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Disclosures
The faculty and planners for this program disclose the following:
• Andrew F. Shorr, MD, MPH Speaker for, consultant to or goKen research support from: Actavis, Astellas, AZ, Bayer, Cubist/Merck, Pfizer, Roche, Theravance, Wockhardt, Medco, and Consultant/Advisor for Alios, AKP, Cempra, Entasis, Zavante Therapeu2cs
• Yehuda Carmeli, MD, MPH Consultant to, researcher/inves2gator for, or spoken for: Achaogen, Allecra Therapeu2cs, AstraZeneca, Biomerieux SA, DaVolterra, Durata Therapeu2cs, Valneva SE, Merck, Nabriva Therapeu2cs, Omnix, PPD, Rempex Pharmaceu2cals, Roche, Syntezza Bioscience LTD, Takeda Pharmaceu2cal Company Limited
• Keith Rodvold, PharmD, FCCP, FIDSA Research Grants and Contracts: Allergan, Theravance Biopharma, ARLG / NIAID / NIH; Consultant / Advisory Board: Achaogen, Allergan, Bayer, Janssen Pharmaceu2cals, Melinta Therapeu2cs, Merck, Mo2f Biosciences, Nabriva Therapeu2cs, Spero Therapeu2cs, Tetraphase Pharmaceu2cals, Theravance Biopharma, Wockhardt, Zavante Therapeu2cs; Speaker’s Bureau: Allergan, Medicine Company, Merck
• CED planners and reviewers have nothing to disclose.
This informa,on can be found in the Program Book
Agenda
The Clinical Impacts of Resistant Gram-‐Nega)ve Infec>ons Andrew F. Shorr, MD, MPH
Gram-‐Nega)ve Resistance and Its Impact on Treatment Decisions
The Evolu>on of An>bio>cs to Treat Gram-‐Nega)ve Pathogens
Yehuda Carmeli, MD
Keith Rodvold, PharmD, FCCP, FIDSA
THE CLINICAL IMPACTS OF RESISTANT GRAM-‐NEGATIVE INFECTIONS Andrew F. Shorr, MD, MPH
Washington Hospital Center
Georgetown University
Disclosures
• Actavis • Astellas • AstraZeneca • Bayer • Cubist/Merck
• Pfizer • MedCo
• Roche
• Theravance • Wockhardt
• Alios • AKP • Cempra
• Entasis Therapeu2cs • Zavante Therapeu2cs
I have served as a consultant to, researcher/inves2gator for, or spoken for:
Overview
• Defini2ons • Epidemiology
• Outcomes
• Drivers of Resistance
The Vocabulary
• MDR = Resistant to more than 1 agent in 3 or more an2microbial categories
• XDR = Nonsuscep2ble to more than 1 agent in all but 2 categories
• PDR = Resistant to all categories
Only acquired resistancewas considered, thus intrinsic species-wide resistance to spe-cific antimicrobial agents was not considered in defining classes of resistance. MDR isdefined as nonsusceptible tomore than 1 agent from 3 ormore antimicrobial categories,XDR is definedas nonsusceptible tomore than 1 agent in all but 2 categories, andPDR isdefined as resistant to all categories. The antimicrobial categories and breakpoints fordetermining nonsusceptibility are individually defined for each clinically significant classof GNB (ie, Enterobacteriaceae, PA, and ACCB) (Table 3).Epidemiologic definitions used for nonsusceptibility are not always concordant with
outcome data from treating infections attributable to nonsusceptible organisms. Forsome drug-organism combinations, minimum inhibitory concentration (MIC) valuesare shown to be more predictive of clinical outcome than characterization as suscep-tible, intermediate, or resistant by MIC. For most GNB, the Clinical Laboratory andStandards Institute (CLSI) have recently reduced the MIC breakpoint for susceptibilityto most cephalosporins and carbapenems to 1 mg/mL or less, based on clinicaloutcome data (see Table 3).24 However, patients with GNB bloodstream infectionsnonsusceptible to a carbapenems with a MIC of 2 mg/mL or less were more likely tohave a good outcome than those with a MIC of 4 mg/mL or greater.25 Conversely, for
Table 1Definitions of multidrug resistance and predominant mechanisms of resistance to traditionalgram-negative antibiotics
Common Resistance Phenotypes Major Mechanisms of Resistance
Enterobacteriaceae Third- ! fourth-generationcephalosporins
Carbapenem resistanceFluoroquinolones
Aminoglycosides
ESBL, AmpC b-lactamases
CarbapenemasesDNA gyrase and topoisomerase
mutationsAminoglycoside-modifying
enzymes
Pseudomonasaeruginosa
Carbapenem resistance andother b-lactam resistance
Metallo-b-lactamasesAmpC and other b-lactamasesMultidrug efflux pumpsDeletion of membrane porins
Fluoroquinolones DNA gyrase and topoisomerasemutations
Aminoglycosides Aminoglycoside-modifyingenzymes
Acinetobacter spp Cephalosporin and carbapenemresistance
CephalosporinasesCarbapenemasesMultidrug efflux pumpsPorin mutationsPenicillin-binding protein changes
Aminoglycoside resistance Aminoglycoside-modifyingenzymes
Fluoroquinolone resistance DNA gyrase and topoisomerasemutations
Resistance categorydefinitions
MDR is defined as resistant to more than 1 agent in 3 or moreantimicrobial categories
XDR is defined as nonsusceptible to more than 1 agent in all but2 categories
PDR is defined as resistant to all categoriesIntrinsic resistance to specific antimicrobial agent would automatically
eliminate that agent from being included in defining resistance
Resistant Gram-Negative Infections 897
Fraimow H, et al. Crit Care Clin 2013; 29: 895-‐21.
Defining Resistance
levofloxacin, patients with GNB bacteremia in whom levofloxacin MIC was 1 mg/mL,well below the susceptibility cutoff, had poorer outcomes than those with MICs of0.5 mg/mL or less.26 The conclusion to be drawn from these data is that breakpointsfor susceptibility need to be continually reassessed based on clinical outcomes foremerging resistances. However, there may still be reasons for using agents that testas nonsusceptible for the treatment of resistant organisms.
MANAGEMENT OF INFECTIONS CAUSED BY RESISTANT GNB
The cornerstone of treating of resistant gram-negative infections is administration ofmaximally effective antimicrobial therapy. Whether this can be accomplished dependson several key factors including host status, the type of resistance(s) encountered andavailable treatment options, the site(s) of infection, and whether source control of in-fection is achievable. Many resistant GNB infections are treatable with availablegram-negative agents such as third- and fourth-generation cephalosporins, b-lactam/b-lactamase inhibitor (BL/BI) agents, carbapenems, or fluoroquinolones. However,some MDR infections are only treatable with more toxic agents including polymyxinsand aminoglycosides.27,28 Treatment of XDR and PDR organisms may require combi-nations of partially active or individually inactive agents. Optimizing pharmacody-namics of available agents by use of extended infusion times and novel deliverymethods including aerosolization may also improve outcomes for marginally treatableinfections.29–31 PDR infections for which there are no available effective treatments areincreasingly reported.1,2 This discussion focuses on treatment of documented resis-tant GNB infections, but similar principles apply to empiric therapy for severe infectionsin individuals at high risk for resistant GNB, including colonized patients or patients inan outbreak setting.
ANTIMICROBIAL AGENTS FOR INFECTIONS CAUSED BY MDR GNB
There are often many options for treating resistant GNB with single-class antimicrobialresistance. Rarely, however, do resistant GNB demonstrate single-class resistance.Multidrug resistance is selected by sequential exposures to different antibiotics, by hor-izontal transfer of multiple resistance traits clustered on mobile genetic elements, orby selection for characteristics such as permeability changes or upregulation of effluxpumps that alter susceptibility to multiple drug classes.8 Knowledge of local suscepti-bility patterns from current antibiograms, especially unit-specific antibiograms, mayhelp guide initial therapy. Combination antibiograms demonstrating patterns ofcross-resistance may be even more useful for this.32 Standard broad-spectrumgram-negative agents including third- and fourth-generation cephalosporins,
Table 3Breakpoints for susceptibility as approved by EUCAST, SCLIS, and FDA (in mg/mL)
EUCASTCefepime/Imipenem/Tobramycin
CLSICefepime/Imipenem/Tobramycin
FDACefepime/Imipenem/Tobramycin
Enterobacteriaceae !1 !2 !2 !2 !1 !4 !8 !4 !4
Pseudomonas aeruginosa !8 !4 !4 !8 !2 !4 !8 !4 !4
Acinetobacter spp — !2 !4 !8 !4 !4 !8 !4 !4
Abbreviations: CLSI, Clinical and Laboratory Standards Institute; EUCAST, The European Committeeon Antimicrobial Susceptibility Testing; FDA, US Food and Drug Administration.
