Novel Treatment Options for Multi-Drug Resistant Gram-Negative Infections

NOVEL TREATMENT OPTIONS FOR MULTI-DRUG RESISTANT GRAM-NEGATIVE INFECTIONS

KARRINE BRADE, PHARMD, BCPS INFECTIOUS DISEASES CLINICAL SPECIALIST LEAD BOSTON MEDICAL CENTER OBJECTIVES

1. Recognize the prevalence and significance of Multi-drug resistant (MDR) Gram-negative infections and their impact on patient outcomes

2. List the newly approved agents active against these MDR organisms

3. Describe the evidence supporting the use of novel antibiotics in the treatment of these infections

4. Identify the potential roles in therapy for these antibiotics in the treatment of infections caused by MDR Gram-negative organisms MULTI-DRUG RESISTANT BACTERIA

• Increase in infections caused by Gram-negative bacteria • Development of multidrug-resistant (MDR) strains is a cause of major concern

• 2 million people/year in the US develop a resistant bacterial infection (Gram-positive and/or Gram-negative) • > 23,000 deaths

• Majority of deaths related to Gram- negative infections, particularly health care–acquired infections caused by • Extended-spectrum β-lactamase (ESBL)- producing Enterobacteriaceae • Carbapenem-resistant Enterobacteriaceae (CRE) • MDR Acinetobacter baumannii • MDR Pseudomonas aeruginosa

Kaye KS, et al Pharmacotherapy. 2015 Oct;35(10):949-62 CDC. Antibiotic Resistance Threats in the United States, 2013 Perez F, et al. Cleve Clin J Med 2013;80:225–33 MULTI-DRUG RESISTANT BACTERIA

• Emerging threats associated with antibiotic resistance are the ESKAPE pathogens, which cause the majority of US hospital infections and “escape” the effects of antibiotics • Enterococcus faecium • Staphylococcus aureus • Klebsiella pneumoniae • Acinetobacter baumanii • Pseudomonas aeruginosa • Enterobacteriaceae • Resistance to previously effective antimicrobial agents • Limited options available with toxic side effects (polymyxins, aminoglycosides, etc)

• Few new antibiotics under development that are effective against these resistant Gram-negative bacteria

Kaye KS, et al. Pharmacotherapy. 2015 Oct;35(10):949-62 CDC. Antibiotic Resistance Threats in the United States, 2013. Boucher HE, et al. Clinical Infectious Diseases 2009; 48:1–12 MECHANISMS OF RESISTANCE

Wright GD. BMC Biol 2010 Sep 20;8:123 MECHANISMS OF RESISTANCE

Opal SM, Pop-Vicas A. “Molecular mechanisms of antibiotic resistance in bacteria” Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 2016 ΒETA-LACTAMASES

Kaye KS, et al Pharmacotherapy. 2015 Oct;35(10):949-62 NOVEL ANTIBIOTICS

Drug FDA? MDR Organisms Ceftolozane/tazobactam Ceftazidime/avibactam Ceftaroline/avibactam Aztreonam/avibactam Imipenem/relebactam Meropenem/vaborbactam Eravacycline Finafloxacin Cefiderocol BAL30072 CEFTOLOZANE/TAZOBACTAM

• FDA approved for patients18 years or older with complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs)

• Ceftolozane is a zwitterionic anti-pseudomonal cephalosporin similar to cefepime • Stable against AmpC-type enzymes • Lower sensitivity toward common combinations of porin loss and up regulation of efflux pumps • Minimally stable against most ESBL enzymes • No activity against carbapenemase producers • Potent activity against P. aeruginosa • MICs at four- to 16-fold dilutions below the comparative MICs for ceftazidime

• Tazobactam extends the spectrum to include some ESBL-producing organisms • Minimal impact on P. aeruginosa susceptibility

• Pharmacokinetics • The binding of ceftolozane and tazobactam to human plasma proteins is approximately 16% to 21% and 30%, respectively • Ceftolozane and tazobactam are eliminated in urine as unchanged drug (> 95% and 80%), with the remainder of tazobactam hydrolyzed to form an inactive metabolite • Renal dose adjustments necessary

Zerbaxa [package insert] Lexington, MA: Cubist Pharmaceuticals;2014 Gentile I, et al. Expert Rev Anti Infect Ther. 2016 Oct;14(10):875-8 Arizpe A. et al. Curr Infect Dis Rep. 2016 Dec;18(12):39 Mai-Chi H, et al. Infect Drug Resist. 2013; 6: 215–223 CEFTOLOZANE/TAZOBACTAM

P. aeruginosa • Greater potency (2 to 8-fold) compared to ceftazidime and cefepime • Inhibition of 97.7% of the isolates (compared to 80.9% for ceftazidime and 80.7% for cefepime) • Activity against ceftazidime non-susceptible strains (88.2%), meropenem non-susceptible strains (89.6%) • Unaffected by up regulation of efflux pumps or loss of porin channels

Enterobacteriaceae • 99.3% of E. coli strains inhibited (compared to 87.7% for ceftriaxone and 91.5% for ceftazidime) • 92.1% of Klebsiella strains were inhibited compared to 84.4%, 86.2%, and 90.0% for ceftriaxone, ceftazidime, and cefepime

β-lactamase-producing organisms • Ceftolozane is minimally affected by primitive β- lactamases (TEM-1, TEM-2, SHV-1, and OXA-1) • Activity reduced against ESBL-producers • Addition of tazobactam at a concentration of 8 mg/L restored susceptibility in 93% of the isolates • Ceftolozane/tazobactam retains activity against 94.6%, 68.0%, and 100% of ESBL-producing E. coli, K. pneumoniae, and Proteus mirabilis

