Genova, 23 settembre 2016 La batteriocidia sierica: passato e presente Dott.ssa Maddalena Giannella Clinica di Malattie Infettive AOU Policlinico Sant Orsola Malpighi
Case 1 Case 2 Summary: Cured of cancer Dying of resistant infection
Strategy For Treating MDR Bacteria 1. Use standard antibiotics at doses that result in higher PK exposure, so PK:PD targets are still achieved 2. Use non-standard antibiotics for which resistance has not yet occurred 3. Use combination therapy with antibiotics from option #1 and option #2
Strategy For Treating MDR Bacteria 1. Use standard antibiotics at doses that result in higher PK exposure, so PK:PD targets are still achieved 2. Use non-standard antibiotics for which resistance has not yet occurred 3. Use combination therapy with antibiotics from option #1 and option #2
Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Daikos GL Clin Microbiol Infect 2011;17:1135-41 Carbapenems retain meaningful activity against isolates with MICs of 4 mg/l: Animal studies In vitro studies Clinical experiences PK/PD studies on high-dose/prolonged infusion
Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox? 19 pts with KPC-Kp BSI Meropenem dosage (3-h infusion) 15: 2 g x 3 3: 2 g x 12 1: 3 g x 3 Meropenem MIC 15: 1024 mg/l 3: 512 mg/l 1: 256 mg/l Del Bono V et al. VIRULENCE 2016, 1 8
Strategy For Treating MDR Bacteria 1. Use standard antibiotics at doses that result in higher PK exposure, so PK:PD targets are still achieved 2. Use non-standard antibiotics for which resistance has not yet occurred 3. Use combination therapy with antibiotics from option #1 and option #2
Treating infections caused by carbapenemase-producing Enterobacteriaceae. Tzouvelekis LS et al Clin Microbiol Infect 2014;20:862-72. Twenty clinical studies (including those describing the largest cohorts of CPE-infected patients) were reviewed. The data summarized here indicate that treatment with a single in vitro active agent resulted in mortality rates not significantly different from that observed in patients treated with no active therapy, whereas combination therapy with two or more in vitro active agents was superior to monotherapy, providing a clear survival benefit (mortality rate, 27.4% vs. 38.7%; p <0.001). Inappropriate Mono Combo Combo without Carba Combo with Carba
Strategy For Treating MDR Bacteria 1. Use standard antibiotics at doses that result in higher PK exposure, so PK:PD targets are still achieved 2. Use non-standard antibiotics for which resistance has not yet occurred 3. Use combination therapy with antibiotics from option #1 and option #2 Which combination is correct for the patient? How do we monitor combination therapy?
In vitro synergy studies Proof of concept Small number of studies and limited in scope Perez F et al. Expert Opinion On Pharmacotherapy 2016; 17: 761 781 Ideally they would consider: MIC distribution Population pharmacokinetics in specific settings Pharmacodynamic interactions observed in vivo Lewis RE Virulence 2016
Serum Bactericidal Test It is the only laboratory test that combines: the susceptibility of the pathogen patient pharmacokinetics drug protein binding synergistic or antagonistic interactions of drug combinations
Limitations of the test Results (bactericidal titers) may not be available before 48-96 hours Intra- and inter- laboratory reproducibility is unknown Several aspects of SBT are not well standardized for modern antibiotics Limited data to establish whether the test is clinically useful Published studies often did not apply rigorous statistical approaches to assess the diagnostic or prognostic utility Wolfson & Swartz. N Eng J Med 1985; April 11, 1985
The diagnostic meta-analysis: Database: 1000 patients