Fraimow & Nahra900
Fraimow H, et al. Crit Care Clin 2013; 29: 895-‐21.
EPIC II
• Point prevalence study • Interna2onal ICUs (n=1265)
– Popula2on: 13796 pa2ents; 51% infected • Cohort
– Mean SOFA: 6.3 – 28% medical, 72% surgery/trauma – 56% on MV
Vincent JA, et al. JAMA 2009; 302: 2323-‐9.
Globally, Majority of ICU infec>ons Are Due to Gram-‐nega>ve Bacteria
Vincent et al. JAMA. 2009;302:2323-‐9.
Pseudomonas spp.
Escherichia coli
Klebsiella spp.
Other Enterobacterspp.
Acinetobacterspp.
70% of infected pa>ents have posi>ve cultures; 62% are Gram-‐nega>ve 31% of Gram-‐nega>ve cultures are Pseudomonas spp. 31
26
20
14 11
27
0
5
10
15
20
25
30
35
Gram-‐nega>
ve isolates (%
)
Data from the Extended Prevalence of Infec2on in Intensive Care (EPIC II) Study, a global, 1-‐day point prevalence study of 13,796 pa2ents from 1265 ICUs in 75 countries in 2007.
CDC Iden>fied Threats: 2013
0
5000
10000
15000
20000
25000
30000
CRE ESBL AB MDR PA
Cases
Fatali2es
Num
ber o
f Pa>
ents
Case Fatality Rate Approximately 7% and does NOT vary by pathogen
URGENT THREAT
Assembled from: hKp://www.cdc.gov/drugresistance/about.html
Klebsiella pneumoniae Percentage of Invasive Isolates with Combined Resistance to Third-‐Genera>on cephalosporins, Fluoroquinolones and Aminoglycosides
EU/EEA, 2010 EU/EEA, 2014
Percentage (%) Resistance
European Centre for Disease Preven2on and Control. An2microbial resistance surveillance in Europe 2014.
Acinetobacter species: Percentage of Invasive Isolates with Combined Resistance to Fluoroquinolones, Aminoglycosides and Carbapenems
EU/EEA, 2014
EBSL: Classifica>on
• Rou2nely encountered in Enterobacteriaceae (eg E. coli & K. Pneumoniae) but not limited to these species
• Classified as: – Bush-‐Jacoby-‐Medeiros: 2be – Ambler: Class A
• Major enzyme types: – SHV – TEM – CTX
• AmpC: Unique beta-‐lactamase not inhibited by clavulanate
Harris PNA, et al. Lancet ID 2015; 15: 475-‐85
Predicted Trends in EBSL UTI Hospitaliza>ons 9 4 4 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY SEPTEMBER 2 0 1 3 , VOL. 3 4 , NO. 9
B.
5 -
4 -
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f= 2 i 03 a. 0
Year
^\#^\#^VV #*# Year
i s .§4 a
§2 3 1 • J CO 52 0 u Ul ^vvvv#vv #v
Year
###^\o^VV V Base
Lower bound
Upper bound
p _c*> -<<S c9> .cS>
Year
FIGURE i. Annual urinary tract infection (UTI) hospitalization rates with the resistant pathogen of interest per 1,000 hospitalizations, 2000-2009. A, multidrug-resistant Pseudomonas aeruginosa (MDR PA). B, extended-spectrum j3-lactamase-producing Escherichia coli (EC ESBL). C, extended-spectrum /3-lactamase-producing Klebsiella pneumoniae (KP ESBL). D, carbapenem-resistant Enterobacteriaceae (CRE).
Our findings also echo a more recent report from the CDC by Hidron,9 which quantified the prevalence of various re-sistant organisms in 4 HAIs, including CAUTI, among hos-pitalized patients during 2006-2007. In this study, the rates of resistance to third-generation cephalosporins among uri-nary E. coli and K. pneumoniae were similar to those in the earlier study, or 5.5% (6.1% in 2006 and 6.9% in 2007 in our data) and 21.2% (15.5% in 2006 and 14.9% in 2007 in our data), respectively. Specific to urinary sources, pseudo-monal resistance to ceftazidime was 12.6%, whereas that to carbapenems was 25.1%.9 In our study, the corresponding years of data yielded a slightly higher rate of ceftazidime resistance and a lower rate of carbapenem resistance (17.9% and 16.1%, respectively). These differences are likely due to the differences in hospital and patient mix contributing to the 2 sample frames. Because our data come from a nationally representative sample of hospitals, they add new and nec-essary perspective on the burden of resistant gram-negative
UTI as a proportion of all hospitalizations in the United States.
Understanding the patterns of gram-negative resistance is important for several reasons. Treating a serious infection with an empirical antimicrobial regimen that fails to cover the culprit pathogen(s) has been consistently associated with poorer outcomes, including an increased risk of hospital death.17"25 A precise knowledge of pathogen distribution therefore becomes integral to clinical decision making. On the other hand, overly broad coverage when it is not war-ranted is unhelpful to the patient individually and fosters spiraling antibiotic resistance.26 On a population level, this leaves the public with fewer treatment options for serious infections.27 Current data on the prevalence and patterns of resistance can help clinicians to tailor their decision making to the probability of the individual patients in front of them of harboring a resistant pathogen. Although our data fail to provide granularity necessary for such individualized decision
AB Resistance Based on Infec>on Site
0
10
20
30
40
50
60
70
80
90
CLABSI CAUTI VAP SSI
MDR3
CRAB
% of Isolates
Sievert DM, et al. ICHE 2013; 34: 1-‐14.
Epidemic Can Become Endemic
• Retrospec2ve analysis • Single center experience • Longitudinal evalua2on of AB isola2on
• n=4484 first isolates
Clinical Investigations
Critical Care Medicine www.ccmjournal.org 2735
A. baumannii BM4547 as recipient. Selection was performed on agar plates supplemented with ticarcillin (100 µg/mL) and rifampin (100 µg/mL) for mating-out assays and ticarcillin (100 µg/mL) for electroporation assays.
To determine the diversity of plasmids harbored by a series of representative strains of each cluster, plasmid DNA was extracted by using the Kieser method and analyzed by agarose gel electrophoresis as described previously (30, 31). Plasmid sizes were analyzed by eye with a ladder.
Statistical MethodsLogistic regression was used to test the association between units or sources and the probability of finding a carbapenem susceptible A. baumannii isolate aggregated over years. Results are reported as frequencies and percents with odds ratios, 95% CIs, and p values. To test for significant differences in the pre-dicted regression line of the number of cases A. baumannii over the years, we used a cubic polynomial regression for a Pois-son distributed variable. Separate intercepts and slopes were fit to test for differences between the number of susceptible and nonsusceptible isolates. A generalized linear mixed model approach was used so that we could include a random resid-ual term to control for overdispersion. Comparisons between group intercepts and slopes were made. The two-tailed 0.05 α level was used to determine statistical significance. SAS 9.3 (SAS Institute, Cary, NC) was used for all analyses.
RESULTS
Descriptive EpidemiologyDuring 18 years, 9,334 A. baumannii isolates were detected, being 4,484 of them (48%) considered first isolates. Of the 4,484 first isolates, 3,141 isolates (70%) were identified in the ICUs and 1,343 isolates (30%) were found in wards (p < 0.0001) (Table 1). Similarly, 3,943 isolates (87.9%) were identified in adult units, and only 541 isolates (12%) were identified in pediatric wards (p < 0.0001). Regarding antibi-otic susceptibilities, 3,638 isolates (81.1%) were carbapenem susceptible and 846 isolates (18.9%) were carbapenem nonsus-ceptible (p < 0.0001). Most of the nonsusceptible first isolates were located in the ICUs (712 of 846; 84.1%), especially in the trauma (205 of 846; 24.2%), medical (150 of 846; 17.7%), and surgical (143 of 846; 16.9%) ICUs. Throughout the 18 years of observations, these three units combined experienced 58.8% of all carbapenem nonsusceptible first isolates.
Regarding bodily sources of first isolates, respiratory samples were the most frequent source of collection (49%), followed by wound/drainage (14%), and blood (11%). Similarly, when all isolates from all patients were aggregated (n = 9,334), respi-ratory samples still corresponded to the main bodily source (51%), followed by wound/drainage and blood (11% each).
A total of 676 blood A. baumannii isolates (only one per unique patient) were identified through the years. Similarly to the first analysis, first blood isolates were most frequently detected among ICU patients rather than general ward patients (596 of 676; 88.2%; p > 0.05) and in adult unit rather than in pediatric
unit (651 of 676; 96.3%; p > 0.05). With regard to susceptibilities, 191 (28.3%) were carbapenem nonsusceptible isolates and 485 (71.7%) were carbapenem susceptible isolates. Of the 191 car-bapenem nonsusceptible blood isolates, 66 (34.5%) were located in the trauma ICU, 41 (21.4%) in the medical ICU, and 35 (18.3%) in the surgical ICU; combined, these three units had 142 of the 191 carbapenem nonsusceptible blood isolates (74.3%).