Mai-Chi H, et al. Infect Drug Resist. 2013; 6: 215–223 CEFTOLOZANE/TAZOBACTAM

50 US hospitals nosocomial blood (n=1118) and respiratory (n=527) isolates of E. coli (n=811), K. pneumoniae (n=835), and P. aeruginosa (n=814)

• Of 1646 E. coli and K. pneumoniae, 173 isolates (10.5%) were ESBL positive • 95% meropenem vs 79% ceftolozane/tazobactam susceptible

• 3 E. coli and 37 K. pneumoniae were carbapenemase-producing

• 14% (n=116) of the P. aeruginosa were MDR • 78% ceftolozane/tazobactam vs 17% meropenem susceptible

Southerland CA, et al. Ann Clin Microbiol Antimicrob. 2016 Jun 17;15(1):39 CEFTOLOZANE/TAZOBACTAM

• Phase III trial evaluating ceftolozane/tazobactam in complicated intra-abdominal infection (ASPECT-cIAI) • Double-blind, non-inferiority, randomized control trial

• Ceftolozane-tazobactam 1.5 g IV every 8 hours plus metronidazole 500 mg IV every 8 hours

• Meropenem 1g IV every 8 hours

• Clinical cure rates in microbiological intent-to-treat population • 83.0% for ceftolozane/tazobactam plus metronidazole • 87.3% with meropenem • Meet statistical criteria for non-inferiority

• Non-inferiority demonstrated for the microbiologically evaluable population • Clinical cure rates of 94.2% and 94.7%

Solomkin J, et al. Clin Infect Dis. 2015 May 15;60(10):1462-71 Wagenlehner FM, et al. Lancet. 2015 May 16;385(9981):1949-56 CEFTOLOZANE/TAZOBACTAM

• ASPECT-cUTI was a randomized, double-blind, double-dummy, non-inferiority Phase III trial evaluating ceftolozane-tazobactam versus levofloxacin for cUTI or pyelonephritis • Resistant organisms: 2.7% for ceftolozane-tazobactam and 26.7% for levofloxacin • Ceftolozane/tazobactam met non-inferiority in mMITT population (76.9% vs 68.4%) • Ceftolozane-tazobactam was superior to levofloxacin for composite cure in both populations

Wagenlehner FM, et al. Lancet. 2015 May 16;385(9981):1949-56 CEFTOLOZANE/TAZOBACTAM

Arizpe A, et al. Curr Infect Dis Rep. 2016 Dec;18(12):39 CEFTOLOZANE/TAZOBACTAM

• Phase 1 trials

• Phase 3 trial

Clinicaltrials.gov NOVEL ANTIBIOTICS

Drug FDA? MDR Organisms Ceftolozane/tazobactam YES AmpC, ESBL, and MDR P. aeruginosa, but not active against carbapenemases Ceftazidime/avibactam Ceftaroline/avibactam Aztreonam/avibactam Imipenem/relebactam Meropenem/vaborbactam Eravacycline Finafloxacin Cefiderocol BAL30072 CEFTAZIDIME/AVIBACTAM

• FDA approved for patients18 years or older with complicated intra- abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs)

• Avibactam vs other β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) • Structure: • Diazabicyclooctanone derivative employs reactive urea rather than β-lactam to inhibit serine β-lactamases

• Mechanism of inhibition: • Covalent, but reversible, in contrast to other β-lactamase inhibitors which are irreversible • β-lactam-based β-lactamase inhibitors bind and irreversibly generate an acyl-enzyme intermediate that undergoes hydrolysis or chemical rearrangement, restoring the activity of the β-lactamases • Since the acylation reaction of avibactam is reversible, the hydrolysis does not take place and the activity of avibactam is restored

• Expanded spectrum of β-lactamase inhibition: • Inhibits activity of Ambler class A (ESBL and KPC), class C (AmpC) and some class D (OXA- 48) enzymes • Not active against metallo β-lactamases (MBLs) (NDM, VIM, IMP, VEB, PER) • Not active against Acinetobacter OXA-type carbapenemases

Hidalgo JA, et al. Drug Des Devel Ther. 2016 Jul 26;10:2379-86 Falcone M, et al. J Antimicrob Chemother. 2016 Oct;71(10):2713-22 CEFTAZIDIME/AVIBACTAM

Pharmacokinetic parameters

• Cmax and AUC of ceftazidime increase in proportion to dose • Avibactam demonstrates linear pharmacokinetics across doses studied • No appreciable accumulation of either has been observed following multiple infusions • Both ceftazidime (10%) and avibactam (5-8%) have low protein binding • Volumes of distribution of ceftazidime and avibactam are 17 L and 22.2 L • Both ceftazidime and avibactam are excreted mainly by the kidneys • Dose adjustments needed in CrCl < 50 mL/min

Shampa D, et al. Pharmacol Res Perspect. 2015 Oct; 3(5): e00172 Avycaz® [Package insert] GlaxoSmithKline. Verona, 37135 Italy.2015 CEFTAZIDIME/AVIBACTAM

Activity against Enterobacteriaceae

Falcone M, et al. J Antimicrob Chemother. 2016 Oct;71(10):2713-22 CEFTAZIDIME/AVIBACTAM

Activity against P. aeruginosa

Activity against A. baumannii

Falcone M, et al. J Antimicrob Chemother. 2016 Oct;71(10):2713-22 CEFTAZIDIME/AVIBACTAM

