharmacological aspects for emergence
of resistance
PHARMACOKINETIC
• Insufficient antibiotic concentration at the
site of infection
PHARMACODYNAMIC
• Unsuitable dose
• Too long intervals between administrations
• Short treatment duration
Continuation of the ingestion process
Rohde, Chhatwal, Kaplan, 2004
GABHS INTERNALIZATION
/R
Biofilm
Sociomicrobiologia
Pseudomonas
aeruginosa
Staph aureus
Haemophilus
influenzae
S.Pneumoniae
possono formare
biofilm
che sono inattaccabili
da
• anticorpi
• fagociti
Where are Biofilms to be found
in chronic/recurrent
infections?
 ENT:
Pharyngotonsillitisitis, acute otitis
media, rhino-sinusitis, otitis media with
effusion, cholesteatoma
 ENT
DEVICE-ASSOCIATED
INFECTIONS:
Tympanostomy tubes; endotracheal tubes
Costerton et al., Science, 2002; Chole et al., Arch. Otolaryngol. Head & Neck
Surg., 2003; Post et al., Curr. Opin. Otolaryngol. Head & Neck Surg., 2004
Bacterial biofilms in
adults with chronic
sinusitis
undergoing sinus
surgery
Present in 14 of 18
specimens
Sanderson AR,
Laryngoscope 2006
Hall-Stoodley L et al, JAMA 2006; 296:202
Tempo in cui le concentrazioni rimangono sopra la
MIC in S. pneumoniae penicillino sensibile (pen S) o
penicillino intermedio (pen I) di vari antibiotici
betalattamici orali
Farmaco
Co-Amoxiclav
Cefaclor
Cefuroxime
Cefixime
Ceftibuten
Cefpodoxime
Dose
500 mg x3
500mg x3
500 mg x2
400 x1
400 x1
200x2
R Auckenthaler . JAC- 2000
pen S
MIC90(mg/L)
/
T>MIC (%)
Pen I
MIC90(mg/L
)/
T>MIC (%)
0.125/ 113.8
1/49.3
0.25/73.1
1/48.1
8/19.9
0.125/112.6
1/65
16/11.8
2/43.1
16/0
16/9.9
1/52.6
Tempo in cui le concentrazioni rimangono sopra
la MIC in H. influenzae di vari antibiotici
betalattamici orali
Farmaco
CoAmoxiclav
Cefaclor
Cefuroxime
Cefixime
Ceftibuten
Cefpodoxime
Dose
500 mg x3
500mg x3
250 mg x2
400 x1
400 x1
200x2
R Auckenthaler . JAC- 2000
b-lattamasi +
MIC90(mg/L)/
T>MIC (%)
b-lattamasi MIC90(mg/L)/
T>MIC (%)
1/65
32/2.4
2/43.1
0.25/81.5
0.25/69.9
0.25/92.6
1/65
16/11.8
2/43.1
0.25/81.5
0.25/69.9
0.25/92.6
Tempo in cui le concentrazioni rimangono sopra la MIC in
M.catarrhalis di vari antibiotici betalattamici orali
Farmaco
Co-Amoxiclav
Cefaclor
Cefuroxime
Cefixime
Ceftibuten
Cefpodoxime
Dose
b-lattamasi +
MIC90(mg/L)/
T>MIC (%)
500 mg x3
500mg x3
250 mg x2
400 x1
400 x1
200x2
0.25/97.5
1/49.3
2/43.1
0.5/64.8
4/29.9
0.5/72.6
R Auckenthaler . JAC- 2000
Tempo in cui le concentrazioni rimangono sopra la MIC in
S. pyogenes di vari antibiotici betalattamici orali
Farmaco
Co-Amoxiclav
Cefaclor
Cefuroxime
Cefixime
Ceftibuten
Cefpodoxime
Dose
500 mg x2
500mg x3
250 mg x2
400 x1
400 x1
200x2
MIC90(mg/L)/
T>MIC (%)
OK
MEF concentrations of azithromycin
in total or free cell fraction
C+
C-
BAS
0
0
4h
0.38 + 0.24
0.11 + 0.04
12h
0.9 + 0.3
0.12 + 0.08
24h
1.05 + 0.3
0.23 + 0.12
Scaglione et al 1998
Cefixime
Rapporto MEF/MIC90 (media volte)
C+
C-
4.8
12.8