Regarding first isolates compared based on carbape-nem susceptibilities, the intercepts were significantly dif-ferent (nonsusceptible [β ± SE, p]: 5.033 ± 0.125, p < 0.001; susceptible: 3.388 ± 0.313, p < 0001; difference: p < 0.001). The linear components for carbapenem nonsusceptible and susceptible isolates were significantly different (nonsuscep-tible: –0.305 ± 0.039, p < 0.001; susceptible: 0.300 ± 0.090, p = 0.002; difference: p < 0.001). The cubic component was positive and significant for nonsusceptible isolates but nega-tive and nonsignificant for susceptible isolates (nonsuscep-tible: 0.004 ± 0.001, p < 0.001; susceptible: –0.001 ± 0.002, p = 0.259; difference: p = 0.013) (Fig. 1A). Interestingly, there was a shift in the proportions of carbapenem susceptible and non-susceptible isolates around 2004..
Regarding first blood isolates, the intercepts were sig-nificantly different (nonsusceptible [β ± SE, p]: 3.132 ± 0.142, p < 0.001; susceptible: 2.362 ± 0.221, p < 0001; difference: p = 0.007). The linear components for nonsusceptible and
Figure 1. Yearly trends of Acinetobacter baumannii in both first isolate per single patient (A) and first blood isolate per single patient (B). Susceptible A. baumannii isolates: observed counts (solid line), predicted counts (rhomboids); nonsusceptible A. baumannii isolates: observed counts (dashed line), predicted counts (triangles).
Munoz-‐Price LS, et al. CCM. 2013: 41; 2733-‐42
Outcomes: Predictors in GNR Sep>c Shock
• Retrospec2ve analysis • Subjects: GNR bacteremia resul2ng in sep2c shock
• N=1064 – E. coli: 27% – K. pneumoniae: 20% – P. auerginosa: 17%
• Endpoint: Mortality
inappropriate empiric treatment (Table 6). Becausethe risk for drug resistance is very high among theseorganisms, the observed elevated rates of non-IAATare probably not because the clinician did not considertheir risk for resistance, but rather due to his/her deter-mination that these were not likely pathogens. This ap-proach therefore represents a slightly different mechanism
for causing non-IAAT and implies a different solution.Rather than understanding the antibiogram of commonpathogens, this requires a clinician to be aware of the ratesof specific less common organisms at his/her institution.An additional important mechanism for receiving non-IAAT exists based on the timing of empiric therapy.Fully one-quarter of all non-IAAT fell into this categorywhen there was no evidence of empiric treatment within
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Severe sepsis Pressors Mechanicalventilation
MDR Non-IAAT
Died Survived
Figure 1 Sepsis severity, resistance and initial treatment. IAAT, initially appropriate antibiotic therapy; MDR, multidrug resistant. P <0.001 foreach comparison.
Table 3 Predictors of hospital mortalitya
Odds ratio 95% confidenceinterval
P value
Non-IAAT 3.872 2.770 to 5.413 <0.001
Chronic liver disease 1.942 1.319 to 2.860 0.001
Septic shock 1.846 1.335 to 2.553 <0.001
Pneumonia 1.766 1.237 to 2.522 0.002
Mechanical ventilation 1.669 1.172 to 2.376 0.005
APACHE II score (per 1 point) 1.076 1.047 to 1.105 <0.001
Surgery 0.701 0.560 to 0.879 0.002
Admitted from home 0.677 0.489 to 0.936 0.018
Urosepsis 0.675 0.469 to 0.972 0.034aIndependent variables included but not retained in the model at alpha ≤0.05:age, race, admission sources other than home (nursing home or transfer fromanother facility), comorbidities of congestive heart failure, chronic obstructivepulmonary disease, chronic kidney disease and human immune deficiencyvirus infection, Charlson comorbidity score, healthcare-associated infection riskfactors (hemodialysis, immune suppression, prior hospitalization, prior antibiotics),mechanical ventilation, and infection source other than urine (lung, abdomen,line, central nervous system, skin). Variables pressors and severe sepsis wereexcluded because of collinearity with septic shock. APACHE, Acute Physiologyand Chronic Health Evaluation; IAAT, initially appropriate antibiotic therapy. Areaunder the receiver operating characteristics curve = 0.777; Hosmer–LemeshowP = 0.823.
Table 4 Predictors of receiving initially inappropriateantibiotic therapya
Odds ratio 95% confidenceinterval
P value
Multidrug resistant 13.05 7.00-24.31 <0.001
HIV 3.64 1.02-12.95 0.046
Transferred from anotherhospital
2.86 2.00-4.08 <0.001
Nursing home resident 2.28 1.35-3.84 0.002
Prior antibiotics 2.06 1.47-2.87 <0.001
Polymicrobial 1.90 1.30-2.77 0.001
Congestive heart failure 1.61 1.11-2.35 0.013
APACHE II score (per 1 point) 1.05 1.02-1.07 <0.001aIndependent variables included but not retained in the model at alpha ≤0.05:age, admission source other than transfer from another hospital (home ornursing home), comorbidities of chronic obstructive pulmonary disease, chronickidney disease, diabetes and malignancy, healthcare-associated infection riskfactors hemodialysis, immune suppression and prior hospitalization, priorbacteremia, hospital length of stay prior to the onset of bacteremia, surgery,central line, total parenteral nutrition, septic shock, and infection source. APACHE,Acute Physiology and Chronic Health Evaluation. Area under the receiveroperating characteristics curve = 0.738, Hosmer–Lemeshow P = 0.664.
Zilberberg et al. Critical Care 2014, 18:596 Page 7 of 13http://ccforum.com/content/18/6/596
Zilberberg MD, et al. Crit Care Med 2014. 18: 596.
Predictors of Hospital Mortality
Inappropriate Therapy: A Modifiable Risk Factor
inappropriate empiric treatment (Table 6). Becausethe risk for drug resistance is very high among theseorganisms, the observed elevated rates of non-IAATare probably not because the clinician did not considertheir risk for resistance, but rather due to his/her deter-mination that these were not likely pathogens. This ap-proach therefore represents a slightly different mechanism
for causing non-IAAT and implies a different solution.Rather than understanding the antibiogram of commonpathogens, this requires a clinician to be aware of the ratesof specific less common organisms at his/her institution.An additional important mechanism for receiving non-IAAT exists based on the timing of empiric therapy.Fully one-quarter of all non-IAAT fell into this categorywhen there was no evidence of empiric treatment within
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Severe sepsis Pressors Mechanicalventilation
MDR Non-IAAT
Died Survived
Figure 1 Sepsis severity, resistance and initial treatment. IAAT, initially appropriate antibiotic therapy; MDR, multidrug resistant. P <0.001 foreach comparison.
Table 3 Predictors of hospital mortalitya
Odds ratio 95% confidenceinterval
P value
Non-IAAT 3.872 2.770 to 5.413 <0.001
Chronic liver disease 1.942 1.319 to 2.860 0.001
Septic shock 1.846 1.335 to 2.553 <0.001
Pneumonia 1.766 1.237 to 2.522 0.002
Mechanical ventilation 1.669 1.172 to 2.376 0.005
APACHE II score (per 1 point) 1.076 1.047 to 1.105 <0.001
Surgery 0.701 0.560 to 0.879 0.002
Admitted from home 0.677 0.489 to 0.936 0.018
Urosepsis 0.675 0.469 to 0.972 0.034aIndependent variables included but not retained in the model at alpha ≤0.05:age, race, admission sources other than home (nursing home or transfer fromanother facility), comorbidities of congestive heart failure, chronic obstructivepulmonary disease, chronic kidney disease and human immune deficiencyvirus infection, Charlson comorbidity score, healthcare-associated infection riskfactors (hemodialysis, immune suppression, prior hospitalization, prior antibiotics),mechanical ventilation, and infection source other than urine (lung, abdomen,line, central nervous system, skin). Variables pressors and severe sepsis wereexcluded because of collinearity with septic shock. APACHE, Acute Physiologyand Chronic Health Evaluation; IAAT, initially appropriate antibiotic therapy. Areaunder the receiver operating characteristics curve = 0.777; Hosmer–LemeshowP = 0.823.
