1. health and fitness
2. therapy

Why do we all need antibiotic
Controversies
in
the
treatment
of
stewardship as a matter of
MDR
GNB
urgency?
Adrian Brink
Clinical Microbiologist, Ampath National
Laboratory Services, Milpark Hospital,
Johannesburg
Scope of the presentation
• Introduction
• Treating serious ESBL infections with ertapenem, cefepime or
β-lactam/ β-lactamase inhibitors
• Combination vs monotherapy:
• Combination vs monotherapy for Pseudomonas aeruginosa
bacteremia
• Adding rifampicin to colistin for the treatment of serious XDR
Acinetobacter baumannii infections
• Continuous infusion or extended infusion of β-lactams vs
intermittent infusion
• Conclusions
Introduction
Introduction
Introduction
• Many daily practices regarding antibiotic choice, antibiotic
combinations, dosing regimens and alternative administration
schedules, occur off-label and without sufficient evidence
emanating from prospective, randomized, controlled trials
• This is particular true in the case of empiric or directed therapy
for MDR Gram-negatives and more so in the ICU setting
• For example, no prospective, randomized, controlled trials
have ever been conducted analyzing the preferred therapeutic
management of ESBL-producing Enterobacteriaceae
infections.
TreatingIntroduction
serious ESBL infections
with ertapenem, cefepime or βlactam/ β-lactamase inhibitors?
Treatment of serious ESBL infections
• Few small retrospective trials have demonstrated the relative
superiority of carbapenems over other agents and included
imipenem and meropenem, which have been the preferred
agents for bacteraemic ESBL infections (although their
antipseudomonal activity is unnecessary)
• Summarized by a meta-analysis of 21 studies involving 1584
patients where carbapenems had a lower mortality vs. nonBL/BLI (cephalosporins/quinolones) as definitive or empirical
Rx (RR 0.60 95% CI 0.33-0.77)
Vardakas et al. JAC 2012; 67:2793
Collins et al. Antimicrob Agents Chemother 2012;56:2173-77
Ertapenem: Treatment of serious ESBL
infections
• Collins et al, recently aimed to compare the efficacies of
ertapenem and imipenem/meropenem for the treatment of
bloodstream infections due to ESBL-producing
Enterobacteriaceae (n=261)
• Outcomes were equivalent between patients treated with
ertapenem and those treated with group 2 carbapenems
(mortality rates of 6% and 18%, respectively; P=0.18).
Collins et al. Antimicrob Agents Chemother 2012;56:2173-77
Ertapenem: Treatment of serious ESBL
infections
Collins et al. Antimicrob Agents Chemother 2012;56:2173-77
Ertapenem: Treatment of serious ESBL
infections
• Patients receiving ertapenem were significantly more likely to have
bacteremia from a urinary source (P=0.01) and to have E. coli ESBL infection
(P= 0.001).
• The length of hospital stay prior to ESBL-producing Enterobacteriaceae
isolation was shorter in patients receiving ertapenem (P = 0.002), and
patients receiving ertapenem were less likely to have been in the ICU prior to
culture (P=0.005)
• Severe levels of sepsis, per SIRS criteria, were significantly less common in
the ertapenem-treated group than in the group 2 carbapenem-treated group
(10% versus 33.3%, respectively; OR 0.23; P= 0.002)
• In a multivariate analysis, the type of carbapenem (group 1 versus group 2)
was not associated with increased mortality (adjusted OR 0.26; P= 0.12).
• Adjusted predictors of mortality included the severity of sepsis (P< 0.005)
and the McCabe score at admission.
• After controlling for a propensity score of receiving ertapenem consolidative
therapy, ertapenem was not associated with increased risk for death (OR
0.50 [95% CI 0.12 to 2.1]; P = 0.34).