Bla pos
M.catarrhalis
S.pneumoniae
Pen-S
2.4
2.4
6.4
6.4
2.4
6.4
Pen-I
0.3
0.8
H.influenzae
Bla neg
Cmax MEF 1.2 mg/L + 0.6 SD (C+) e 3.2 mg/L + 1.4 SD (C-) (10)
C+ titolata con componente cellulare MEF
C- titolata senza componente cellulare MEF
Boccazzi et al, 2003
S.pyogenes (1056)
Evolution of macrolide-resistance in Italy
%R 45
*
40
PROTEKT
ITALY
*
35
(2002)
30
*
25
20
15
10
*
5
0
1993
1995
1996
1997
1998
1999
2000
2002
* two studies. Schito et al., JAC, 1997; Varaldo et al., CID, 1999; Crotti, Medori and
D’Annibale, GIMMOC 2001; Rondini, GIMMOC 2001; Schitot et al.,GIMMOC, 2003
S.pneumoniae (848)
Trend of penicillin-resistance in Italy
%R
25
PROTEKT
ITALY
(2002)
20
15
H-L
L-L
10
5
0
1992 1995 1996 1997 1998 1999 2000 2001 2002
Felmingham et al., JAC, 1996; Felmingham et al., JAC, 2000; Marchese et al., MDR
2001; Marchese et al., SIM Congress, 2002; Schito et al., ICAAC, 2003
S. pneumoniae
Trend della eritromicino-resistenza in Italia
%R 45
PROTEKT
ITALIA
(2002)
40
35
30
25
20
15
10
5
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Felmingham et al., JAC, 1996; Felmingham et al., JAC, 2000;
Marchese et al., MDR 2001; Marchese et al., SIM Congress, 2002
Correlazione tra resistenza (%) di 4 antibiotici nei
tre differenti fenotipi di S. pneumoniae (552 ceppi)
in Italia nel 2000
Percentuale di ceppi resistenti a:
Fenotipo (n, %)
E
SXT
TE
LEV
PenS (461, 83,5)
34,9
34,5
25,6
0,2
PenI
50,0
41,2
42,6
0
43,5
87,0
26,1
0
(68, 12,3)
PenR (23, 4,2)
eritromicina (E), cotrimossazolo (SXT), tetraciclina (TE), levofloxacina (LEV)
Dead Bugs Don’t Mutate
C.W. Stratton, 2003
Mutant prevention concentration (MPC)
Definizione
Concentrazione minima di antibiotico in grado
di prevenire la crescita di ceppi batterici resistenti
(inoculo in piastra di 1010 batteri)
Fornisce informazioni sul possibile sviluppo di resistenza
Drlica e Schmitz, 2002
Serum or tissue drug concentration
Mutant Selection Window (MSW)
Above MPC – both susceptible and first-step
resistant cells inhibited – no selective
amplification of resistance subpopulation.
MPC
MSW
MSW
- susceptible cells inhibited.
- first step resistant cells not inhibited.
- selective amplification of resistant
subpopulation
MIC
Sub MIC – neither susceptible nor firststep resistant mutants inhibited – no
selective amplification of resistant
subpopulation.
Time post-administration
Blondeau et al, 2004, J.Chemo
Correlazione tra le concentrazioni sieriche di
moxifloxacina e levofloxacina ed MPC vs S. pneumoniae
Moxifloxacina
Levofloxacina
8
8
7
7
6
6
5
Cmax=4,5ug/ml
4
3
3
2
2
1
0
1
Cmax=5,7ug/ml
5
4
MPC90=2ug/ml
Finestra
di selezione
dei mutanti
MPC90=8ug/ml
Finestra
di selezione
dei mutanti
MIC90=1ug/ml
1
MIC90=0,25ug/ml
6
12
Ore
18
24
0
1
6
12
Ore
18
24
Wise 1999, Blondeau et al. 2001, Hansen et al. 2002, Hansen et al. 2003
Correlazione tra sviluppo di resistenze in P.