Table 4 Predictors of receiving initially inappropriateantibiotic therapya
Odds ratio 95% confidenceinterval
P value
Multidrug resistant 13.05 7.00-24.31 <0.001
HIV 3.64 1.02-12.95 0.046
Transferred from anotherhospital
2.86 2.00-4.08 <0.001
Nursing home resident 2.28 1.35-3.84 0.002
Prior antibiotics 2.06 1.47-2.87 <0.001
Polymicrobial 1.90 1.30-2.77 0.001
Congestive heart failure 1.61 1.11-2.35 0.013
APACHE II score (per 1 point) 1.05 1.02-1.07 <0.001aIndependent variables included but not retained in the model at alpha ≤0.05:age, admission source other than transfer from another hospital (home ornursing home), comorbidities of chronic obstructive pulmonary disease, chronickidney disease, diabetes and malignancy, healthcare-associated infection riskfactors hemodialysis, immune suppression and prior hospitalization, priorbacteremia, hospital length of stay prior to the onset of bacteremia, surgery,central line, total parenteral nutrition, septic shock, and infection source. APACHE,Acute Physiology and Chronic Health Evaluation. Area under the receiveroperating characteristics curve = 0.738, Hosmer–Lemeshow P = 0.664.
Zilberberg et al. Critical Care 2014, 18:596 Page 7 of 13http://ccforum.com/content/18/6/596
Predictors of Receiving Ini>ally Inappropriate An>bio>c Therapy
Appropriate Ini>al Therapy
• Every hour’s delay un2l appropriate therapy resulted in a 12% increase in mortality
• Compared with star2ng appropriate therapy within 1 hour of the onset of hypotension, the OR for mortality increased from 1.67 in Hour 2 to 92.54 with delays >36 hours
An earlier study of sep>c shock (n = 2,731) explicitly demonstrated the importance of an>microbial >ming
Kumar A, et al. Crit Care Med. 2006;34:1589-‐1596.
Odd
s Ra2
o of Death
(95%
Con
fiden
ce Interval)
100
10
1
Time From Hypotension Onset (hr)
Impact of Resistance on Outcomes How Many Time Do We Have to Get it Right to Save One Life?
• Retrospec2ve analysis of impact of appropriate therapy on mortality
• 1250 subjects with sep2c shock
• Inappropriate an2bio2cs: 3.4 x independent increase in risk for death
• NNT calculated per pathogen
For every 5 pa>ents given appropriate therapy
one added survivor! Vazquez-‐Guillamet C, et al. CCM 2014; 42: 2342-‐9.
SO HOW DID WE GET HERE?
Resistance Driving Resistance: The ESBL / Carbapenem Resistance Loop
Increased MDR enterics (ESBLs)
X transmiss. +
spread of R-‐ genes
Select carbapenem-‐R strains
Increased carbapenem use
Increased carbapenem-‐R strains
Pseudomonas aeruginosa
Enterobacteriaceae
Acinetobacter
Carbapenem-‐resistant K. pneumoniae (CRKP)
Mul>variate analysis of risk factors for the emergence of CRKP Variables Odds ra>o 95% C.I. P
Prior fluoroquinolone use 1.87 1.07-‐3.26 0.026
Prior carbapenem use 1.83 1.02-‐3.27 0.042
ICU admission 4.27 2.49-‐7.31 >0.001
Exposure to at least 1 ABX drug prior to isola2on of K. pneumoniae 1.02 1.00-‐1.03 0.012
Hussein K, et al. Infect Control Hosp Epidemiol. 2009;30:666-‐671.
Correla>on Between Carbapenem Consump>on and P. aeruginosa Resistance
Lepper PM, et al. An2microb Agents Chemother. 2002;46:2920-‐2925.
Car
bape
nem
resi
stan
ce (%
)
Carbap
enem
con
sump>
on (D
DDs)
ARE WE EVEN DOSING ANTIBIOTICS IN THE ICU CORRECTLY?
Udy AA, et al. ICM. 2013; 39: 2070-‐82.
Changes in the Cri>cally Ill Pa>ent Affec>ng An>bio>cs
Systemic Inflamma2on
Altered Major Organ Blood Flow
• Large volume IV fluid resuscita2on • Obesity • Vasopressor medica2ons • Extracorporeal circuits • Low plasma protein concentra2ons • Drug-‐drug interac2ons
Deranged CL (AKI or ARC) Increased Vd (hydrophilic agents)
Reduced An2bio2c Exposure
Higher MIC
Treatment Failure and/or the Selec2on of Resistant Organisms
+
+
+ Endothelial Dysfunc2on and Capillary Leak
Udy et al Clin Pharmacokinet 2010; 49:1-‐16
Explana>on of Augmented Renal Clearance
• ARC arises from interac2on of: – Systemic inflamma2on
– Physiologic reserve • ARC noted in:
– Young pa2ents – Trauma pa2ents
Inflamma2on
Burns Infec2on
Pancrea22s Surgery
RBF IV fluids
Vasoac2ve medica2ons
GRF
SIRI
CO Vasodila2on
Renal reserve
ARC
β-‐lactam Underdosing in Pa>ents with Augmented Renal Clearance (ARC)?
• ARC = supranormal glomerular filtra2on
• ClCr > 130 ml/min/1.73m2
• Cockcrop Gault CrCl • Most common in cri2cally ill pa2ents with: – SIRS/Sepsis – Trauma
Trou
gh c
once
ntra
tion:
MIC
1
10
100
50 100 150 200 250 300 350
ClCr (ml/min/1.73m2)
Udy AA et al. Chest 2012;142:30-‐39. Bap2sta JP et al. Crit Care 2011;15:R139.
Basilea (On File)
Cepobiprole 500 mg q 8
vs. Linezolid 600 mg q 12 hours &
Cepazidime 2 g q 8
Infec>on type Treatment group
Predicted mortality*
(%)
Actual mortality
(%)
Non-‐VAP Cepobiprole 18.5 18.8
Non-‐VAP Linezolid/Cepazidime 19.0 21.2
VAP Cepobiprole 24.2 33.7
VAP Linezolid/Cepazidime 24.2 22.6
*Based on Knaus et al. Crit Care Med 1985;13:818
Study primary enrolled -‐Young pa2ents with normal es2mated renal func2on
-‐Trauma pa2ents
Dosing Malers: Was This All Due to ARC?
Doripenem 7-‐day course
Imipenem 10-‐ day course
n N % n N % Diff (%) 95% CI
Clinical cure rate MITT 36 79 45.6 50 88 56.8 -‐11.2 ( -‐26.3; 3.8) ME 28 57 49.1 36 59 66.1 -‐17.0 ( -‐34.7; 0.8) Crea2nine clearance* (MITT) ≥ 150 mL/min 8 18 44.4 20 28 71.4 -‐27.0 (-‐55.4; 1.4) ≥80 -‐ 150 31 15 48.4 37 19 51.4 -‐3.0 -‐26.8; 20.9
>50 -‐ <80 23 12 52.2 18 9 50.0 2.2 -‐28.7; 33.0
>30 -‐ ≤50 5 0 0 2 1 50.0 -‐50.0
≤30 2 1 50.0 3 1 33.3 16.7 All cause 28-‐day mortality MITT 17 79 21.5 13 88 14.8 6.7 (-‐5.0; 18.5) MITT = Microbiological ITT, ME = Microbiologically Evaluable * Calculated using Cockcrop -‐Gault formulas rela2ng serum crea2nine with age & body weight
Kollef, MH, et al. Crit Care 2012;16(6):R218.