• In terms of AS efforts, ertapenem should be considered as an option for the
Rx of bactaraemic ESBL-infections
Collins et al. Antimicrob Agents Chemother 2012;56:2173-77
Cefepime: Treatment of serious ESBL
infections
• A retrospective study of monomicrobial bacteremia caused by
ESBL producers at 2 medical centers between May 2002 and
August 2007 was performed (n=178)
• The patients definitively treated with in vitro active cefepime
(cases) were compared with those treated with a carbapenem
(controls) in a propensity score–matched analysis to assess
therapeutic effectiveness. The 30-day crude mortality was the
primary endpoint.
• Multivariate regression revealed that a critical illness with a Pitt
bacteremia score ≥4 points (OR 5.4; 95% CI, 1.4–20.9; P =
.016), a rapidly fatal underlying disease (OR 4.4; 95% CI, 1.5–
12.6; P = .006), and definitive cefepime therapy (OR 9.9; 95%
CI, 2.8–31.9; P < .001) were independently associated with 30day crude mortality.
Lee et al. Clin Infect Dis 2013:56:488-495
Cefepime: Treatment of serious ESBL
infections
Mortality (%)
Based on the current CLSI susceptible breakpoint of cefepime
(MIC ≤8 µg/mL), cefepime definitive therapy is inferior to
carbapenem therapy in treating patients with so-called cefepimesusceptible ESBL-producer bacteremia (except if MIC ≤ 1mg/L).
Cefepime MIC level (μg/mL)
Figure 1. Mortality rates of 3 subgroups of patients who receive cefepime
therapy (n = 33) by the cefepime minimum inhibitory concentration (MIC)
βL/βL-inhibitors: Treatment of serious ESBL
infections
• Recently, a post hoc analysis of patients with bloodstream
infections due to ESBL-producing E coli from 6 published
prospective cohorts, provided insight into the potential role of
βL/βL-inhibitors.
• Amoxicillin-clavulanic acid [AMC] and piperacillin-tazobactam
[PTZ]) or carbapenem were compared in 2 cohorts: the
empirical therapy cohort (ETC, n=103) and the definitive
therapy cohort (DTC, n=174).
• Mortality rates at day 30 for those treated with BLBLI versus
carbapenems were 9.7% versus 19.4% for the ETC and 9.3%
versus 16.7% for the DTC, respectively (P > 0.2, log-rank
test).
Rodriquez-Bano et al.. Clin Infect Dis 2012:54:167-74
βL/βL-inhibitors: Treatment of serious ESBL
infections
• After adjustment for confounders, no association was found
between either empirical therapy with BLBLI (adjusted hazard
ratio [HR], 1.14; 95% confidence interval [CI], .29–4.40; P =
.84) or definitive therapy (adjusted HR, 0.76; 95% CI, .28–
2.07; P= .5) and increased mortality.
• The results suggest that AMC and PTZ are suitable
alternatives to carbapenems for treating patients with BSIs
due to ESBL-EC if active in vitro and would be particularly
useful as directed therapy, in a carbapenem-conserving
program
• This was confirmed by Peralta et al, in a multicentre cohort
study evaluating the impact of empirical treatment in ESBLproducing E. coli and Klebsiella spp. bacteremia.
Rodriquez-Bano et al.. Clin Infect Dis 2012:54:167-74
Peralta et al. BMC Infectious Diseases 2012, 12:245
βL/βL-inhibitors: Treatment of serious ESBL
infections
• Mortality at 30 days in patients empirically treated with pip/tazo
4.5 grams q 6 hours
• 4.5% (1/22) if the MIC was <4 mg/L
• 23% (3/13) if the MIC was >4 mg/L
Rodriquez-Bano et al.. Clin Infect Dis 2012:54:167-74
S≤16; I =32-64; R≥128
Piperacillin –tazobactam resistance amongst
Enterobacteriaceae in South Africa
Blood culture isolates (n=161) of Enterobacteriaceae Charlotte Maxeke Johannesburg
Academic Hospital
Lowman South Afr J Epidemiol Infect 2013;28:16-21
S≤16; I =32-64; R≥128
Brink et al. South African Med J 2008;98:586-592
Introduction
Combination vs monotherapy for
MDR GNB?
Combination
vs monotherapy for
Introduction
Pseudomonas aeruginosa
bacteremia
Combination therapy for Pseudomonas
aeruginosa ?