• Complicated urinary tract infections • Phase II study conducted in 135 hospitalized patients with cUTI (pyelonephritis or cUTI) for 7 to 14 days • Randomized 1:1 • Ceftazidime/avibactam 500 mg/125 mg every 8 h • Imipenem/cilastatin 500 mg/500 mg every 6 h • Option to switch to oral ciprofloxacin after completion of at least 4 days of IV therapy • Favorable microbiological response achieved in 70.4% of patients receiving ceftazidime/avibactam and 71.4% receiving imipenem/cilastatin [observed difference 21.1% (95% CI: 227.2% to 25.0%)]. • Among patients with ceftazidime-resistant uropathogens, a response was observed in 6/7 (85.7%) receiving ceftazidime/avibactam

• Complicated intra-abdominal infections • Ceftazidime/avibactam plus metronidazole compared to meropenem in hospitalized patients with cIAI for 5 to 14 days • Randomized 1:1 • Cceftazidime/avibactam 2000 mg/500 mg plus metronidazole 500 mg q8h • Meropenem 1000 mg plus placebo q8h • All E. coli isolates were susceptible to both ceftazidime/ avibactam and meropenem • Favorable clinical response achieved in 91.2% and 93.4% of ceftazidime/avibactam plus metronidazole and meropenem patients [observed difference of – 2.2% (95% CI: 220.4% to 12.2%)]

Hidalgo JA, et al. Drug Des Devel Ther. 2016 Jul 26;10:2379-86 Falcone M, et al. J Antimicrob Chemother. 2016 Oct;71(10):2713-22 CEFTAZIDIME/AVIBACTAM

Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for CRE

• Retrospective study of patients with CRE infection Pittsburgh Medical Center from April 2015 to Feb 2016 • Ceftazidime-avibactam 2.5 g IV every 8 hours

• 37 consecutive patients treated for ≥ 3 days • Median age of 64 years (range, 26–78) and 57% (21/37) men • 30% (11/37) were transplant recipients (9 solid organ and 2 bone marrow) • Infections included • Pneumonia ((n = 12) with 50% ventilator-associated and 50% healthcare-associated) • Bacteremia (n = 10) • Intra-abdominal infection (n = 4) • Skin/soft tissue infection (n = 4) • Pyelonephritis ((n = 4) 50% bacteremic)) • Mediastinitis, subdural empyema/ventriculitis, and purulent tracheobronchitis (1 each) • Most common pathogens: • Carbapenem-resistant K. pneumoniae (CR-Kp) (84%, 31/ 37) • Carbapenem-resistant E. coli (8%, 3/37) • Carbapenem-resistant E. cloacae (5%, 2/37) • Carbapenem-resistant E. aerogenes (3%, 1/37)

Shields RK, et al. Clin Infect Dis. 2016 Sep 13 [Epub ahead of print] CEFTAZIDIME/AVIBACTAM

• Ceftazidime-avibactam was administered as monotherapy in 70% of patients • Combination agents started concomitantly and administered for 72 hours or longer • Combinations included gentamicin IV or inhaled, colistin IV or intrathecal, and tigecycline

• Median treatment duration was 14 days (range, 4–71)

• Survival • 30-day survival rate was 76% (28/37) • 90-day survival rate was 62% (23/37)

• Clinical success achieved in 59% (22/37) • No difference between patients receiving monotherapy (58% [15/26]) or combination therapy (64% [7/11]) • Failures were due to death (n = 9), recurrence (n = 4), or the absence of clinical improvement (n = 2) • Recurrent CRE infections occurred in 23% of patients with 30-day clinical success • Median time to recurrence was 74 days (range, 34–84)

• 10% (3/31) of patients developed acute kidney injury within 7 days of treatment initiation

Shields RK, et al. Clin Infect Dis. 2016 Sep 13 [Epub ahead of print] CEFTAZIDIME/AVIBACTAM

• Microbiologic failures in 27% (10/37) of patients • Failure due to recurrent infections within 30 (5) and 90 days (4)

• Resistance detected in 3/10 of microbiologic failures • Resistance developed following a median of 15 days (range, 10–19) of therapy

Shields RK, et al. Clin Infect Dis. 2016 Sep 13 [Epub ahead of print] CEFTAZIDIME/AVIBACTAM

• Phase 2 trials

• Phase 3 trial

Clinicaltrials.gov NOVEL ANTIBIOTICS

• Ceftaroline • Novel cephalosporin that binds to PBPs with high affinity for PBP 2a • Potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus • Active against Gram-negative bacteria • Inactive against ESBL-, AmpC-, MBL-, or KPC-producers

• Ceftaroline/avibactam • Potent against ESBL-producing E. Coli, AmpC-producing E. Coli, Klebsiella spp., Enterobacter spp., and Proteus spp., and KPC-producing E. coli, K. pneumoniae

• Pharmacokinetics • Half-life of ceftaroline of 2.3 to 2.8 hours and avibactam of 1.7 to 1.8 hours • Excretion by kidneys: • 47-71% of ceftaroline and 7-8% of its active metabolite (ceftarline M-1) found in urine • 76-100% of avibactam excreted in the urine

Falgas ME, et al. Expert Rev Anti Infect Ther. 2016 Aug;14(8):747-63 Testa R, et al. Int J Antimicrob Agents. 2015 Jun;45(6):641-6 CEFTAROLINE/AVIBACTAM