Clinical Cure & All-‐Cause 28-‐Day Mortality
Beta-‐Lactam (BL) Infusion in Severe Sepsis Trial (BLISS) • Prospec2ve, randomized, non-‐blinded
• Interven2ons – Bolus infusion (BI) of BL vs – Con2nuous infusion (CI)
• Agents: cefipeme, pip/taz, meropenem
• Subjects: (n=140), Adults, severe sepsis, & organ dysfunc2on • Endpoints
– Clinical cure 14d aper d/c abx – PK/PD targets (BL levels measured in central lab)
Abdul Aziz MH, et al. ICM; published online Jan. 2016
BLISS
Abdul Aziz MH, et al. ICM; published online Jan. 2016 CI = Con2nuous Infusion IB = IntermiKent Bolus
BLISS
0
20
40
60
80
100
T>MIC (Day 1) T>MIC (Day 3) Clinical Cure
BI CI %
of P
a2en
ts
* * **
*p<0.001, **p<0.01
Abdul Aziz MH, et al. ICM; published online Jan. 2016 CI = Con2nuous Infusion IB = IntermiKent Bolus
Conclusions
• Resistance among GNR increasing
• PaKern seen globally and in mul2ple pathogen types
• Resistance drives inappropriate therapy • We know very liKle about how to use an2bio2cs in the pa2ents who need them most urgently
GRAM-‐NEGATIVE RESISTANCE & ITS IMPACT ON TREATMENT DECISIONS CARBAPENEM-‐RESISTANT ENTEROBACTERIACEAE (CRE): A REAL LIFE EXPERIENCE Yehuda Carmeli, MD, MPH
The Na2onal Center for Infec2on Control and An2microbial Resistance,
Tel Aviv Medical Center, Israel
Disclosures
• Achaogen • Allecra Therapeu2cs • AstraZeneca • Biomerieux SA
• DaVolterra • Durata Therapeu2cs, Inc • Valneva SE • Merck & Co. Inc
• Nabriva Therapeu2cs • Omnix
• PPD • Rempex Pharmaceu2cals
• Roche • Syntezza Bioscience LTD • Takeda Pharmaceu2cal Company Limited
I have served as a consultant to, researcher/inves2gator for, or spoken for:
Israel
• Size and popula2on ~ New Jersey – Size: 8,500 square miles – Popula2on: 8 million
• 15,000 acute hospital beds – 28 hospitals
• 3,500 PACs (chronic ven2la2on, skilled nursing) beds
– 14 hospitals • 25,000 LTCFs beds
– 300 facili2es
Adapted from Colodner R. DMID 2007; Leavit A, AAC 2009
0
1
2
3
4
5
6
Ertapenem Imipenem Meropenem
1,030 ESBL producing E. coli & Klebsiella spp. Collected during 2004 from 10 largest hospitals
% non
-‐suscep2
bly to carbape
nems
No Carbapenamases in 2004: All carbapenem non-‐suscep>bile strains due to ESBL+porin loss
0
5
10
15
EARSS (5 hospitals) 3 hospitals (>500 bed)
% carba
pene
m re
sistan
ce
2006
2005
Bacteremia
All sites
Na>onwide emergence of carbapenem-‐resistant Kpn -‐ Israel
0
5
10
15
20
25
30
35
1st 2nd 3rd
Greece 2002-‐2004
Israel 2005-‐2007
Cyprus 2007-‐2009
Italy 2009-‐2011
Romania 2012-‐2014
Year of CRE Outbreak
Prop
or>o
n Re
sistan
t to Ca
rbap
enem
s
Natural history of carbapenem-‐resistant K. pneumoniae spread in countries without regional infec>on control
Friedman D. SubmiKed for publica2on
0
20
40
60
80
100
120
140
160
180
Number of Isolations
Jan-05
Feb-05
Mar-05
Apr-05
May-05
Jun-05
Jul-05
Aug-05
Sep-05
Oct-05
Nov-05
Dec-05
Jan-06
Feb-06
Mar-06
Apr-06
May-06
Jun-06
Jul-06
Aug-06
Sep-06
Oct-06
Nov-06
Dec-06
Jan-07
Feb-07
Mar-07
Apr-07
Month
First-time CRE isolations per clinical culture, Jan 05-April 07
2005
2006
2007
The Israeli CRE na>onal outbreak
700 cases 44% mortality
Es>mates: Incidence: 1600 inpa>ents infec>ons Reservoir: 17,000 carriers Mortality: 700 fatali>es (100 per million)
Carbapenem resistant K. pneumonia status in 2007
0.3
11
25
0
5
10
15
20
25
30
2005 2006 2007
% carba
pene
m re
sistan
ce
Year
EARSS report Schwaber M. AAC 2008
Azita LeaviK et al. An2microb. Agents Chemother. 2007;51:3026-‐3029
Emergence of KPC-‐2 and KPC-‐3 in Carbapenem-‐Resistant Klebsiella pneumoniae Strains in an Israeli Hospital
One hospital experience • Tel Aviv Medical Center
– Ter2ary care teaching hospital – 1500 beds – 100,000 pa2ents admissions per year
• 27% of pa2ents with CRE had bacteremia • 21 of 48 pa2ents infected with CRE died (CFR 44%) • Colis2n was used empirically in units where CRE was isolated • At hospital emergency staff mee2ng Chief of surgery stated: “situa2on at surgical ICU become too risky to admit pa2ents for elec2ve colorectal surgery, dras2c measures are required to ensure pa2ent safety”
• 3 of 4 pa2ents carriers of CRE who underwent BMT – died aper transplant due to CRE bacteremia
• Ethical commiKee convened to discuss if it is ethical to perform BMT in CRE carriers given the individual risk and risk to others
Schwaber M. AAC 2008
Cohor>ng with dedicated staff
• It become evident that CRE outbreak risks the hospital ability to provide safe care to pa2ents
• Cohor2ng of all CRE carriers in isola2on units effec2ve but difficult:
– At the peak 32 carriers in Medical, surgical and ICU cohorts
– Difficul2es to discharge carriers to LTCFs
0
2
4
6
8
10
12
14
16
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
NO. OF CASES
TIME (weeks)
LAG TIME
Incidence of KPC-‐producing Klebsiella spp.
P=0.01
Schechner V, ICAAC 2007
0
5
10
15
20
25
30
35
40
NO OF PA
TIEN
TS
DATE
No_Posi>ve_Pat No_Nega>ve_Pat <1% posi2vity
Targeted screening for CRE upon admission
Ben-‐David D. ICHE 2010
Poten>al Role of Ac>ve Surveillance in the Control of a Hospital-‐Wide Outbreak of Carbapenem-‐Resistant Klebsiella pneumoniae Infec>on
Gastrointes>nal coloniza>on by KPC-‐producing Klebsiella pneumoniae following hospital discharge: dura>on of carriage and risk factors for persistent carriage
Feldman N. CMI 2013
In pa2ents admiKed from and discharged to home: 50% clear carriage at 3 months.
Pa2ents in LTFCs, may remain carriers for prolonged periods.
JCM 2013
Environmental Contamina>on by Carbapenem-‐Resistant Enterobacteriaceae
Risk of transmission is not uniform: Environmental CRE contamina>on
020
4060
8010
0
Num
ber o
f env
ironm
enta
l CR
E c
olon
ies
0 .2 .4 .6 .8 1Fraction of patients
Lerner A. CMI 2014
January February March April Patient 1 Pa>ent 2 Pa>ent 3 * Pa>ent 4 * Pa>ent 5 * Pa>ent 6 X Pa>ent 7 X Pa>ent 8 * Pa>ent 9 * Pa>ent 10 * Pa>ent 11 * Pa>ent 12 Pa>ent 13 X * Pa>ent 14 * Pa>ent 15 * Pa>ent 16 Pa>ent 17 X * Pa>ent 18 * Pa>ent 19 X * Pa>ent 20 X * Pa>ent 21 X * Pa>ent 22 * Pa>ent 23 * Pa>ent 24 * Pa>ent 25 Pa>ent 26 X * Pa>ent 27 * Pa>ent 28 * Pa>ent 29 * Pa>ent 30 X *
Internal medicine X Internal medicine Y Internal medicine Z Internal medicine W Positive KPC Kp clinical culture * Positive KPC Kp surveillance culture X Negative surveillance culture Dedicated KPC Kp ward
Note:
Index case
The movement of KPC Kp through 30 pa>ents in 4 different wards
Schechner V. ICAAC 2008
CRE nosocomial acquisi>ons, clinical culture, general hospitals, 2005-‐08/2015
Interven2ons in LTCF
% carbapenem resistance among K. pneumoniae blood isolates Decreased from a peak of 25% (2007) to <4% (2015)
Update on: Schwaber MJ. CID 2014
An Ongoing Na>onal Interven>on to Contain the Spread of Carbapenem-‐Resistant Enterobacteriaceae
The story of one nursing home
14 29 31
78
0
20
40
60
80
100
120
2008 2009 2010
גילויים בבתי חולים אחרים Detectedסיקורים במוסד on other facility
Jan 2010: all residents were screened 48% were CRE carriers
Detected on same facility
Interven>on
• Infec2on control educa2on • Periodic hospital-‐wide ac2ve screening • Implementa2on of screening on admission
• Separa2on into 4 cohorts (physical and staff) – known carriers – unknown new admissions – prior carriers – no carriage
• Closed for new admissions un2l full compliance was achieved (3 months)
Nursing home CRE acquisi>ons 2008-‐2015
14
29 31
7 9 5
78
27 30
11
1 1 0
20
40
60
80
100
120
2008 2009 2010 2011 2012 2013 2014 2015
גילויים בבתי חולים אחרים Detectedסיקורים במוסד on same facility Detected on other hospitals
Comparison Between 4 PPS in PACHs Prevalence of new CRKP
12.2
9.1
7.9
3.5
0 2 4 6 8 10 12 14
2008
2010
2011
2013
Prevalence of CRKP%
CRE incidence – PACHs, 2012-‐15
KPC OXA-‐48
The changing CRE epidemiology 2016
Friedman D. SubmiKed 2016
NDM
Distribu>on of CPE in Israel 2016 (%)
2016 Israeli Tes>ng Guidelines for CPE Suspected CPE
PCR (KPC, NDM, OXA-‐48, VIM)
Posi2ve CPE
Nega2ve CARBA NP/MHT
Posi2ve Send to reference lab
CARBA NP
Nega2ve If Meropenem MIC>1
Non-‐CPE CRE
Posi2ve CPE
PCR (KPC, NDM, OXA-‐48, VIM)
Nega2ve Send to reference lab
Asymptoma>c rectal carriage of blaKPC producing carbapenem-‐resistant Enterobacteriaceae: who is prone to become clinically infected?
