Treatment of infections caused by MDR-Gramnegatives

Literature review

José Ramón Paño Unidad de Enfermedades Infecciosas y Microbiología Clínica

Medicina InternaH.U. La Paz (Madrid)February 19th, 2014

Methods

Surveillance (RSS feeds)• CID, JID, JAC, AAC, The Lancet Infectious

Diseases, JAMA, NEJM

Period: Jan 2013-Feb 2014

Selection• I have followed my own criteria • Of initially selected articles, some will be commented

Outline

• Carbapenemase-producing Enterobacteriaceae

• “Weird” combinations for XDR-GNR

• Optimization of AB dosing

• Carbapenem-sparing regimens

Carbapenemase-producing Enterobacteriaceae

Falagas ME. AAC. 2014;58(2):654–63

• 20 nonrandomized studies comprising 692 patients who received definitive treatment

• 7/20 prospective, 12/20 retrospective and 1 case-control study

• 15/20 CPE (carbapenemase-producing E) and 5/20 CRE (carbapenem-resistant E)

• 14/20 K. pneumoniae as the sole pathogen and 5/20 as the predominant one; E. cloacae sole pathogen in 1/20

• 8/20 BSI was the predominant type of infection (>50%). Pneumonia and UTI prevailed in 12/20

• KPC 8/20 (316); MBL/OXA 5/20 (201)

CP-K.pneumomiae: Combination therapy

Falagas ME. AAC. 2014;58(2):654–63

Antimicrobial Regimen Number of Patients (Number of Studie)

28d/30d mortality

Tigecycline + colistin

51 patients(4 studies)

0-30%

Tigecycline +colistin

11 patients (VIM)(1 study)

67%

Tigecycline + gentamicin

15 patients(2 studies)

0-50%

Carbapenem +colistin

25 patients(4 studies)

0-67%*

Colistin + gentamicin

30 patients(3 studies)

40-61%

* Highest mortality amongst ICU ant solid-organ transplant

CP-K. pneumoniae: Monotherapy

Falagas ME. AAC. 2014;58(2):654–63

AntimicrobialRegimen

Number of Patients (Number of Studie)

28d/30d mortality

Carbapenem 29 patients(3 studies)

9-50%

Tigecycline 38 patient(4 studies)

0-53%

Colistin 102 patients(8 studies)

33-57%

Gentamicin 26 patients [19/26 UTI](3 studies)

6.8-80%

Carbapenemase-producing Enterobacteriaceae

Falagas ME. AAC. 2014;58(2):654–63

Conclusion

• Too much heterogeinity of patients/studies to obtain solid conclusions

Clin Microbiol Rev. 2012;25(4):682–707

• Pubmed search

• 34 clinical studies: clinical, microbiological and therapeutical data

• 301 patients : 160 KPC y 141 MBL

• Type of infection: 244 BSI; 32 Pneumonia

Carbapenemase-producing Enterobacteriaceae

Clinical Studies

Tzouvelekis LS et al. Clin Microbiol Rev. 2012;25(4):682–707

Combo (Carb

)

Combo (≠Carb

)

Aminoglyc

Carb Tige

Colistin

Inappropria

te0

10

20

30

40

50

60

Clinical Failure (%)

N=36

N=63

N=21N=36

N=14

N=72N=56

Carbapenemase-producing Enterobacteriaceae

Tzouvelekis LS et al. Clin Microbiol Rev. 2012;25(4):682–707

• Concordantly with PK/PD, success rate is related to carbapenem MIC

Carbapenemase-producing Enterobacteriaceae

Estudios Clínicos

N=36

N=63

N=21N=36

N=14

N=72

N=56

Link

Principles• Combo for severe infections• Dosing has to be optimized

- Search for highest tolerated dose if feasible

• Most frequently active antimicrobials

- Aminoglycosides- Colistin

- Tigecycline- Fosfomycin

- b-lactams: carbapenem, aztreonam*, 3rd Cephalosporins** * Sólo para MBL sin BLEE asociada

** Sólo para OXA-48 sin BLEE asociada

- If active (infrequent): Quinolones and TMP/SMX are good therapeutic options

Carbapenemase-producing Enterobacteriaceae

HULP flow-chart for CPE therapy

Moderate-Severe infections: Recomendaciones1st Is b-lactam available?