• Activity against Enterobacteriaceae • Avibactam made ceftaroline more active against β-lactam resistant organisms, including MDR strains • Potentiated activity against ceftaroline- resistant, KPC-producing strains • Not potent against IMP- or VIM-positive Enterobacteriaceae

• Activity against non-fermenting Gram-negative organisms • Limited activity against S. maltophilia, A. baumannii, and P. aeurginosa

• Phase 2 study completed with results pending (clinicaltrials.gov):

Falgas ME, et al. Expert Rev Anti Infect Ther. 2016 Aug;14(8):747-63 Testa R, et al. Int J Antimicrob Agents. 2015 Jun;45(6):641-6 NOVEL ANTIBIOTICS

• Aztreonam main mechanisms of resistance: • Alterations of bacterial PBPs • Decreased permeability of outer membrane • Hydrolysis by β-lactamases • Active against MBLs • Hydrolyzed by ESBL-, AmpC-, and KPC-producing organisms

• Addition of avibactam to broaden activity • MBL-positive bacteria may simultaneously express β-lactamases or carbapenemases

• A concentration-dependent relationship was observed with increasing avibactam concentrations • Aztreonam/avibactam MICs decreased to 1/512 to 1/16 of the monotherapy values • Greatest decrease in E. coli and K. pneumoniae • Pharmacokinetics • Half-life of aztreonam and avibactam are both ~2 hours • Renally eliminated, requiring dose adjustments in patients with reduced renal function

Falgas ME, et al. Expert Rev Anti Infect Ther. 2016 Aug;14(8):747-63 Sy SK, et al. J Antimicrob Chemother. 2016 Jul;71(7):1866-80 AZTREONAM/AVIBACTAM

• Metallo-β-lactamases (MBLs) can hydrolyze the vast majority of β-lactams with exception of monobactams

• However, MBL producing isolates can be resistant to aztreonam due to the presence of other β-lactamases, (Including AmpC- producers), increased expression of efflux pumps, and loss of outer membrane proteins

• 133 metallo-β-lactamase producers • 68 Enterobacteriaceae • 47 Pseudomonas spp. • 18 Acinetobacter spp.

• Inhibited 94.1% of the MBL-producing Enterobacteriaceae vs 27.9% for aztreonam alone

• Activity against MBL-producing Pseudomonas and Acinetobacter was similar to that of ATM alone

Falgas ME, et al. Expert Rev Anti Infect Ther. 2016 Aug;14(8):747-63 AZTREONAM/AVIBACTAM

• Phase 2 trial recruiting:

NOVEL ANTIBIOTICS

• Relebactam • Bicyclic diazabicyclooctane, non-β-lactam, β-lactamase inhibitor • Core is similar to avibactam with addition of piperidine ring

• Activity against wide spectrum of β-lactamases, including Ambler class A (ESBLs and KPC) and class C (AmpC) enzymes

• Addition of relebactam (REL) to imipenem (IMI) has shown significant reductions in MICs and synergistic killing for resistant strains of P. aeruginosa and K. pneumoniae • K. pneumoniae isolates that express KPCs and ESBLs • P. aeruginosa that overexpress AmpC and lack the OrpD porin

• Pharmacokinetics • Relebactam’s distribution into epithelial lining fluid to imipenem (AUC of 54% and 53%) • Excreted entirely by kidneys • Half-life of avinactam (1.2 hrs) similar to imipenem (1 hr) • Adjustment in dose needed with renal dysfunction

Toussaint KA, et al. Ann Pharmacother. 2015 Jan;49(1):86-98 Falgas ME, et al. Expert Rev Anti Infect Ther. 2016 Aug;14(8):747-63 IMIPENEM-CILASTATIN/RELEBACTAM

• Nov. 2013 to Jan. 2014 patient isolates of E. coli, K. pneumoniae, Enterobacter spp., P. aeruginosa, and A. baumannii collected from 11 hospitals in NY

• Relebactam restored imipenem susceptibility to 97% of K. pneumoniae isolates with blaKPC

• Addition of relebactam resulted in ~4-fold decreases in imipenem MIC50 and MIC90 against P. aeruginosa, and imipenem susceptibility rates increased from 70% to 98%

• Addition of relebactam did NOT improve the activity of imipenem against A. baumannii • MICs were unchanged for isolates with overexpression of ampC and/or blaOXA-51

• Diminished inhibitor activity against K. pneumoniae with OXA-48 and absent activity against pathogens harboring metallo β-lactamases

Toussaint KA, et al. Ann Pharmacother. 2015 Jan;49(1):86-98 IMIPENEM-CILASTATIN/RELEBACTAM

• Multicenter, double-blind, controlled phase 2 dose-ranging study

• Complicated intra-abdominal infection

• Randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo • Each given with imipenem-cilastatin 500 mg q6h for 4 to 14 days

• 255 patients included in primary efficacy endpoint (proportion of microbiologically evaluable population with a favorable clinical response at discontinuation of IV therapy) • Both doses were well tolerated with safety profiles similar to IMI alone • Most common adverse events were nausea, vomiting, and diarrhea • Most common diagnoses: complicated appendicitis (53%) and cholecystitis (17%) • 36 patients (13%) had imipenem-resistant Gram-negative infections • Clinical response rates were similar and non-inferior to imipenem alone • 250 mg REL plus IMI (96.3%) • 125 mg REL plus IMI (98.8%) • IMI alone (95.2%; one-sided P < 0.001)

Toussaint KA, et al. Ann Pharmacother. 2015 Jan;49(1):86-98 IMIPENEM-CILASTATIN/RELEBACTAM