• Pseudomonas remains one of the ultimate Gram-negative
pathogens due to the rapidity with which patients succumb to
severe pseudomonal infections, as up to 50% of patients with
PA bacteremia die within the first 24–72 hours; therefore,
prompt administration of effective treatment seems essential.
• Empirical combination therapy is recommended for patients
with known or suspected P.aeruginosa infection (Surviving
Sepsis guidelines) as a means to:
– decrease the likelihood of administering inadequate antimicrobial
treatment
– to prevent the emergence of resistance
– to achieve a possible additive or even synergistic effect
Combination therapy for Pseudomonas
aeruginosa ?
• Meta analysis published in 2004 to determine if combination
antibiotics reduced survival in Gram-negative bacteremia
• No benefit shown, BUT:
• Analysis restricted to P aeruginosa bacteremia, OR for
combination therapy 0.5 (0.32-0.79, P=0.007), and a 50%
relative reduction in mortality with use of combination therapy
Safdar N, et al. Lancet Infect Dis 2004;4:519-27
Combination therapy for Pseudomonas
aeruginosa ?
• In meta-analysis, Safdar et al included aminoglycoside
monotherapy as adequate1
• Single aminoglycoside therapy associated with increased
mortality in P aeruginosa bacteremia compared to other
antibiotics
• Benefit of combination therapy was no longer significant if odds
ratio for mortality was recalculated after exclusion of this
therapy2
Safdar et al. Lancet Infect Dis 2004;4:519-27
Paul et al. Lancet Infect Dis 2005; 5:192-3
2013: Combination therapy for Pseudomonas
aeruginosa?
• First large prospective study of P aeruginosa specifically
addressing issue of combination versus monotherapy
• 593 patients in 10 public hospitals with a single episode
of PA bloodstream infection included. 30-day mortality
was 30%
• Treatment with combination antibiotic therapy did not
reduce mortality compared with single antibiotic
- 69.4% survival adequate empiric combination Rx
(95% CI 59.1–81.6)
- 73.5% survival adequate empiric single-drug
therapy (95% CI 68.4-79%)
Pena et al. Clin Infect Dis 2013;57:208-16
2013: Combination therapy for P. aeruginosa?
All cause mortality empirical combo vs mono
Rx
Paul et al. Editorial comment Clin Infect Dis 2013;57:217 -220
2013: Combination therapy for P.aeruginosa?
All cause mortality directed combo vs mono Rx
Paul et al. Editorial comment Clin Infect Dis 2013;57:217 -220
Combination antibiotic therapy for septic
shock?
Does this apply to severe pseudomonal
sepsis and septic shock?
Kumar et al. Crit Care Med 2010;38:1651-64
Combination antibiotic therapy for septic
shock?
• Survival benefit with combination Rx in this setting has been
confirmed by 2 other studies
• “Administering a combination of antimicrobials with different
mechanisms of action is associated with decreased mortality”
• “For patients in septic shock who have a high baseline risk of
mortality, combination empiric antibiotic therapy for several
days with 2 drugs of different mechanisms of action and with
likely activity for the putative pathogen is appropriate.
Monotherapy is recommended for patients who are not
critically ill and at high risk of death”.
Diaz-Martin Crit Care 2012;16:R223
Abad et al. Crit Care Clin 2011:27:e1-27
Caveats: Combination therapy for
Pseudomonas aeruginosa?
• The main caveats are:
– We do not have data on specific antibiotic
combinations on which the rationale of synergism lies
– The CIs of adjusted analyses are broad
– The benefit of the increased spectrum of coverage in
the empirical phase of treatment has not been
assessed.
– RCTs have not addressed this study population i.e P
aeruginosa
Paul et al. Editorial comment Clin Infect Dis 2013;57:217 -220
Adding rifampicin
to colistin for the
Introduction
treatment of serious XDR
Acinetobacter baumannii infections
• This multicenter, parallel, randomized, open-label clinical trial
enrolled 210 patients with life-threatening infections due to
XDR A. baumannii from ICUs of 5 tertiary care hospitals.