¿MBL+ & aztreonam S (no ESBL)?Yes Aztreonam

+ 2nd agentNo

¿Carbapenem MIC (mero)?≤8 Carbapenem

(mero)+ 2nd agent>8

Other 2 agents

- Source- Micro Activity (MIC)

- Toxicity profile/Comorbidity

Respiratory: Coli/Tige/Fosfo/Aminogluc

Intraabdominal: Tige/Coli/Fosfo/Aminogluc

Urinary: Aminogluc/Fosfo/Coli/Tige

Catheter: Coli/Fosfo/aminogluc/Tige

2nd agent priority scale

Carbapenemase-producing EnterobacteriaceaeDouble carbapenem therapy?

AAC 2013; 57(5):2388-2390

J Antimicrob Chemother. 2014 Feb 11

• Six difficult cases, that cured with double-carbapenem therapy despite very high carbapenem MIC

Carbapenemase-producing Enterobacteriaceae

Carbapenem efficacy in infections caused by CPE: Is it just an MIC dependent issue? Does the genotype matter?

Antimicrob Agents Chemother. 2013;57(8):3936–40

Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]

Carbapenemase-producing Enterobacteriaceae

Antimicrob Agents Chemother. 2013;57(8):3936–40

Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]

• PK/PD animal model-based studies (neutropenic murine thigh infection models)

• Comparison of several humanized b-lactam regimens against carbapenemase-producing, carbapenemase+ESBL and wild type K. pneumoniae strains (KP454)

Carbapenem efficacy in infections caused by CPE: Is it just an MIC dependent issue? Does the genotype matter?

Carbapenemase-producing EnterobacteriaceaeCarbapenem efficacy: MIC-dependent issue or genotype (NDM-KPC)

Antimicrob Agents Chemother. 2013;57(8):3936–40

Change in log10 CFU/ml after 24 h observed in four clinical NDM-1-producing Enterobacteriaceae isolates after treatment with human-simulated doripenem at 2 g every 8 h as a 4-h infusion (black bars) or ertapenem at 1 g every 24 h (white bars)

Carbapenemase-producing EnterobacteriaceaeCarbapenem efficacy: MIC-dependent issue or genotype (NDM-KPC)

Antimicrob Agents Chemother. 2013;57(8):3936–40

Carbapenemase-producing EnterobacteriaceaeCarbapenem efficacy: MIC-dependent issue or genotype (OXA-48)

Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]

Efficacy of human simulated regimens of (A) ceftazidime 2 g IV every 8 h as a 2-h infusion, (B) levofloxacin 500 mg IV every 24 h, (C) doripenem 2 g every 8 h as a 4-h infusion, and (D) ertapenem 1 g every 24 h against a distribution of OXA-48 producing Enterobacteriaceae isolatesa in a neutropenic murine thigh infection model. Error bars represent standard deviations

Carbapenemase-producing Enterobacteriaceae

Carbapenem efficacy: Is it just an MIC-dependent issue? Does the genotype matter?

Antimicrob Agents Chemother. 2013;57(8):3936–40

Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]

• Genotype might matter: For the same MIC, Carbapenem seems less active against OXA-48 producing Enterobacteriaceae as compared to NDM/KPC

Conclussions/Further questions

• Does double-carbapenem therapy work for OXA-48-producing Enterobacteriaceae?

Antimicrob Agents Chemother. 2014;58(2):851–8.

“Weird” combinations for XDR-GNR

• Colistin acts on the A. baumannii outer membrane….

• …enabling glycopeptides access to cell wall targets (from which they are usually excluded)

• Gordon NC. AAC 2010;54(12):5316–22. • Wareham DW JAC 2011;66(5):1047–51.

Wareham DW JAC 2011;66(5):1047–51.

Without colistin Subinhibitory colistin

Wareham DW JAC 2011;66(5):1047–51.

Wareham DW JAC 2011;66(5):1047–51.

Antimicrob Agents Chemother. 2014;58(2):851–8.

Can Glycopeptide have any role for the treatment of GNR (rationale)?• Colistin acts on the A. baumannii outer membrane….

• …enabling glycopeptides access to cell wall targets (from which they are usually excluded)

• Gordon NC. AAC 2010;54(12):5316–22. • Wareham DW JAC 2011;66(5):1047–51.

• ¿Are these findings applicable to other GNR? • Vidaillac C- AAC. 2012;56(9):4856–61.

Antimicrob Agents Chemother. 2014;58(2):851–8.