• Phase 3 studies actively recruiting at this time:

Clinicaltrials.gov NOVEL ANTIBIOTICS

Drug FDA? MDR Organisms Ceftolozane/tazobactam YES AmpC, ESBL, and MDR P. aeruginosa, but not active against carbapenemases Ceftazidime/avibactam YES AmpC, ESBL, and KPC producers, and some OXA-48, but not active against MBLs (NDM, VIM, IMP, VEB, PER), or Acinetobacter OXA-type carbapenemases Ceftaroline/avibactam NO AmpC, ESBL, and some KPC-producing Enterobacteriaceae but not against MDR P. aeruginosa and A. baumannii Aztreonam/avibactam NO P. aeruginosa, KPC and AmpC-producing Enterobacteriaceae, but not against MBLs and A. baumannii Imipenem/relebactam NO AmpC, ESBL, KPC-producers but not against OXA-48 K. pneumoniae, MBLs, and AmpC and OXA-51 A. baumannii Meropenem/vaborbactam Eravacycline Finafloxacin Cefiderocol BAL30072 MEROPENEM/VABORBACTAM

• Vaborbactam • Cyclic boronic acid β-lactamase inhibitor of Ambler class A (ESBL and KPC) and class C β-lactamases (AmpC) • Designed and synthesized to be potent inhibitor of carbapenemases (KPC) • Formation of a covalent bond between boron moiety and serine side chain of the β–lactamase

• Pharmacokinetics • Vaborbactam’s distribution into epithelial lining fluid (79% and 65%) and intrapulmonary concentrations similar to meropenem (53% and 63%) • Half-life about 2 hours • Excreted entirely by kidneys • 80% to 90% recovered in urine as unchanged drug following single or multiple doses • Adjustment in dose necessary in patients with renal dysfunction

Thaden JT, et al. Virulence. 2016 Jul 6:1-14 Castanheira M, et al. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5454-8 Griffith DC, et al. Antimicrob Agents Chemother. 2016 Sep 23;60(10):6326-32 Falgas ME, et al. Expert Rev Anti Infect Ther. 2016 Aug;14(8):747-63 MEROPENEM/VABORBACTAM

• Meropenem (MRP) tested with vaborbactam (VBM)at concentrations from 0.5 to 32 g/ml

• 68 - 97% inhibited at 1 mg/L of MRP with 0.5 to 32 g/ml of VBM

• 78 - 98% inhibited at 8 mg/L of MRP combined with 0.5 to 32 mg/L of VBM

• Activity of MRP at least 64-fold greater when combined with fixed concentration of VBM of 8 mg/L

Thaden JT, et al. Virulence. 2016 Jul 6:1-14 Castanheira M, et al. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5454-8 MEROPENEM/VABORBACTAM

• Activity of MRP/VBM with fixed concentration of 8 g/ml against KPC (n=208) • 93.3% inhibited at 1 mg/L and 96.6% inhibited at 4 and 8 mg/L • Against KPC-producing K. pneumoniae, MRP/VBM at least 64-fold more active than meropenem alone

• Clinical isolates of E. coli, Enterobacter spp., K. pneumoniae, A. baumannii, and P. aeruginosa from hospitals in NY from Nov. 2013 to Jan. 2014 • Enhanced activity limited to isolates where KPC production was main mechanism of resistance • VBM did not enhance effect of MRP against most A. baumannii and P. aeruginosa • Differing mechanisms resistance (Class D β-lactamases, loss or alteration of porins channels, and increased activity of efflux systems) may explain lack of effect in A. baumannii • Decreased permeability and increased efflux (primary mechanisms of carbapenem resistance among P. aeruginosa) • Other approaches will be necessary to address the problem of MDR A. baumannii and P. aeruginosa Thaden JT, et al. Virulence. 2016 Jul 6:1-14 Castanheira M, et al. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5454-8 Lapuebla A, et al. Antimicrob Agents Chemother. 2015 Aug;59(8):4856-60 MEROPENEM/VABORBACTAM

• Phase 3 studies pending:

Thaden JT, et al. Virulence. 2016 Jul 6:1-14 Castanheira M, et al. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5454-8 NOVEL ANTIBIOTICS

Drug FDA? MDR Organisms Ceftolozane/tazobactam YES AmpC, ESBL, and MDR P. aeruginosa, but not active against carbapenemases Ceftazidime/avibactam YES AmpC, ESBL, and KPC producers, and some OXA-48, but not active against MBLs (NDM, VIM, IMP, VEB, PER), or Acinetobacter OXA-type carbapenemases Ceftaroline/avibactam NO ESBL, AmpC, and some KPC-producing Enterobacteriaceae but not against MDR P. aeruginosa and A. baumannii Aztreonam/avibactam NO P. aeruginosa, KPC and AmpC-producing Enterobacteriaceae, but not against MBLs and A. baumannii Imipenem/relebactam NO KPC-producing K. pneumoniae but not against meropenem-resistant P. aeruginosa and A. baumannii Meropenem/vaborbactam NO AmpC, ESBL, and KPC producing Enterobacteriaceae but not for most A. baumannii and P. aeruginosa Eravacycline Finafloxacin Cefiderocol BAL30072 ERAVRACYCLINE

• Fluorocycline antibiotic

• Similar to tetracyclines, potent inhibitor of the bacterial ribosome

• Modifications at both the C-7 (fluorine) and C-9 [2-(pyrrolidin-1-yl) ethanamido] positions on the tetracyclic core that were made possible by using a totally synthetic route • Minimally affected by tetracycline-specific efflux and ribosome protection and inactivation, potentially a prospective agent for treatment of infections by MDR organisms

