1. Clinical Case Study 2: How to deal with an ESBL
Benoit GUERY-Infectious Diseases- CHRU Lille-FRANCE

2. Mrs Louise G…, 69 years old
Admitted in the ER for severe sepsis related to a community acquired pneumonia

3. Mme G… / Previous history
Appendicectomy
Obesity (170 cm-110 kg)
Non insulin dependant Diabetes
Blood Hypertension
Already admitted 2 and 4 month ago in the hospital (diabetes and bronchitis)

4. Mme G… /Recent history Admitted in the ICU
Treated by ceftriaxone 2g IV+ levofloxacin (500mgx2) IV
On the 7th day she developed a fever (38°5C)
Clinical examination
Pallor, sweating
Oliguria
Arterial pressure: 90/60mmHg, Cardiac frequency: 130/min
Blood analysis: WBC /mm3, CRP 68mg/L
X-ray: bilateral pneumonia
The patient often displays weakness, pallor, excessive sweating, and cold skin as a result of excessive loss of fluid, electrolytes, and protein into the abdominal cavity.
Decreased intestinal motility and paralytic ileus result from the effect of bacterial toxins on the intestinal muscles. Intestinal obstruction causes nausea, vomiting, and abdominal rigidity.
Other typical clinical features include hypotension, tachycardia, signs of dehydration (oliguria, thirst, dry swollen tongue, pinched skin), acutely tender abdomen associated with rebound tenderness, temperature of 103° F (39.4° C) or higher, and hypokalemia. Inflammation of the diaphragmatic peritoneum may cause shoulder pain and hiccups.
Abdominal distention and resulting upward displacement of the diaphragm may decrease respiratory capacity. Typically, the patient with peritonitis tends to breathe shallowly and move as little as possible to minimize pain.

5. Mme G… / Endotracheal aspiration: What treatment do you start?
Gram negative bacilli on direct examination
What treatment do you start?

6. Bacteriological data
What do you think?

7. ß-lactam : ESBL Amoxicillin Amoxi-clav Ticarcillin Ticar-clav
Piperacillin
Piper-tazo
Cefalotin
Cefotetan
Cefotaxime
Ceftazidime
Cefepime
Imipenem
Nalidixic acid
Pefloxacin
Ciprofloxacin R I S
ß-lactam : ESBL

8. ß-lactam : ESBL Reading Interpretation Amoxicillin Amoxi-clav
Ticarcillin
Ticar-clav
Piperacillin
Piper-tazo
Cefalotin
Cefotetan
Cefotaxime
Ceftazidime
Cefepime
Imipenem
Nalidixic acid
Pefloxacin
Ciprofloxacin R I S R I S
ß-lactam : ESBL

9. Do you need to take additional measures for this patient?

10. Infection control program
Paterson et al, CMR 2005

11. Detection and confirmation
Disk diffusion method
Screening by dilution antimicrobial susceptibility test
Confirmation
CSP/clavulanate combination disk
Broth microdilution
Commercially available
E test for ESBL
Vitek ESBL cards
Microscan panels
BD Phoenix automated Microbiology system

12. Infection control Hand hygiene: hydro-alcoholic solutions
Contact isolation
Gloves
Gowns
Selective digestive decontamination
Polymixin, neomycin, nalidixic acid
Colistin, tobramycin
Norfloxacin
NEVER CSP!
Cohorting of the patients (rectal swabs)
Case
Contact.. (exemple of the VRE in France..)

13. Infection control
Close attention to practices that may lead to breakdowns in infection control
hygiene team with CONTROLS OF PRACTICE
Guidelines for each isolation procedure, waste elimination, surface decontamination…
Decrease ceftazidime use… not enough (Rice et al, AAC 1990)
Withdraw CSP…(Rahal et al, JAMA 1998)
… and it’s good for CDI!

14. Mme G… /Evolution
Antibiotics: Imipenem 50mg/kg/d IV + ciprofloxacine 400mgx3/d
The patient significantly improved within the next 4 days
Apyrexia in 3 days
Decrease in FiO2

15. Only nosocomial?
Rodriguez-Bano et al, CID 2006

16. Risk factors Case control in taiwan: Worldwide study
Univariate: Tracheostomy, Foley catheter, endotracheal tube, nasogastric tube, central venous catheter
Multivariate: tracheostomy, prior use of ceftazidime (Lin et al, J Hosp Inf 2003)
Worldwide study
Previous use of cefuroxime, ceftriaxone, cefotaxime, ceftazidime, aztreonam (Paterson Ann Intern Med 2004)

17. ESBL treatment
Plasmids bearing the genes encoding ESBL frequently carry genes encoding resistance to
Aminoglycosides
TMP/SMX
Quinolones
Plasmid encoded decrease resistance associated with CSP
Porin loss (found only in ESBL + Klebsiella, Martinez Martinez AAC 2002)
Active efflux associated