Design• Multicenter (3) observational retrospective study

Patients• Cohort of critically ill patients receiving colistin (Jan´10-Jan´11)

Statistical analysis

• Early deaths after onset of colistin (<5 days) were excluded

Aim• To evaluate the frequency of colistin + glycopeptide combination• To determine the impact of this combo on outcome

• Risk factors for 30 day mortality: Cox regression

Antimicrob Agents Chemother. 2014;58(2):851–8.

Results• 184 (166 GNR) patients received a colistin-based regimen (20% empirically)

Antimicrob Agents Chemother. 2014;58(2):851–8.

Results (ii)

Text: 68 (41%)??

Results (iii)

Text: 68 (41%)??

Antimicrob Agents Chemother. 2014;58(2):851–8.

Results (iii)

Antimicrob Agents Chemother. 2014;58(2):851–8.

Conclusions

Antimicrob Agents Chemother. 2014;58(2):851–8.

• Colistin-Glycopeptide is a frequently used antimicrobial combination among critically-ill infected patients.

• Colistin-Glycopeptide Combo for ≥5 days was a factor independently associated with better outcomes among all the patients and among those with only MDR A. baumannii infection

• Is this effect logistic regression magic?: Prospective, randomized studies are needed

Clin Infect Dis. 2013;57(3):349–58

“Weird” combinations for XDR-GNR

At last, a randomized clinical trial for the therapy of XDR-MO!!!

Li J. Clin Infect Dis 2007; 45:594–8

Rationale

A) In vitro sinergy

• Giamarellos-Bourboulis EJ. Diagn Microbiol Infect Dis 2001; 40:117–20

• Tripodi M-F. Int J Antimicrob Agents 2007; 30:537–40

• Li J. Clin Infect Dis 2007; 45:594–8

“Weird” combinations for XDR-GNR

Li J. Clin Infect Dis 2007; 45:594–8

Rationale

A) In vitro sinergy

“Weird” combinations for XDR-GNR

Rationale

A) In vitro sinergy

B) Experimental studies in animals• Pantopoulou A. Int J Antimicrob Agents 2007; 29:51–5

• Pachon-Ibanez ME. Antimicrob Agents Chemother 2010; 54: 1165–72

- Of note: Strains were rifampin-”susceptible” (CMI 4-16)

- Two different animal models, involving A. baumannii…

- …showing benefits with colistin-rifampin combination

C) Clinical Studies• Petrosillo N. Clin Microbiol Infect 2005; 11:682–3

• Bassetti M JAC 2008; 61:417–20

- High response rates with colistin+rifampin combo

“Weird” combinations for XDR-GNR

Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58

Design• Multicenter (5) open-label RCT

Hypothesis• Addition of rifampin to colistin 30-d mortality (compared w/colistin [monoRx]

Patients• Critically ill patients with microbiologic evidence of a life-threatening

nosocomial infection due to XDR* AB (*only susceptible to colistin)HAP, VAP, BSI, Complicated intrabdominal infections

Therapeutic arms• Intervention arm: Colistin 2MU TID* + Rifampin 600mg BID (10-21 days) • Control arm: Colistin 2MU TID* (10-21 days)

Sample Size• Expected 30-d mortality in control group: 60%• Expected 30-d mortality in intervention group: 40% Sample size: 207• a (two-tail) 0.05; Power 0.8

“Weird” combinations for XDR-GNR

*No loading dose. Low maintenance dose

Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58

Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58

Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58

Clin Infect Dis. 2013;57(3):359–61

• Colistin-Rifampin did NOT show any clinically significant benefit in the clinical trials

• Would you devote money/time in further clinical trials using this combo????

Optimization of AB dosing

Bauer KA. AAC. 201;57(7):2907–12

Design• Non randomized before (20´ bolus)-after (4 h extended infusion)

intervention [cefepime 2g TID]

Patients• Consecutive patients with cefepime-susceptible (MIC ≤ 8mcg/mL)

Pseudomonas bacteremia or pneumonia between 2008 and 2011

• …receiving ≥at least 48h of cefepime within 72h of + blood cultures

• Exclusion criteria: administration of other b-lactam concomitantly with cefepime

Optimization of AB dosing

Bauer KA. AAC. 201;57(7):2907–12

Results

Optimization of AB dosing

Bauer KA. AAC. 201;57(7):2907–12

Results

Optimization of AB dosingResults

30-day mortality• Bolus infusion (20%) vs Extended infusion (3%); p= 0.03

Optimization of AB dosing

Discussion

Were both populations comparable?

Bauer KA. AAC. 201;57(7):2907–12

• BSI: 28 (bolus) vs 18 (extended infusion)• Is “pneumonia” really a pneumonia?