• In vitro microbiological studies demonstrated broad-spectrum Gram-positive and Gram-negative antibacterial activity • Enterobacteriaceae isolates expressing resistance genes from multiple classes of ESBLs and carbapenem-resistant mechanisms • Carbapenem and multidrug-resistant Acinetobacter baumannii • Methicillin resistant Staphylococcus aureus (MRSA) • Vancomycin-resistant Enterococcus (VRE)

Sutcliffe JA, et al. Antimicrob Agents Chemother. 2013 Nov;57(11):5548-58 Thaden JT, et al. Virulence. 2016 Jul 6:1-14 ERAVRACYCLINE

• In vitro activity evaluated against 2,644 Gram-negative aerobic isolates

• MIC50 of 0.25 mg/L and MIC90 of 0.5 mg/L against E. coli with I/R phenotypes for third-generation cephalosporins • Equally potent against the fluoroquinolone-resistant (n=143), aminoglycoside-resistant (n=79), and MDR(n=40) isolates

• MIC50/90 for 157 tetracycline-resistant E. coli isolates was also 0.25/0.5 mg/L • P. aeruginosa (n=145) and Burkholderia cepacia (n =10) isolates were relatively less susceptible (MIC50/90 = 8/32 mg/L)

Sutcliffe JA, et al. Antimicrob Agents Chemother. 2013 Nov;57(11):5548-58 Thaden JT, et al. Virulence. 2016 Jul 6:1-14 ERAVRACYCLINE

• Phase 2, randomized, double-blind study evaluated efficacy and safety of eravacycline compared with ertapenem in adult hospitalized patients with cIAIs • Primary efficacy endpoint of clinical response in the ME population at the test-of-cure visit (10-14 days after the last dose of study drug) • Eravacycline 1.5 mg/kg q24h = 92.9% (39/42) • Eravacycline 1 mg/kg q12h = 100% (41/41) • Ertapenem 1000 mg q24h = 92.3% (24/26)

• Phase 3, double-blind trial evaluated efficacy and safety of eravacycline compared with ertapenem in patients with cIAIs • Clinical cure in the microbiological intent-to-treat population • Eravacycline (86.8%, 191/220) compared to Ertapenem (87.6%, 198/ 226)

• Phase 3 trial of eravacycline as an IV to oral transition therapy compared to levofloxacin for the treatment of cUTIs • Inferior to levofloxacin at the post-treatment visit (60.4% vs. 66.9%; difference, –6.5% [95% CI, –14.1 to 1.2]) • Achieved several secondary outcomes including efficacy against levofloxacin-resistant pathogens and composite response rate at the end of antibiotic treatment • Data remain unpublished

• Further studies neededed to establish the role of eravacycline in treating CRE • May have advantages over tigecycline due to its improved in vitro activity against CRE isolates, higher serum levels, and better tolerability, though further investigation is needed

Sutcliffe JA, et al. Antimicrob Agents Chemother. 2013 Nov;57(11):5548-58 Thaden JT, et al. Virulence. 2016 Jul 6:1-14 NOVEL ANTIBIOTICS

Drug FDA? MDR Organisms Ceftolozane/tazobactam YES AmpC, ESBL, and MDR P. aeruginosa, but not active against carbapenemases Ceftazidime/avibactam YES AmpC, ESBL, and KPC producers, and some OXA-48, but not active against MBLs (NDM, VIM, IMP, VEB, PER), or Acinetobacter OXA-type carbapenemases Ceftaroline/avibactam NO ESBL, AmpC, and some KPC-producing Enterobacteriaceae but not against MDR P. aeruginosa and A. baumannii Aztreonam/avibactam NO P. aeruginosa, KPC and AmpC-producing Enterobacteriaceae, but not against MBLs and A. baumannii Imipenem/relebactam NO KPC-producing K. pneumoniae but not against meropenem-resistant P. aeruginosa and A. baumannii Meropenem/vaborbactam NO AmpC, ESBL, and KPC producing Enterobacteriaceae but not for most A. baumannii and P. aeruginosa Eravacycline NO ESBL, and KPC producing A. baumannii but not P. aeruginosa Finafloxacin Cefiderocol BAL30072 FINAFLOXACIN

• 8-cyano-fluoroquinolone

• Broad-spectrum activity covering Enterobacteriaceae, Gram-positive, anaerobic, and atypical pathogens

• Unique pH activation profile where antibacterial activity is enhanced in acidic environments (pH 5.0 to 6.5) • Infection sites such as urine, abscesses, wounds, chronically infected tissues, and stomach mucosa

• MICs compared with other fluoroquinolones at pH 5.8 were 2 to 256-fold lower

• FDA approved as 0.3% otic suspension

Patel H, et al. Antimicrob Agents Chemother. 2011 Sep; 55(9): 4386–4393 Pucci MJ, et al. Clin Microbiol Rev. 2013 Oct;26(4):792-821 Higgins PG, et al. Antimicrob Agents Chemother. 2010 Apr;54(4):1613-5 FINAFLOXACIN

• Finafloxacin vs. ciprofloxacin against cipro-sensitive and resistant A. baumannii • At normal pH, finafloxacin and ciprofloxacin either had the same MIC or were within one dilution