Probability The probability of clinical cure or survival during antibiotic therapy is assocaited with SBT results 1 2 4 8 16 32 64 128 256 512 1024 2048 4096 1 2 4 8 16 32 64 128 256 512 1024 2048 4096 Data are analyzed by logistic regression (shaded areas represent 95% CI of predicted probability) clinical cure a. b. survival 1.9.8.7.6.5.4.3.2.1 0 SBT peak OR 1.01 (1.001-1.02), P=0.02 SBT trough OR 1.06 (1.02-1.10), P=0.0004 1.9.8.7.6.5.4.3.2.1 0 SBT peak OR 1.02 (1.01-1.03), P<0.0001 SBT trough OR 1.05 (1.02-1.09), P=0.003 Reciprocal serum bactericidal titer
results: bactericidal titers and clinical cure Plot versus criterion values for reciprocal peak (a) and trough (c) SBTs versus clinical cure and associated arocs (b, d). Each cross hatch equals one patient. Shaded areas in the aroc curves represented the 95% CI interval. Diagonal line in aroc graphs is the line of nondiscrimination (aroc 0.5)
Tigecycline Reduces the Serum Bactericidal Activity of Meropenem-Colistin Combination Regimens Against Extended-Spectrum Beta-Lactamase and KPC- Carbapenemase Producing Klebsiella pneumoniae Gaibani P et al. Submitted data Therapy No. of patients sera Median (mg/l) Mean ± SD concentration (mg/l) IQR (mg/l) Meropenemtigecycline Meropenemcolistin Meropenemcolistintigecycline 5 28 24.43 ± 13.19 21.3-33.7 5 21.7 45.76 ± 48.26 8.4-81.7 5 46.2 46.5 ± 6.83 44.9-46.9
ESBL n=7 Median meropenem MIC 1, IQR 0.06-2 KPC n=14 Median meropenem MIC 32, IQR 16-64 Coli-S Coli-R
meropenemcolistin meropenemtigecycline-colistin meropenemtigecycline Study limitations Lack of correlation with patient outcome Lack of P/T levels of tigecycline and colistin
Our clinical experience 212 pts 14 died within 48 h from index BCs 198 pts 60 died during therapy or within 7 days after the EOT 138 pts CRKP BSI recurrence in 29/138 pts (21%) Median time 37 (IQR 25-46) days after the index BCs Median time 17 (IQR 6-22) days after the EOT
198 pts 18% 19% BSI source 10% 28% 25% 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% LRTI IAI Primary CVC UTI 89% Susceptibility distribution 17% S I R 66% 12% Meropenem Colistin Tigecycline Gentamicin Median number of in vitro active drugs 1 (IQR 0-1) meropenem plus colistin (50, 25.3%) meropenem pus colistin plus tigecycline (45, 22.7%) meropenem plus tigecycline (24, 12.1%) Median days of therapy 13 (IQR 7-19)
198 pts Cox regression analysis 14-day mortality HR 95%CI p Severe sepsis /septic shock 4.42 1.98-9.87 <0.001 Apache II 1.04 1.00-1.09 0.04 Source control 0.50 0.26 0.97 0.04 Number of in vitro active drugs 0.68 0.42-1.10 0.12 Mero-coli 1.25 0.64 2.43 0.51 Mero-coli-tige 0.65 0.26-1.62 0.35 Mero-tige 0.27 0.06-1.15 0.07
Infection source factor?!
Men, 50-year-old Li-K-Tx
Serum inhibitory and bactericidal titers of three different regimens against pandrug-resistant (PDR) KPC-producing K. pneumoniae strain Combination therapy Reciprocal serum inhibitory titer Reciprocal serum bactericidal titer (SIT) (SBT) Trough Peak Trough Peak COL, MER, ERT 2 4 2 2 GEN, MER, ERT ND 4 ND 4 CAZ-AVI, ERT 8 8 8 8
Serum bactericidal titers of combinations including CAZ- AVI for infections due to PDR KPC-producing K. pneumoniae Pt Strain Source Combination therapy SBT Peak Trough 1 Kp PDR BSI (TIPS?) CAZ-AVI, ERT 8 8 2 Kp PDR BSI-TIPS CAZ-AVI, GENTA 32 32 3 Kp PDR VAP CAZ-AVI, GENTA 8 8 4 Kp PDR Primary BSI (HSCT) CAZ-AVI, ERT, GENTA 32 4
CAZ-AVI for CRE Microbiologic failures 37 pts with CRE infection: 70% mono, 30% combo Clinical success 59% (22/37), 30-day survival 72% Microbiologic failures: 27% (10/37) recurrence within 30 and 90 days (n=9) urinary colonization (n=1) CAZ-AVI resistance (MIC >8 µg/ml) in 30% (3/10) of microbiologic failures following a median of 15 days (10 19) of therapy (mono!!!) Shields RK et al. Clin Infect Dis 2016 13 Sept
Could the SBT test be potentially clinically useful in the antibiotic treatment of MDR Gram negative bacteria? Probably yes Prospective studies accounting for: Patient setting Infection source Comprehensive outcome (cure, survival, recurrence)
Acknowledgments Russell Lewis Paolo Gaibani Irene Zaghi Caterina Campoli Lorenzo Marconi Elena Graziano Francesco Cristini Fabio Tumietto Sara Tedeschi Michele Bartoletti Fabio Trapani Luigi Raumer Pierluigi Viale