Further insight on how to improve colistin dosing

Clinical Infectious Diseases. 2014;58(1):139–41.

Letter to the Editor written by the promoters of the “First International Conference on Polymyxins” (Prato, Italy, May 2-4th, 2013)

There is need to be aware of confusing terminology used in articles published in journals

• IU vs mg (colistin base activity)• 1.000.000 IU = 30 mg CBA

Contains comprehensive information on colistin

Nice PK/PD blog

Further insight on how to improve colistin dosing

JAC. 2013;68(10):2311–7

• HPLC and elemental analysis of vials of 4 brands from 3 continents

• PK analysis (CMS and formed colistin) in rats after iv administration

• As CMS is an inactive prodrug, the use of microbiological assays to standardize antibacterial activity in vitro may not reflect the exposure to formed colistin in vivo

JAC. 2013;68(10):2311–7

RP-HPLC profiles at 214 nm for (a) blank control, (b) colistin and 4 marketed products (c-f)

• ¾ brands had very similar chromatographic profiles• Multiplicity of peaks mixture of different derivatives

JAC. 2013;68(10):2311–7

PK profile

Colismethate (CMS) Colistin

• The were significant differences in the AUC0-180min among different products suggesting differences in the conversion of CMS to colistin

• The plasma concentration – time profiles of CMS were generally consistent among all four products

• In vitro studies demonstrate excellent susceptibility of AmpC β-lactamase–producing organisms to cefepime. In addition it seems to be a poor AmpC inducer

Tamma PD Clin Infect Dis. 2013;57(6):781–8

Carbapenem-sparing regimens

Rationale

Hypothesis• “Cefepime is a valuable therapeutic option for infections caused by AmpC producing

Enterobacteriaceae”

• Infections caused by AmpC β-lactamase–producing organisms can successfully be treated with carbapenems

• AmpC β- lactamases can be expressed at levels either by induction or selection for derepressed mutants in the presence of 3rd generation ceph and, thus, should be avoided

• In vitro studies also suggest that an inoculum effect exists and that cefepime may be a less reliable agent for the treat- ment of high inoculum infections

Tamma PD Clin Infect Dis. 2013;57(6):781–8

Carbapenem-sparing regimensDesign• Single-center (Johns Hopkins) retrospective cohort observational study (2010-12)

Patients• Patients with BSI, Pneumonia or intrabdominal infection in which…• Enterobacter* spp, Citrobacter* or Serratia* were isolated…• having received cefepime or carbapenem for at least 72h

*If AmpC was not phenotypically detected by any of the following methods, patient were excluded: a) cefotetan–boronic acid disk tests and b) cefotetan-cloxacillin Etest strips

Outcome variable• Primary: 30-day mortality• Secondary: Length of hospital stay (LOS) since 1st + culture

Propensity score matching• Propensity score methods were used to ensure similarity of the 2 groups (age,

microorganism, LOS til 1st culture, severity, ICU, source control)

Tamma PD Clin Infect Dis. 2013;57(6):781–8

Carbapenem-sparing regimensResults

Frequency of AmpC: Enterobacter (38%); Serratia (15%); Citrobacter spp (1%)

• Propensity score matching yielded 32 matched pairs

• Patients receiving meropenem had higher risk of MDRO colonization, comorbidity and immune-supression

Tamma PD Clin Infect Dis. 2013;57(6):781–8

Carbapenem-sparing regimensResults

Tamma PD Clin Infect Dis. 2013;57(6):781–8

Carbapenem-sparing regimensResults

Tamma PD Clin Infect Dis. 2013;57(6):781–8

Carbapenem-sparing regimens

Discussion

Has this study enough power to proof the non-inferiority of cefepime vs meropenem?

Carbapenem-sparing regimensRetamar P. AAC 2013;57(7):3402–4

Design• Single-center (HVM) prospective cohort observational study

Patients• Patients with ESBL-producing monomicrbial E. coli bacteremia• …who received empirically Pip/Tazo within 24h of blood culture

Outcome variable• Primary: 30-day mortality

Analysis• Considering MIC

High MIC (≥16)Intermediate MIC (4-8)Low MIC (≤2)

Carbapenem-sparing regimens

Retamar P. AAC 2013;57(7):3402–4

Tamma PD Clin Infect Dis. 2013;57(6):781–8

Carbapenem-sparing regimens

Discussion

How do these findings should influence empiric therapy? Should they?