• During subsequent 2 years (May 2007 and 30 April 2009)
– 5% (10,040) pa2ents admissions considered high risk popula2on screened for carriage of CRE
– 502 were newly iden2fied CRE rectal carriers – 44 (8.8%) developed subsequent posi2ve clinical cultures with CRE
CMI 2012
7 days Case Fatality rate: Non CRE GNR 24% CRE 39% No pathogen specific Predictors iden2fied
CMI 2015
Bloodstream infec>ons among carriers of carbapenem-‐resistant Klebsiella pneumoniae: e>ology, incidence and predictors
Summary
• CRE may spread rapidly within and between ins2tu2ons
• May lead to units closure and to limit the healthcare system to provide advanced safe care
• Substan2al efforts and resources may be required to limit the spread of CRE
• CRE carriers are at high risk to develop CRE as well as other mostly GNR infec2ons.
• These infec2ons are associated with exteremely high case-‐fatality rate
• Preven2ve and treatment strategies are required to confront the global epidemic of CRE
THE EVOLUTION OF ANTIBIOTICS TO TREAT GRAM-‐NEGATIVE PATHOGENS Keith A. Rodvold, Pharm.D., FCCP, FIDSA
Colleges of Pharmacy and Medicine
University of Illinois at Chicago
Disclosure Statement (past 12 months)
• Research Grants and Contracts: Allergan, Theravance Biopharma, ARLG / NIAID / NIH
• Consultant / Advisory Board: Achaogen, Allergan, Bayer, Janssen Pharmaceu2cals, Melinta Therapeu2cs, Merck, Mo2f Biosciences, Nabriva Therapeu2cs, Spero Therapeu2cs, Tetraphase Pharmaceu2cals, Theravance Biopharma, Wockhardt, Zavante Therapeu2cs
• Speaker’s Bureau: Allergan, Medicine Company, Merck
An>bio>c Resistance Threats in the United States, 2013
Gram-‐Nega>ve Organism Cases (%)
Deaths (%)
Threat Level
ESBL-‐producing Enterobacteriaceae 26,000 (1.93)
1700 (7.44) Serious
Carbapenem-‐resistant Enterobacteriaceae 9300 (0.69)
610 (2.67) Urgent
Mul2drug-‐resistant Pseudomonas aeruginosa 6700 (0.5)
440 (1.92) Serious
Mul2drug-‐resistant Acinetobacter spp. 7300 (0.54)
500 (2.18) Serious
Thabit AK, et al. Expert Opin Pharmacother 2015; 16: 159-‐177 hKp://www.cdc.gov/drugresistance/pdf/ar-‐threats-‐2013-‐508.pdf
Es2mated annual incidence of infec2on due to notable an2microbial-‐resistant organisms Total: 1,349,766 cases and 22,840 deaths ESBL, extended-‐spectrum beta-‐lactamase
An>bio>c Treatment of Resistant Gram-‐Nega>ve Organisms • Infec2ons caused by resistant Gram-‐nega2ve organisms are associated with increased morbidity and mortality compared to suscep2ble counterparts
• Choice of empiric therapy has become more difficult for serious infec2ons because an2microbial resistance to first-‐line agents
• Clinicians also have the dilemma between choosing:
– an agent that is inac2ve versus broad-‐spectrum agent – monotherapy versus combina2on therapy – determining the role of adjunc2ve therapy – newer versus older agents
Colis>n and Polymyxin B
• Assumed an important role as “salvage therapy” for otherwise untreatable Gram-‐nega2ve infec2ons
• Emerging pharmacokine2c-‐pharmacodynamic data indicate the monotherapy is unlikely to generate plasma concentra2ons that are reliably efficacious
• Regrowth and the emergence of resistance with monotherapy are commonly reported even when concentra2ons exceed those achieved clinically
• Combina2on therapy has been suggested as a possible means of increasing an2microbial ac2vity and reducing the development of resistance
Bergen PJ, et al. Pharmacother 2015; 35: 34-‐42 Kassamali Z, Danziger L. Pharmacother 2015; 35: 17-‐21
Combina>on An>bio>c Treatment of Resistant Gram-‐Nega>ve Organisms • Choice of agents open involves:
– Aminoglycosides – Polymyxins – Beta-‐lactam-‐beta-‐lactamase inhibitors – Rifampin – Carbapenem – Tetracyclines – Fosfomycin – Tigecycline
• Clinical evidence regarding effec2veness of different treatment regimens is principally derived from retrospec2ve studies, case reports or small prospec2ve studies; no randomized clinical trials
• Need for new an2microbial agents to treat resistant gram-‐nega2ve organisms is inevitably important
Evolu>on of Novel An>bacterial Agents Chronological Order of First Public Reports
Pucci MJ, Page MGP, Bush K. Microbe 2014; 9: 147-‐52
Agents Being Developed to Treat Resistant Gram-‐Nega>ve Bacteria
Agent Related-‐Class Sponsor Cepolozane -‐ Tazobactam BL-‐BLI Merck Cepazidime -‐ Avibactam BL-‐BLI Allergan Meropenem -‐ Vaborbactam BL-‐BLI Medicine Company Imipenem -‐ Relebactam BL-‐BLI Merck Aztreonam -‐ Avibactam BL-‐BLI Astra-‐Zeneca S649266 Cephalosporin Shionogi BAL30072 Monocyclic BL Basilea Plazomicin Aminoglycoside Achaogen Eravacycline Tetracycline Tetraphase
BL, Beta-lactam; BLI, beta-lactamase inhibitor
Cevolozane -‐ Tazobactam
• Cephalosporin plus beta-‐lactamase inhibitor
• Spectrum of ac2vity: Gram-‐nega2ves, including MDR Pseudomonas aeruginosa and ESBL-‐producing strains
• FDA approval in December 2014 – Complicated Urinary Tract Infec2ons, including Pyelonephri2s – Complicated Intraabdominal Infec2ons (plus metronidazole) – IV dose: 1.5 g (1 g cepolozane; 0.5 g tazobactam) q8h (1-‐h infusion)
• Clinical trial: Ven2lated nosocomial pneumonia at an increased dose: 3.0 g (2 g cepolozane; 1 g tazobactam) q8h – Ongoing trial (NCT02070757; clinicaltrials.gov) – Plasma-‐to-‐epithelial lining fluid penetra2on: ~30%
van Duin D, Bonomo RA. Clin Infect Dis 2016; 63: 234-‐41 Chandorkar G, et al. J An,microb Chemother 2012; 67: 2463-‐9 Nicolau DP, et al. J Clin Pharmacol 2016; 56: 56-‐66
Cevazidime -‐ Avibactam
• Cephalosporin plus beta-‐lactamase inhibitor
• Spectrum of ac2vity: Gram-‐nega2ves, including MDR Pseudomonas aeruginosa, ESBL-‐producing strains, KPCs
• FDA approval in February 2015 (based Phase 2 data) – Complicated Urinary Tract Infec2ons, including Pyelonephri2s – Complicated Intraabdominal Infec2ons (plus metronidazole) – For pa2ents with limited or no alterna2ve treatment op2ons – IV dose: 2.5 g (2 g cepazidime; 0.5 g avibactam) q8h (2-‐h infusion) – Unavailable as of August 8, 2016 – shortage of ac2ve ingredient
• Clinical trial: Nosocomial pneumonia -‐ Dose of 2.5 g q8h – Trial was completed January 2016 (NCT01808092; clinicaltrials.gov) – Plasma-‐to-‐epithelial lining fluid penetra2on ~30%
van Duin D, Bonomo RA. Clin Infect Dis 2016; 63: 234-‐41 Nicolau D, et al. J An,microb Chemother 2015; 70: 2862-‐9
Carbapenem plus Beta-‐Lactamase Inhibitor
• Vaborbactam (RPX7009) – Cyclic boronic acid-‐based beta-‐lactamase inhibitor
• Creates a covalent bond between boron moiety and serine hydroxyl beta-‐lactamase
– Good affini2es for many class A and C serine beta-‐lactamases • High inhibitory potency against KPC-‐producing isolates
– Currently combined with meropenem (Carbavance™) • Relebactam (MK-‐7655)