18. Use of cephamycin as a first line?
In vivo selection of a cephamycin-resistant, porin-deficient mutant of Klebsiella pneumoniae producing a TEM-3 beta-lactamase. J Infect Dis 1989

19. Cephalosporins?
Paterson et al, JCM 2001

20. Paterson et al, JCM 2001

21. Cefepime 4th generation CSP More stable than CSP against ESBL
Stable against AmpC-type b-lactamase
Ramphal et al, CID 2006

23. Target to reach
PK/PD target for ESBL equivalent to non ESBL: 60%T>MIC (>4µg/mL)
Cefepime 4g in continuous infusion had a 77% probability to reach the target
1g/8h: 65%
2g/12h: 58%
Generally superior to pip-taz
Reese et al, IJAA 2005

24. b-lactam/b-lactamase inhibitors?
Pip vs Pip-Taz vs Imipenem
Paired rat thigh abcess model
ESBL (OXA-14) P. aeruginosa
Results (log 10 colony-forming units per gram)
IMP / and /- 1.66
Pip-Taz / and /- 1.97
Pip / and /- 0.99
BACKGROUND: We compared the antibacterial effect of piperacillin, piperacillin-tazobactam and imipenem in a paired rat thigh abscess model. METHODS: Two abscesses were provoked in the thighs of rats, one on the right with an extended-spectrum beta-lactamase (OXA-14)-producing Pseudomonas aeruginosa (Ps-162) and the other on the left thigh with a control strain. RESULTS: The colony counts from the abscesses in log 10 colony-forming units per gram (mean +/- SD) in the imipenem group were / and /- 1.66, in the piperacillin-tazobactam group / and /- 1.97, and in the piperacillin group / and / for Ps-162 and the control strain, respectively. The mean colony counts were significantly different (p < 0.05) between Ps-162 and the control strain in the piperacillin and piperacillin-tazobactam groups. CONCLUSION: These data showed that piperacillin and piperacillin-tazobactam were significantly less effective against extended-spectrum beta-lactamase-producing P. aeruginosa, while imipenem was equally effective against both Ps-162 and the control strain in this abscess model.
Karadenizli et al, Chemotherapy 2001

25. 43 BSI due to ESBL E coli Results 9 patients died
B-lact-b-lactamase inhib and IMP 9% death
CSP and FQ 35% death
CID 2006

26. 35 bacteremia to Klebsiella TEM-52 ESBL 8/10 complete response to IMP
2/7 partial response to CIP, 5/7 failure
Treatment failure could be ascribed to the inability of the drug to reach therapeutic concentrations at infected sites.
The treatment outcome of 35 cases of bacteremia due to Klebsiella pneumoniae isolates producing TEM-52 extended-spectrum -lactamase was studied. Twenty-eight cases, classified as "nonfatal disease" using the McCabe and Jackson classification, were investigated with regard to ciprofloxacin and imipenem response. Because ciprofloxacin was active in vitro against 21 of 28 isolates, only the treatment outcome of the ciprofloxacin-susceptible subgroup was evaluated. Eight of 10 cases occurred in patients who experienced a complete response to imipenem; 2 of 10 failed to respond. In contrast, only 2 of 7 cases had a partial response to ciprofloxacin, and, in 5 of 7 cases, the treatment failed. Statistical analysis revealed a significant difference in the treatment outcome of the 2 groups (P = .03). Because the isolates had minimum inhibitory concentrations of ciprofloxacin close to the susceptibility breakpoint, treatment failure could be ascribed to the inability of the drug to reach therapeutic concentrations at infected sites.

27. Carbapenem, Drug of choice?
In vitro and in vivo data (Paterson CMR 2005)
IMP vs Meropenem
MIC lower for Meropenem
Clinical experience greatest with IMP
MPM: drug of choice in nosocomial meningitis
Ertapenem: nursing homes, out of hospital?

28. Carbapenem, Drug of choice?
Retrospective study
Nosocomial BSI
ESBL E coli or K pneumoniae
Treatment with IMP associated to a better chance of survival compared to CSP
Du et al, Int Care Med 2002

29. Carbapenem resistant Klebsiella isolates
Very rare
Can be achieved by
the combination of porin loss and plasmid mediated b-lactamase (Martinez-Martinez et al, AAC 1999)
b-lactamase capable of hydrolysis of carbapenem (plasmid mediated) (Koh et al, AAC 2004; Yigit et al, AAC 2001)
Change in affinity of PBP: not yet described
Treatment: Tigecycline or polymixin