• At lower pH, finafloxacin MIC50 and MIC90 both lowered from 16 to 2 mg/L, compared to ciprofloxacin MIC50 and MIC90 rising from 8 to 32 mg/L and from 16 to 128 mg/L • Finafloxacin demonstrated similar activity at pH 7.2, and superior activity under acidic conditions • Promising new agent for the treatment of A. baumannii infections at acidic body compartments

• Preliminary results of phase II trial in patients with cUTIs (70 % with pyelonephritis) • Finafloxacin 800 mg daily (IV and oral) for 5 or 10 days vs ciprofloxacin 400 mg BID for 10 days • Higher, more rapid and more sustained levels of microbiological eradication, as well as improved clinical outcomes in finafloxacin group • At test of cure evaluation, composite response (both microbiological eradication and elimination of clinical symptoms) was achieved in 70% and 68% in groups receiving finafloxacin for 5 or 10 days, compared to 57 % of patients on ciprofloxacin

• Two randomized, double-blind phase II trials of finafloxacin in patients with UTIs are complete but full results are pending • Preliminary results from the trial evaluating cUTI are available • No results are available regarding the trial in patients with uncomplicated UTI, in which oral finafloxacin 300 mg will be compared with oral ciprofloxacin 250 mg, both administered twice daily for 3 days

Higgins PG, et al. Antimicrob Agents Chemother. 2010 Apr;54(4):1613-5 McKeage K. Drugs 2015. 75:687-93 NOVEL ANTIBIOTICS

Drug FDA? MDR Organisms Ceftolozane/tazobactam YES AmpC, ESBL, and MDR P. aeruginosa, but not active against carbapenemases Ceftazidime/avibactam YES AmpC, ESBL, and KPC producers, and some OXA-48, but not active against MBLs (NDM, VIM, IMP, VEB, PER), or Acinetobacter OXA-type carbapenemases Ceftaroline/avibactam NO ESBL, AmpC, and some KPC-producing Enterobacteriaceae but not against MDR P. aeruginosa and A. baumannii Aztreonam/avibactam NO P. aeruginosa, KPC and AmpC-producing Enterobacteriaceae, but not against MBLs and A. baumannii Imipenem/relebactam NO KPC-producing K. pneumoniae but not against meropenem-resistant P. aeruginosa and A. baumannii Meropenem/vaborbactam NO AmpC, ESBL, and KPC producing Enterobacteriaceae but not for most A. baumannii and P. aeruginosa Eravacycline NO ESBL, and KPC producing A. baumannii but not P. aeruginosa Finafloxacin NO Ciprofloxacin-resistant A. baumannii in acidic environments Cefiderocol BAL30072 SIDEROPHORE ANTIBIOTICS

• Antibiotic resistance is partly due to hindered diffusion through the membrane of microbial cells and active transport mechanisms • Approach to counter such resistance uses the bacterial iron transport system • Extracellular free iron is scarce in vertebrates, yet essential for microbial growth • Mechanism displayed by bacteria to cope with iron scarcity involves the production of siderophores • Low molecular weight molecules bear affinity to iron that exceeds by several orders of magnitude that of transferrin • Under iron starvation, siderophores are excreted, scavenge ferric ions and the complex is shuttled inside the cell • The Trojan horse approach (THA) relies on the iron-siderophore uptake system to deliver an antibiotic • Aiming to improve antibiotic uptake by pathogenic bacteria, efforts have been made in the design of siderophore- antibiotic conjugates

de Carvalho CC, et al. Front Microbiol. 2014 Jun 12;5:290 CEFIDEROCOL

• Siderophore cephalosporin

• Molecule that has greater outer membrane penetration coupled with intrinsic β-lactamase stability

• Enhance bacterial cell penetration by virtue of carrying ferric ions into the cell by iron transporters

• Catechol side chain enables ferric iron ion binding, resulting in a complex actively transported via ferric iron transporter systems

• Accelerated influx enhances its activity against Gram-negative bacteria, including strains producing b-lactamases and MDR strains

Ito A, et al. J Antimicrob Chemother. 2016 Mar;71(3):670-7 Ito-Horiyama T, et al. Antimicrob Agents Chemother. 2016 Jun 20;60(7):4384-6 CEFIDEROCOL

• Two types of global clinical isolate collections • A. baumannii, P. aeruginosa and S. maltophilia • Collected by 2 internationally recognized microbiology facilities

• Randomly collected clinical isolates from 2009- 2011 • 104 isolates of A. baumannii • 104 isolates of P. aeruginosa • 108 isolates of S. maltophilia

Ito A, et al. J Antimicrob Chemother. 2016 Mar;71(3):670-7 CEFIDEROCOL

• β-lactam-resistant strains from 2000-2009 • 99 strains of A. baumannii • 103 strains of P. aeruginosa

• MBL-producing carbapenemase strains of P. aeruginosa including GIM-1, IMP, SPM-1 and VIM • MIC50 and MIC90 of 0.5 and 4 mg/L

• Carbapenem-resistant strains of A. baumannii possessed carbapenemases such as IMP-1, OXA-23, OXA-24, OXA-51/ISAba1 or OXA-58 • MIC50 and MIC90 of Cefiderocol were 0.5 and 8 mg/L