– Diazebicyclooctanone, non-‐beta-‐lactam, beta-‐lactamase inhibitor – Similar chemical structure and spectrum of ac2vity as avibactam
• Class A and C ac2vity with minor D ac2vity • Lacking ac2vity against MBLs and most OXAs
– Currently combined with imipenem-‐cilasta2n
Falagas ME, et al. Expert Rev An,-‐Infect Ther 2016; 14: 747-‐63 Papp-‐Wallace KM, Bonomoa RA. Infect Dis Clin North Am 2016; 30: 441-‐64
In Vitro Ac>vity: Meropenem – Vaborbactam • 4,500 isolates collected from 11 hospitals in Brooklyn and Queens, NY from November 2013 to January 2014
• Addi2on of RPX7009 resulted in a 64-‐ to 512-‐fold decrease in meropenem MIC in majority of KPC-‐posi2ve isolates
• All but 2 of these isolates (98.3%) were inhibited by 1 µg/mL meropenem combined with RPX7009 at 8 µg/mL
Species (n) Meropenem
Meropenem-‐Vaborbactam
Meropenem-‐Vaborbactam
MIC50 MIC90 MIC50 MIC90 MIC50 MIC90
Klebsiella pneumonia (KPC+) (121) 8 64 0.06 / 4 2 / 4 0.03 / 8 0.5 / 8 Pseudomonas aeruginosa (96) 8 32 8 / 4 32 / 4 8 / 8 32 / 8 Acinetobacter baumannii (98) 32 64 32 / 4 64 / 4 32 / 8 64 / 8
Lapuebla A, et al. An,microb Agents Chemother 2015; 59: 4856-‐4860
MIC values in µg/mL
Meropenem – Vaborbactam (RPX7009) • In vitro hollow-‐fiber model (simula2ng human exposure of 2 g meropenem plus 2 g vaborbactam q8h 3-‐hour infusion) was bactericidal against KPC-‐producing Enterobacteriacea
• In vivo efficacy in murine thigh infec2on model against KPC-‐producing isolates of K. pneumoniae, E. coli, and E. cloacae (MICs ranging from ≤0.06 to 8 µg/mL)
• Efficacy, Safety, Tolerability of Carbavance Compared to Piperacillin-‐Tazobactam in Complicated Urinary Tract Infec2ons, including Acute Pyelonephri2s, in Adults (TANGO 1) – Completed trial in June 2016 (NCT02166476; clinicaltrials.gov) – Overall success in 98.4% of Carbavance treated pa2ents (sta2s2cal
superiority) • Efficacy, Safety, Tolerability of Carbavance Compared to Best Available Therapy in Serious Infec2ons Due to Carbapenem-‐Resistant Enterobacteriaceae in Adults (TANGO 2) – Ongoing trial (NCT02168946; clinicaltrials.gov)
ICAAC 2014 (abstr. F-‐959 & F-‐958) Falagas ME, et al. Expert Rev An,-‐Infect Ther 2016; 14: 747-‐63
In Vitro Ac>vity: Imipenem -‐ Relebactam
• 4,000 isolates collected from 11 hospitals in Brooklyn and Queens, NY from November 2013 to January 2014
Species (n) Imipenem Imipenem -‐ Relebactam
MIC50 MIC90 MIC50 MIC90
Escherichia coli (2778) 0.25 0.25 0.25 / 4 0.25 / 4 Klebsiella pneumonia (891) 0.25 4 0.25 / 4 0.25 / 4 blaKPC-‐possessng K. pneumonia (111) 16 >16 0.25 / 4 1 / 4 Enterobacter spp. (211) 0.5 1 0.25 / 4 0.5 / 4 Pseudomonas aeruginosa (490) 2 16 0.5 / 4 2 / 4 Imipenem-‐resistant P. aeruginosa (144) 8 >16 1 / 4 2 / 4 Acinetobacter baumannii (158) 4 >16 2 / 4 >16 / 4 blaOXA-‐23-‐possessing A. baumannii (58) >16 >16 >16 / 4 >16 / 4
Lapuebla A, et al. An,microb Agents Chemother 2015; 59: 5029-‐5031
MIC values in µg/mL
Imipenem+Cilasta>n – Relebactam (MK-‐7655A) • In vivo efficacy in murine, neutropenic, thigh infec2on model against imipenem-‐resistant Pseudomonas aeruginosa with OprD deficiency and expression of AmpC beta-‐lactamase and imipenem-‐resistant KPC-‐producing Klebsiella pneumoniae strains
• Phase 2 complicated intraabdominal infec2ons trial (n=351 pa2ents): – 1:1:1 ra2o in treatment groups of relebactam 250 mg, 125 mg, placebo – Clinical response: 93.7%, 95.3%, 94.9% (microbiologically evaluable; n=230)
• Efficacy and Safety of Imipenem + Cilasta2n / Relebactam (MK-‐7655A) versus Colis2methate Sodium plus Imipenem + Cilasta2n in Imipenem-‐Resistant Bacterial Infec2ons (RESTORE-‐IMI 1) – Ongoing trial (NCT02452047; clinicaltrials.gov)
• Imipenem/Relebactam/Cilasta2n versus Piperacillin/Tazobactam for Treatment of Par2cipants with Bacterial Pneumonia (RESTORE-‐IMI 2) – Ongoing trial (NCT02493764; clinicaltrials.gov)
ICAAC 2015 (abstr. F-‐259) Mavridou E, et al. An,microb Agents Chemother 2015; 59: 790-‐5 Falagas ME, et al. Expert Rev An,-‐Infect Ther 2016; 14: 747-‐63
S-‐649266 • Siderophore cephalosporin with a catechol moiety and binds mainly to PBP-‐3 of Gram-‐nega2ve bacteria
• Catechol moiety to form a chela2ng complex with ferric iron
• Superior in vitro ac2vity than beta-‐lactam comparators against ESBL-‐, KPC-‐ or metallo-‐beta-‐lactamase-‐posi2ve Enterobacteriaceae isolates, and both MDR Pseudomonas aeruginosa and Acinetobacter baumannii strains
• Ongoing Trials: – Study of Efficacy/Safety of Intravenous S-‐649266 versus Imipenem/Cilasta2n in Complicated Urinary Tract Infec2ons (NCT02321800; ClinicalTrials.gov)
– Study of S-‐649266 or Best Available Therapy for the Treatment of Severe Infec2ons Caused by Carbapenem-‐Resistant Gram-‐Nega2ve Pathogens (CREDIBLE – CR) (NCT02714595; ClinicalTrials.gov)
Ito-‐Horiyama T, et al. An,microb Agents Chemother 2016; 60: 4384-‐6 West KN, et al. An,microb Agents Chemother 2016; 60: 729-‐34 Ito A, et al. J An,microb Chemother 2016; 71: 670-‐7 Falagas ME, et al. Expert Rev An, Infect Ther 2016; 14: 747-‐63
BAL30072
• Siderophore monocyclic beta-‐lactam an2bio2c (monosulfactam) stable to metallo-‐beta-‐lactamases and class C beta-‐lactamases; stable against some types of class A (eg., KPC) and class D (eg., OXA) carbapenemases
• More potent in vitro than beta-‐lactam comparators against MDR Acinetobacter baumannii strains as well as Burkholderia spp. (MIC90 = 0.125 µg/mL) and S. maltophilia (MIC90 = 2 µg/mL)
• Synergy was observed between BAL30072 and carbapenems (and colis2n) against both MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates
Fu H-‐G, et al. Eur J Med Chem 2016; 110: 151-‐63 Landman D, et al. Int J An,microb Agents 2014; 43: 527-‐32 Mima T, et al. Int J An,microb Agents 2011; 38: 157-‐9 Page MGP, et al. An,microb Agents Chemother 2010; 54: 2291-‐302 Falagas ME, et al. Expert Rev An, Infect Ther 2016; 14: 747-‐63
Zhanel GG, et al. Expert Rev Infect Ther 2012; 10: 459-‐73 Dozzo P, Moser HE. Expert Opin Ther Pa,ents 2010; 20: 1321-‐41
Genera>ons of Aminoglycosides Aminoglycoside Year of
Availability
Streptomycin 1944
Neomycin 1949
Kanamycin 1957
Paromomycin 1959
Spec2nomycin 1961
Gentamicin 1963
Tobramycin 1967
Sisomicin 1970
Amikacin 1976
Ne2lmicin 1983
Plazomicin (ACHN-‐490) • Next-‐genera2on aminoglycoside (“neoglycoside”) synthe2cally derived from sisomicin
• In vitro ac2vity against both Gram-‐posi2ve and Gram-‐nega2ve organisms, including isolates harboring any of the clinically relevant aminoglycoside-‐modifying enzymes (e.g., acetyltransferases [AAC], nucleo2dyltransferases [ANT], and phosphotransferases [APH])
• Plazomicin does func2on as a substrate for AAC (2’)-‐I enzymes expressed in Providencia stuar2i and some mycobacterial species
Krause KM, et al. Cold Spring Harb Perspect Med 2016; 6(6) Zhanel GG, et al. Expert Rev An, Infect Ther 2012; 10: 459-‐473