30. Ertapenem, intra abdominal infections
Borbone et al, Antimicrob agents 2006

31. Borbone et al, Antimicrob agents 2006

32. Pipéracilline-tazobactam
Doripenem
Organisme
Doripénème
Imipénème
Ceftazidime
Céfépime
Pipéracilline-tazobactam
E. coli
< 0,015-1
0,03
< 0,015-4
0,5
< 0,03-> 32
0,25
< 0,015-> 32
0,12
< 0,25-> 128 8
K. pneumoniae
< 0,015-2
0,06
< 0,015-8 1 16
P. mirabilis
0,12-8 4
< 0,015-32 2
S. marcescens
0,06-1
E. cloacae
< 0,015-0,5
0,25-4
0,6-> 32
> 32
> 128
Citrobacter spp
128
P. aeruginosa
0,03-> 32
0,25-> 32 32
0,12-> 32
0,5-> 128
A. baumannii
Doripénème (DOR) :
nouveau carbapénème à usage parentéral ;
activité sur les bactéries à Gram positif et négatif, aéro-anaérobies ;
en cours de développement clinique pour les infections urinaires compliquées et les pneumopathies acquises à l’hôpital (y compris acquises sous ventilation).
Chez les entérobactéries, l’activité du DOR est supérieure à celle de l’IMP et des autres bêtalactamines comme la ceftazidime (CAZ), le céfépime (FEP) et l’association pipéracilline-tazobactam (TZP).
Chez Pseudomonas aeruginosa, la CMI90 (4 mg/l) est 8 fois inférieure à celle de l’IMP (32 mg/l).
Chez Acinetobacter baumanii, la CMI90 (8 mg/l) est égale à celle de l’IMP. Le DOR est plus actif que CAZ, FEP et TZP.
L’activité du DOR est supérieure ou égale à celle de l’IMP, et strictement supérieure à celle des céphalosporines et des pénicillines.
Abbréviations : CP : Citrobacter spp ; EA : Enterobacter cloacae ; EC : Escherichia coli ; KP : Klebsiella pneumoniae ; PM : Proteus mirabilis ; SM : Serratia marcescens ; PA : Pseudomonas aeruginosa ; AC : Acinetobacter baumanii.
ICAAC N.P. Brown et al., abstract E-221

33. Pourcentage inhibé à la CMI
Tigecycline
Organisme
Tigécycline
Pourcentage inhibé à la CMI
Pourcentage S
CMI50
CMI90
< 0,5 1 2 4 8
Acinetobacter spp (84)
0,12
0,5 94
98,8
100 ND
E. Faecalis / faecium (79)
0,25
Enterobacteriaceae (493)
81,7
91,1
95,9
99,6
ESBL (8)
87,5
P. aeruginosa (120)
> 16
0,8
12,5
52,5
non déterminé
S.aureus (RM) (43)
S. aureus (SM) (90)
S. pneumoniae (69)
0,06
Haemophilis influenzae (78)
93,6
94,9
Programme TEST (Tigecycline Evaluation Surveillance Trial) : souches isolées en France entre 2004 et Cinq laboratoires participants, un laboratoire central. Les CMI sont déterminées par microdilution en milieu liquide et interprétées selon les critères du CLSI.
Entérobactéries (EB) : 493 souches (148 Escherichia coli, 144 Klebsiella spp, 144 Enterobacter spp, 51 Serratia marcescens, 8 souches de Escherichia coli et Klebsiella spp produisant une BLSE).
Pour les EB, la CMI90 de la tigécycline est à 1 mg/l (équivalente à celle de l’IMP).
95,9 % des souches ont des CMI de tigécycline < 2 mg/l.
Concernant les 8 souches sécrétant une BLSE, la tigécycline inhibe 7 souches sur 8 (88 %) à 2 mg/l, et l’IMP 8 souches sur 8 (100 %).
Acinetobacter spp : 84 souches. La CMI90 de la tigécycline est de 0,5 mg/l vis-à-vis d’Acinetobacter spp, inférieure à celle des autres antibiotiques à large spectre.
Bactéries à Gram positif : CMI90 < 0,25 mg/l.
Staphylocoques dorés. La tigécycline inhibe la croissance des SASM (n = 90) et des SARM (n = 43) avec une CMI < 0,25 mg/l. L’activité de la tigécycline sur les SARM est similaire à celle du linézolide (LZD) et de la vancomycine (VA).
Pneumocoques (n = 69), pneumocoques intermédiaires à la pénicilline (n = 24), pneumocoques résistants à la pénicilline (n = 11).
CMI90 tigécycline = 0,25 mg/l (pas de concentrations critiques disponibles).
CMI = 0,5 mg/l pour 3 souches (1 péni-S, 1 péni-I et 1 péni-R).
Haemophilus influenzae (n = 78, dont 20 souches produisant une bêtalactamase), excellente activité inhibitrice : CMI90 < 0,5 mg/l.
ICAAC Bouchillon et al., abstract E-735

34. Paterson et al, CMR 2005