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

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

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)

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 21 450/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.

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

Bacteriological data What do you think?

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

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

Do you need to take additional measures for this patient?

Infection control program Paterson et al, CMR 2005

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

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..)

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!

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

Only nosocomial? Rodriguez-Bano et al, CID 2006

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)

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

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

Cephalosporins? Paterson et al, JCM 2001

Paterson et al, JCM 2001

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

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

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 2.78 +/- 1.71 and 3.19 +/- 1.66 Pip-Taz 4.36 +/- 0.23 and 2.44 +/- 1.97 Pip 4.44 +/- 0.21 and 3.71 +/- 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 2.78 +/- 1.71 and 3.19 +/- 1.66, in the piperacillin-tazobactam group 4.36 +/- 0.23 and 2.44 +/- 1.97, and in the piperacillin group 4.44 +/- 0.21 and 3.71 +/- 0.99 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

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

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.

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?

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

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

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

Borbone et al, Antimicrob agents 2006

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 2006 - N.P. Brown et al., abstract E-221

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) : 1 252 souches isolées en France entre 2004 et 2006. 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 2006 - Bouchillon et al., abstract E-735

Paterson et al, CMR 2005