• Death within 30 days from randomization occurred in 90 (43%)
subjects, without difference between treatment arms (P = .95).
This was confirmed by multivariable analysis (odds ratio, 0.88
[95% confidence interval, .46–1.69], P = .71).
• A significant increase of microbiologic eradication rate was
observed in the colistin plus rifampicin arm (P = .034).
• No difference was observed for infection-related death and
length of hospitalization.
Durante-Mangone et al. Clin Infect Dis 2013;57:349-58
Introduction
Continuous
infusion or extended
infusion of β-lactams vs
intermittent infusion
Continuous infusion (CI) or extended Infusion
(EI) vs intermittent infusion (II)
• Previously, meta-analysis could not demonstrate benefit of alternative
infusion strategies
• Three recent studies have contributed to our understanding of alternative
β-lactam administrations, and the clinical benefit of such practices
• 1st, Falagas et al, in a systematic review and meta-analysis (nonrandomized observational studies) found mortality to be significantly lower
among patients receiving extended or continuous infusion of carbapenems
or piperacillin-tazobactam compared with those receiving short-term
infusions (relative risk, 0.59; 95% confidence interval,0.41–0.83), and this
difference in mortality was most pronounced in patients with pneumonia
(relative risk, 0.50; 95% confidence interval, 0.26–0.96).
Falagas et al. Clin Infect Dis 2013;56:272-282
Continuous infusion (CI) or extended Infusion
(EI) vs intermittent infusion (II)
Falagas et al. Clin Infect Dis 2013;56:272-282
Continuous infusion (CI) or extended Infusion
(EI) vs intermittent infusion (II)
• 2nd study: Dulhunty et al conducted a small-scale, prospective, doubledummy, randomized controlled trial of CI vs II bolus dosing of piperacillintazobactam, meropenem, and ticarcillin-clavulanate in 5 ICUs across
Australia and Hong Kong.
• Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18
of 22) in the continuous arm, versus 29% (6 of 21) in the intermittent arm
(P = .001).
• Clinical cure was higher in the continuous group (70% vs 43%; P = .037),
but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ
between groups.
• Survival to hospital discharge was 90% in the continuous group versus
80% in the intermittent group (P = .47).
Dulhunty et al. Clin Infect Dis 2013;56:236-44
Reduction of mortality in patients with P. aeruginosa
infections treated with extended-infusion cefepime
• 3rd recent study: Severe P.aeruginosa infections (bacteremia and/or
pneumonia ) treated with cefepime:
– 30-min infusion of 2 g every 8 hr (n=390)
– 4-h infusion of 2 g every 8 hr (n=202)
• Overall mortality significantly lower in the group receiving extended infusion
(20% vs 3%; P=0.03)
• LOS 3.5 days less for patients who received extended infusion (P=0.36). For
patients admitted to the ICU, LOS significantly less in the extended-infusion
group (18.5 days vs 8 days; P=0.04)
• Hospital costs $23,183 less per patient favoring extended infusion (P=0.13)
• Not only clinical, but economic benefits of extended infusions in the
treatment of invasive P. aeruginosa infections.
Bauer et al. Antimicrob Agents Chemother 2013;57:2907-12.
Introduction
Conclusions
Conclusions
• Serious ESBL infections
• Clinical response rate and mortality (incl. very ill patients) is
similar for ertapenem vs mero/imi as empiric treatment
option for for bacteraemic ESBL-infections whilst cefepime,
even if in vitro sensitive, should not be used for directed Rx
of bacteraemic ESBL infections except if MIC ≤ 1mg/L
• However, 2 studies have suggested that de-escalation from
carbapenems to amox-clav and pip-taz, is safe once in vitrosensitivity has been confirmed and might be a valuable
carbapenem-conserving strategy within an ASP
Conclusions
• Antibiotic combination treatment for GNB
• In most instances the evidence for (or against)
combination antibiotic therapy is at best circumstantial
• Targeted therapy should be instituted once cultures are
available in most cases
• Question should rather be: under what circumstances is
combination therapy beneficial?