Plazomicin (ACHN-‐490) • Inhibits bacterial protein synthesis
and exhibits dose-‐dependent bactericidal ac2vity
• Retains in vitro ac2vity against aminoglycoside-‐resistant MDR, PDR, and XDR isolates of Enterobacteriaceae, except the New Delhi metallo-‐beta-‐lactamase (NDM) posi2ve
• In vitro synergy ac2vity when combined with carbapenems against of Acinetobacter baumannii and with cefepime, imipenem, piperacillin-‐tazobactam or doripenem against isolates of Pseudomonas aeruginosa
Zhanel GG, et al. Expert Rev An, Infect Ther 2012; 10: 459-‐73 Falagas ME, et al. Expert Rev An, Infect Ther 2016; 14: 747-‐63
Bacteria MIC50 MIC90 Range
Citrobacter spp. 0.5 1 0.25 -‐ 4
Enterobacter spp. 0.5 1 0.25 -‐ 64
Klebsiella pneumonia 0.5 1 0.12 -‐ 64
Francisella tularensis 0.5 1 0.03 -‐ 1
Yersinia pes2s 0.5 1 0.12 -‐ 1
Escherichia coli 1 2 0.06 -‐ 16
Serra2a spp. 1 4 0.5 -‐ 4
Proteus mirabilis 4 8 1 -‐ 16
Proteus, indole-‐posi2ve 8 16 4 -‐ 16
Acinetobacter baumannii 8 16 0.12 -‐ 128
Pseudomonas aeruginosa 8 32 0.12 -‐ 256 MIC values in µg/mL
Plazomicin • In vitro ac2vity of plazomicin against aminoglycoside-‐suscep2ble and non-‐suscep2ble Pseudomonas aeruginosa:
Walkty A, et al. An,microb Agents Chemother 2014; 58: 2554-‐2563 Landman D, et al. J An,microb Chemother 2011; 66: 332-‐334
Cumula>ve (%) inhibited at MIC in µg/mL of: ≤0.25 0.5 1 2 4 8 16 32 64 >64
Amikacin-‐S (n=561) 2.7 4.1 10.7 38.3 71.1 90.6 98.8 100
Gentamicin-‐S (n=529) 2.6 4.2 11.2 40.6 74.5 93.6 99.6 100
Tobramycin-‐S (n=560) 2.5 3.9 10.5 38.0 70.0 88.2 95.7 98.6 100
Amikacin-‐non-‐S (n=32) 0 0 0 6.3 6.3 12.5 15.6 46.9 75.0 100
Gentamicin-‐non-‐S (n=64) 1.6 1.6 1.6 3.1 10.9 26.6 50.0 73.4 87.5 100
Tobramycin-‐non-‐S (n=33) 3.0 3.0 3.0 12.1 27.3 54.5 69.7 72.7 75.8 100
• Landman et al: plazomicin MIC50 = 8 µg/mL and MIC90 = 32 µg/mL for 679 isolates of P. aeruginosa (amikacin: MIC50 = 8 µg/mL and MIC90 = 16 µg/mL)
• Mechanisms resul2ng in elevated MICs poorly defined; likely that reduced permeability and/or efflux are contribu2ng factors
16S Ribosomal RNA Methyltransferase • High-‐level aminoglycoside resistance caused by produc2on of acquired 16S ribosomal RNA methyltransferase (16S-‐RMTase) in pathogenic Gram-‐nega2ve bacteria was first reported in the early 2000s
• Bacteria that produce 16S-‐RMTase frequently coproduce ESBL, and more recently, carbapenemases, especially New Delhi metallo-‐beta-‐lactamases (NDM)
• Spread of 16S-‐RMTase-‐producing bacteria further compromises the already limited treatment op2ons for infec2ons caused by mul2drug-‐resistant (MDR) and extensively drug-‐resistant (XDR) pathogens
• Plazomicin is not ac2ve against isolates that produce acquired 16S-‐RMTase
Doi Y, et al. Infect Dis Clin North Am 2016; 30: 523-‐37
Plazomicin (ACHN-‐490)
• Human studies have not reported nephrotoxicity or ototoxicity, and lack of ototoxicity in the guinea pig model
• Aper IV 15 mg/kg dose, maximum plasma concentra2on ~113 µg/mL, AUC0-‐24 of 235 µg•h/mL, t1/2 of 4 hours, and apparent Vss of 0.25 L/kg
• Mean (SD) plasma and ELF concentra2on-‐2me profile in healthy subjects following a single 15 mg/kg dose 10-‐minute IV infusion
Zhanel GG, et al. Expert Rev An, Infect Ther 2012; 10: 459-‐473 Cass RT, et al. An,microb Agents Chemother 2011; 55: 5874-‐5880 Cass R, et al. ECCMID 2013, poster # P-‐1637
Plazomicin • A Phase 3, Randomized, Mul2center, Double-‐Blind Study to Evaluate the Efficacy and Safety of Plazomicin Compared with Meropenem Followed by Op2onal Oral Therapy for the Treatment of Complicated Urinary Tract Infec2on, including Pyelonephri2s, in Adults – NCT02486627 ClinicalTrials.gov
• A Phase 3, Mul2center, Randomized, Open-‐Label Study to Evaluate the Efficacy and Safety of Plazomicin Compared with Colis2n in Pa2ents with Infec2on Due to Carbapenem-‐Resistant Enterobacteriaceae (CRE) [CARE] – Plazomicin in combina2on with meropenem or 2gecycline – Colis2n in combina2on with meropenem or 2gecycline – Treatment of pa2ents with bloodstream infec2on, hospital-‐acquired or ven2lator-‐associated bacterial pneumonia
– NCT01970371 ClinicalTrials.gov
Aerosolized An>bio>cs • Local ins2lla2on or aerosoliza2on is a way to enhance an2bio2c penetra2on to the lower respiratory tract
– Polymyxin B and aminoglycosides most commonly used and studied • Microbiological eradica2on was significantly greater in pa2ents receiving aerosolized an2bio2cs in a single prospec2ve randomized trial of “adjunc2ve use” of endotracheal tobramycin with IV therapy in the treatment of VAP (AAC 1990; 34:269-‐272)
• Aerosolized an2bio2cs maybe useful to treat microorganisms that, on the basis of high MIC values, are “resistant” to systemic therapy
• Anecdotal reports of pa2ents with VAP due to MDR Pseudomonas aeruginosa unresponsive to systemic an2bio2cs, but improved with addi2on of aerosolized aminoglycosides or polymyxin B (AJRCCM 2000; 162: 328-‐330)
ATS & IDSA. Am J Respir Crit Care Med 2005; 171: 388-‐416 Wenzler E, et al. Clin Microbiol Rev 2016; 29: 581-‐632
Amikacin Inhala>on Solu>on
• A Prospec2ve, Randomized, Double-‐Blind, Placebo-‐Controlled, Mul2center Study to Evaluate the Safety and Efficacy of BAY 41-‐6551 as Adjunc2ve Therapy in Intubated and Mechanically-‐Ven2lated Pa2ents with Gram-‐Nega2ve Pneumonia (INHALE 1 and INHALE 2)
• Amikacin Inhala2on Solu2on (BAY 41-‐6551) – 400 mg of aerosolized amikacin q12h for 10 days administered using the Pulmonary Drug Delivery System (PDDS Clinical)
– Aerosolized Placebo q12h for 10 days via PDDS • Phase II study supported q12h vs q24h vs placebo, with lower mean number of an2bio2cs per pa2ent per day and similar clinical cure rates (93.8% vs 75.0% vs 87.5%)
ClinicalTrials.gov: NCT01799993 & NCT00805168 Niederman MS, et al. Intensive Care Med 2012; 38: 263-‐271
PDDS and Amikacin Inhala>on Solu>on
Luyt C-‐E, et al. Crit Care 2009; 13: R200 Luyt C-‐E, et al. J Aerosol Med Pulm Drug Deliv 2011; 24: 183-‐190 & 191-‐199
PDDS Clinical Handheld Device
PDDS Clinical On-‐Ven>lator Device
How Useful Will These New Agents be in the Future? • New agents for treatment of Gram-‐nega2ve infec2ons are promising and could help preserve and enhance our an2bio2c armamentarium
• These agents may provide opportuni2es for monotherapy of resistant Gram-‐nega2ve organisms
• These advantages will need to be evaluated and compared to older and generic agents in regards to the use of healthcare resources and pa2ent outcomes
• Results from randomized controlled trials are needed in severely ill pa2ents with resistant Gram-‐nega2ve infec2ons are both older and newer agents and as monotherapy and combina2on therapy
QUESTION & ANSWER SESSION
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