Ito A, et al. J Antimicrob Chemother. 2016 Mar;71(3):670-7 NOVEL ANTIBIOTICS

Drug FDA? MDR Organisms Ceftolozane/tazobactam YES AmpC, ESBL, and MDR P. aeruginosa, but not active against carbapenemases Ceftazidime/avibactam YES AmpC, ESBL, and KPC producers, and some OXA-48, but not active against MBLs (NDM, VIM, IMP, VEB, PER), or Acinetobacter OXA- type carbapenemases Ceftaroline/avibactam NO ESBL, AmpC, and some KPC-producing Enterobacteriaceae but not against MDR P. aeruginosa and A. baumannii Aztreonam/avibactam NO P. aeruginosa, KPC and AmpC-producing Enterobacteriaceae, but not against MBLs and A. baumannii Imipenem/relebactam NO KPC-producing K. pneumoniae but not against meropenem- resistant P. aeruginosa and A. baumannii Meropenem/vaborbactam NO AmpC, ESBL, and KPC producing Enterobacteriaceae but not for most A. baumannii and P. aeruginosa Eravacycline NO ESBL, and KPC producing A. baumannii but not P. aeruginosa

Finafloxacin NO Ciprofloxacin-resistant A. baumannii in acidic environments

Cefiderocol NO ESBL, MBL-producing P. aeruginosa, MDR A. baumannii, including carbapenem-resistant strains possessing IMP-1, OXA-23, OXA-24, OXA-51/ISAba1 and OXA-58 enzymes BAL30072 BAL30072

• Siderophore monosulfactam

• Contains dihydropyridone iron-chelating group which facilitates uptake by allowing additional uptake routes to be exploited

• Enhanced activity against Gram-negative bacteria with Ambler classes A, B, C and D β-lactamases

• More active than other β-lactams against carbapenem-resistant Acinetobacter baumannii and other Gram-negative bacilli with a variety of β-lactamases and carbapenemases

• Enhanced activity against MDR isolates when combined with meropenem

Page MG, et al. Antimicrob Agents Chemother. 2010 Jun;54(6):2291-302 BAL30072

• In vitro activity evaluated against clinical isolates from NYC hospitals (including β-lactam resistant P. aeruginosa, A. baumannii and K. pneumoniae)

• More active than other β-lactams against P. aeruginosa, A. baumannii and KPC K. pneumoniae

• Reduced susceptibility to BAL30072 was often related to the presence of SHV ESBLs • Among isolates lacking ESBLs, activity of BAL30072 was inversely related with expression of efflux pumps

• Enhanced activity of BAL30072 when combined with several other agents • BAL30072 plus meropenem resulted in ≥ 4-fold decrease in MIC for A. baumannii and K. pneumoniae (including KPC-possessing strains) • For isolates with BAL30072 MICs > 4 g/mL, addition of a sub-inhibitory concentration of colistin resulted in a ≥ 4- fold decrease in the MIC of BAL30072 in 44%, 82% and 23% of P. aeruginosa, A. baumannii and K. pneumoniae, respectively • BAL30072 combined with colistin was bactericidal against 20/23 isolates versus only 13/23 for colistin alone

• Additional in vivo studies are needed to determine the clinical utility of BAL30072, better understand the optimal susceptibility testing method, and to clarify the potential benefit of combining BAL30072 with other antibiotic agents

Landman D, et al. Int J Antimicrob Agents. 2014 Jun;43(6):527-32 NOVEL ANTIBIOTICS Drug FDA? MDR Organisms Ceftolozane/tazobactam YES AmpC, ESBL, and MDR P. aeruginosa, but not active against carbapenemases Ceftazidime/avibactam YES AmpC, ESBL, and KPC producers, and some OXA-48, but not active against MBLs (NDM, VIM, IMP, VEB, PER), or Acinetobacter OXA- type carbapenemases Ceftaroline/avibactam NO ESBL, AmpC, and some KPC-producing Enterobacteriaceae but not against MDR P. aeruginosa and A. baumannii Aztreonam/avibactam NO P. aeruginosa, KPC and AmpC-producing Enterobacteriaceae, but not against MBLs and A. baumannii Imipenem/relebactam NO KPC-producing K. pneumoniae but not against meropenem- resistant P. aeruginosa and A. baumannii Meropenem/vaborbactam NO AmpC, ESBL, and KPC producing Enterobacteriaceae but not for most A. baumannii and P. aeruginosa Eravacycline NO ESBL, and KPC producing A. baumannii but not P. aeruginosa

Finafloxacin NO Ciprofloxacin-resistant A. baumannii in acidic environments

Cefiderocol NO ESBL, MBL-producing P. aeruginosa, MDR A. baumannii, including carbapenem-resistant strains possessing IMP-1, OXA-23, OXA-24, OXA-51/ISAba1 and OXA-58 enzymes BAL30072 NO ESBL, AmpC, KPC, and MBL-positive Enterobacteriaceae but reduced susceptibility correlated with mexA/mexX expression (P. aeruginosa), adeB expression (A. baumannii) and SHV-type ESBLs (A. baumannii and K. pneumoniae) SUMMARY

• Global increase of Gram-negative infections, with 2 million people/year developing resistant infections leading to > 23,000 deaths

• Several new drugs being developed for MDR Gram-negative infections, but only 2 approved at this time • Ceftazidime-avibactam and Ceftolozane-tazobactam

• Most of the data available for these agents is in vitro MIC testing, but clinical data for these drugs in MDR Gram- negative infections is lacking

• However, understanding their in vitro activity allows for identification of potential roles in therapy • Most new agents help with KPC and AmpC/ESBL producers but very few will be useful against MBL producers NOVEL TREATMENT OPTIONS FOR MULTI-DRUG RESISTANT GRAM-NEGATIVE INFECTIONS

KARRINE BRADE, PHARMD, BCPS INFECTIOUS DISEASES CLINICAL SPECIALIST LEAD BOSTON MEDICAL CENTER