• Very few RCTs giving clear guidance on the issue
– Emerging evidence for serious CPE infections suggest improved
survival with combination therapy particularly if combined with a
carbapenem
Conclusions
• Antibiotic combination treatment for GNB (cont)
– In contrast, combination therapy for P.aeruginosa appears to
offer no benefit but this has to be confirmed in severe sepsis and
septic shock
– Attempts have been made to improve colistin efficacy for XDR
Acinetobacter infections by unorthodox antimicrobial
combinations, but none of these proved superiority over colistin
monotherapy certainly not in the case of rifampicin
• CI or EI or PI vs conventional bolus infusions
– Positive data from the observational studies (meta-analysis) and
a (small) comparative, double-blinded study suggest that
prolonged or continuous infusion of β-lactams is unlikely to be
advantageous for all hospitalized patient populations, but may be
beneficial for specific groups, such as critically ill patients with
higher MIC pathogens, and appears to offer financial benefit
TreatingIntroduction
serious carbapanemaseproducing
Enterobacteriaceae
2 NB considerations
-Do u Rx
in combination?
(CPE)
with a combination that
-And does combination with a carbapenem make a
should include a carbapenem
difference?
Role of carbapenems in combination for
treatment of CPE
Outcome of 294 infections caused by carbapenemase producing
K pneumoniae according to treatment regimen
Tzouvelekis LS, et al. Clin Micro Reviews 2012;25:682-707
Role of carbapenems in combination for
treatment of CPE
This has been supported by several other studies:
Essentially never use colistin or carbapenems alone
Combination therapy with 2 (or 3 drugs) that includes a carbapenem
(ertapenem or imipenem or meropenem or doripenem) significantly
reduces mortality
Even if carbapenem is resistant (MIC ≥ 1mg/L)
Unfortunately the focus has been on KPC and what do you if carbapenem
MICs > 32 µg/ml?
In essence, new antibiotics are greatly needed, as is additional prospective
research.
Zarkatou et al. Clinical Microbiology and Infection 2011;17:1798-1803
Falagas et al. Future Microbiol 2011;6:653-666
Lee et al. Annals Clin Microb Antimicrob 2012;11:32
Zubair et al. Antimicrob Agents Chemother 2012;56:2108-2113
Tumbarello et al. Clin Infect Dis 2012;55:943-950
Quirasi et al. Antimicrob Agents Chemother 2012: 56:2108-2113
Overtreatment of CPE infections
A study cohort of 42 cases:
The mean age of the cohort was 67.7 ± 13.7 y
Mean APACHE II score was 17.9 ± 8.6
77% of patients were in ICU
K.pneumoniae (84%) was the predominant organism; urine (36%),
tissue/wound/drainage (25%), and blood (20%) were the most common
sites of collection.
All cause mortality was 29%
Though 43% of cases were classified as colonization, 56% of these
cases were treated with antibiotics.
Only 1 patient characterized as colonized subsequently developed
infection, 29 days later
Nearly half of cases represented colonization, yet the majority were treated
with broad-spectrum antibiotics.
Determining infection versus colonization is a critical first step in managing
patients with CPE.
The risk of not treating apparent colonization appears low.
Rihani et al. Scan J Infect Dis 2012 ;44:325-9
CRE score: Bedside score to rule out infection with
CRE among hospitalized patients
Crude and adjusted associations for candidate and final score variables:
N=182 pts (ESBL 166, CRE 16)
Resident in long-term care facility
Renal disease
Neurologic disease
Reduced consciousness at time of illness
Dependent functional status at admission
Diabetes mellitus
ICU admission
Antibiotic exposure in 3 months prior to admission
A score of 32 to define “high CRE risk” had
Sensitivity of 81% (95% CI: 76%-87%)
Specificity of 70% (95% CI: 63%-77%)
Positive predictive value of 21% (95% CI: 15%-27%)
Negative predictive value of 97% (95% CI: 95%-99.8%).
Martin et al. Am J Infect Contr 2013;41:180-182