aeruginosa e utilizzo di levofloxacina e
ciprofloxacina
Ciprofloxacina uso
Levofloxacina uso
Ciprofloxacina sensibilità
Ospedale di Danbury (Danbury, USA)
120
84
82
100
80
78
80
76
72
Uso (%)
40
70
68
20
66
0
64
01
98
02
98
03
98
04
98
01
99
02
99
03
99
04
99
01
00
02
00
03
00
04
00
01
01
02
01
Sensibilità (%)
74
60
03
01
Iannini, Tillotson 2001
Uso di fluorochinoloni e sviluppo di resistenza
vs S. pneumoniae (USA)
Levofloxacina
35
6
30
5
25
4
20
3
15
2
10
1
0
5
0.9
1988
1.2
1989
1993
*IR: Infezioni Respiratorie
1994
1.6
1995
n=1527
(30)
1996
1997
1.4
1998
n=1601
(34)
1999
3.4
2000
n=1531
(33)
2001
0
2002
n=1934
(45)
Prescrizioni per 1000 pazienti per IR*
Pneumococchi con ridotta suscettibilità ai
FQs (%)
Ciprofloxacina
Comparative MIC distribution for azalide/macrolide
compounds against clinical isolates of S. pneumoniae
(n=178).
Drug Concentration (ug/ml)
Compound
Azithromycin
<0.031 0.063
12
58
0.125
0.25
0.5
1
>2
68
11
1
2
26
(BP <0.5/ug/ml)
(16%)
Clarithormycin
120
31
1
1
1
5
(BP <0.25 ug/ml)
Erythromycin
(14%)
8
89
46
7
0
1
(BP <0.25 ug/ml)
Telithromycin
(n=372)
19
25
(15%)
331
11
15
8
4
3
(<1%)
Blondeau et al, Nurnberg Germany Sept/04:ECCMID, 2005
Comparative RPC distribution for azalide/macrolide
compounds against clinical isolates of S. pneumoniae
(n=178).
Drug Concentration (ug/ml)
Compound
Azithromycin
<0.125
1
0.25
0.5
1
>2-8
9
38
50
80
(BP <0.5/ug/ml)
(73%)
Clarithromycin
79
44
14
11
(BP <0.25 ug/ml)
Erythromycin
(23%)
18
60
41
22
(BP <0.25 ug/ml)
Telithromycin
30
37
(33%)
208
16
14 (7 isolates >0.5ug/ml)
(n=245)
Blondeau et al, Nurnberg Germany Sept/04:ECCMID, 2005
Correlazione tra prescrizione antibiotica
nell’OMA e incidenza della mastoidite acuta
Tasso di
prescrizione
antibiotica
Incidenza per
100.000 p.a.
OLANDA
31%
3.8
NORVEGIA
67%
3.5
DANIMARCA
76%
4.2
USA
96%
2.0
INGHILTERRA
99%
1.2
PAESE
Van Zuijlen, 2001
IL PUZZLE
DELL’ANTIBIOTICOTERAPIA
SITO
ANTIBIOTICO
BATTERI
+
MIC
PAZIENTE
Role of Bacterial Interference and beta-Lactamase-Producing
Bacteria in the Failure of Penicillin to Eradicate Group A
Streptococcal Pharyngotonsillitis
Brook, Itzhak MD, MSc; Gober, Alan E. MD
From the Departments of Pediatrics, Georgetown and George
Washington Universities
Schools of Medicine, Washington, DC.
Archives of Otolaryngology-Head & Neck Surgery 121(12),
December 1995, pp 1405-1409
Archives of Otolaryngology-Head & Neck
Surgery 121(12),
December 1995, pp 1405-1409
Archives of Otolaryngology-Head & Neck
Surgery 121(12),
December 1995, pp 1405-1409
Archives of Otolaryngology-Head & Neck
Surgery 121(12),
December 1995, pp 1405-1409