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Treatment of infections caused by MDR-Gramnegatives: Update (Literature review)
1. Treatment of infections caused
by MDR-Gramnegatives
Literature review
José Ramón Paño
Unidad de Enfermedades Infecciosas y Microbiología Clínica
Medicina Interna
H.U. La Paz (Madrid)
February 19th, 2014
2. 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
4. 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)
12. Carbapenemase-producing Enterobacteriaceae
Principles
• Combo for severe infections
• Dosing has to be optimized
- Search for highest tolerated dose if feasible
• Most frequently active antimicrobials
- b-lactams: carbapenem, aztreonam*, 3rd Cephalosporins**
- Colistin
- Aminoglycosides
* Sólo para MBL sin BLEE asociada
** Sólo para OXA-48 sin BLEE asociada
- Tigecycline
- Fosfomycin
- If active (infrequent): Quinolones and TMP/SMX are good
therapeutic options
13. HULP flow-chart for CPE therapy
Moderate-Severe infections: Recomendaciones
1st Is b-lactam available?
¿MBL+ & aztreonam S (no ESBL)?
No
¿Carbapenem MIC (mero)?
>8
Other 2 agents
- Micro Activity (MIC)
- Source
- Toxicity profile/Comorbidity
Yes
≤8
Aztreonam
+ 2nd agent
Carbapenem
(mero)
+ 2nd agent
2nd agent priority scale
Respiratory: Coli/Tige/Fosfo/Aminogluc
Intraabdominal: Tige/Coli/Fosfo/Aminogluc
Urinary: Aminogluc/Fosfo/Coli/Tige
Catheter: Coli/Fosfo/aminogluc/Tige
15. 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]
16. Carbapenemase-producing Enterobacteriaceae
Carbapenem efficacy in infections caused by CPE: Is it just an
MIC dependent issue? Does the genotype matter?
• 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)
Antimicrob Agents Chemother. 2013;57(8):3936–40
Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]
18. Carbapenemase-producing Enterobacteriaceae
Carbapenem efficacy: MIC-dependent issue or genotype (NDM-KPC)
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)
Antimicrob Agents Chemother. 2013;57(8):3936–40
20. 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
21. Carbapenemase-producing Enterobacteriaceae
Carbapenem efficacy: Is it just an MIC-dependent issue? Does
the genotype matter?
Conclussions/Further questions
• Genotype might matter: For the same MIC, Carbapenem
seems less active against OXA-48 producing
Enterobacteriaceae as compared to NDM/KPC
• Does double-carbapenem therapy work for OXA-48producing Enterobacteriaceae?
Antimicrob Agents Chemother. 2013;57(8):3936–40
Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]
22. “Weird” combinations for XDR-GNR
Antimicrob Agents Chemother. 2014;58(2):851–8.
• 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.
23.
24. Wareham DW JAC 2011;66(5):1047–51.
Without colistin
Subinhibitory colistin
27. 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.
28. Antimicrob Agents Chemother. 2014;58(2):851–8.
Aim
• To evaluate the frequency of colistin + glycopeptide combination
• To determine the impact of this combo on outcome
Design
• Multicenter (3) observational retrospective study
Patients
• Cohort of critically ill patients receiving colistin (Jan´10-Jan´11)
Statistical analysis
• Risk factors for 30 day mortality: Cox regression
• Early deaths after onset of colistin (<5 days) were excluded
29. Results
• 184 (166 GNR) patients received a colistin-based regimen (20% empirically)
Antimicrob Agents Chemother. 2014;58(2):851–8.
33. Conclusions
• 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
Antimicrob Agents Chemother. 2014;58(2):851–8.
34. “Weird” combinations for XDR-GNR
Clin Infect Dis. 2013;57(3):349–58
At last, a randomized clinical trial for the therapy of XDR-MO!!!
35. “Weird” combinations for XDR-GNR
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
Li J. Clin Infect Dis 2007; 45:594–8
36. “Weird” combinations for XDR-GNR
Rationale
A) In vitro sinergy
Li J. Clin Infect Dis 2007; 45:594–8
37. “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
- Two different animal models, involving A. baumannii…
- …showing benefits with colistin-rifampin combination
- Of note: Strains were rifampin-”susceptible” (CMI 4-16)
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
38. “Weird” combinations for XDR-GNR
Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58
Hypothesis
•
Addition of rifampin to colistin 30-d mortality (compared w/colistin [monoRx]
Design
• Multicenter (5) open-label RCT
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
*No loading dose. Low maintenance dose
• Expected 30-d mortality in control group: 60%
• Expected 30-d mortality in intervention group: 40%
• a (two-tail) 0.05; Power 0.8
Sample size: 207
43. 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????
44. 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
47. Optimization of AB dosing
Results
30-day mortality
• Bolus infusion (20%) vs Extended infusion (3%); p= 0.03
48. Optimization of AB dosing
Discussion
Were both populations comparable?
• BSI: 28 (bolus) vs 18 (extended infusion)
• Is “pneumonia” really a pneumonia?
Bauer KA. AAC. 201;57(7):2907–12
49. 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
51. Further insight on how to improve colistin dosing
JAC. 2013;68(10):2311–7
• 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
• HPLC and elemental analysis of vials of 4 brands from 3 continents
• PK analysis (CMS and formed colistin) in rats after iv administration
52. 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
53. PK profile
Colismethate (CMS)
Colistin
• The plasma concentration – time profiles of CMS were
generally consistent among all four products
• The were significant differences in the AUC0-180min among
different products suggesting differences in the conversion of
JAC. 2013;68(10):2311–7
CMS to colistin
54. Carbapenem-sparing regimens
Tamma PD Clin Infect Dis. 2013;57(6):781–8
Rationale
• 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
• Infections caused by AmpC β-lactamase–producing organisms can successfully be treated
with carbapenems
• In vitro studies demonstrate excellent susceptibility of AmpC β-lactamase–producing
organisms to cefepime. In addition it seems to be a poor AmpC inducer
• 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
Hypothesis
•
“Cefepime is a valuable therapeutic option for infections caused by AmpC producing
Enterobacteriaceae”
55. Carbapenem-sparing regimens
Design
•
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
56. Carbapenem-sparing regimens
Results
Frequency of AmpC: Enterobacter (38%); Serratia (15%); Citrobacter spp (1%)
• Patients receiving meropenem had higher risk of MDRO colonization, comorbidity and
immune-supression
• Propensity score matching yielded 32 matched pairs
Tamma PD Clin Infect Dis. 2013;57(6):781–8
60. Carbapenem-sparing regimens
Retamar 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)
