New Antibiotics. Will Roland, MD

Transcription

1 New Antibiotics Will Roland, MD

2 FDA Approvals ceftaroline fidaxomicin, telaprevir, boceprevir, spinosad 2012 bedaquiline, raxibacumab, Stribild, 2013 sofosbuvir, simeprevir, dolutegravir 2014 peramivir, ceftolozane/tazobactam, Viekira Pak, Harvoni, oritavancin, tedizolid, dalbavancin, miltefosine, Jublia, Kerydin 2015 daclatasvir, ceftazidime-avibactam 2016 obiltoxaximab, elbasvir and grazoprevir, sofosbuvir and velpatasvir

3 ABSSSIs and CABP Ceftaroline (Teflaro) Binds to PBPs inhibiting cell wall synthesis High affinity for PBP2a - associated w/ methicillin resistance Consistently active against MDR Strep. pneumoniae and S. aureus Methicillin-resistant, vancomycin-intermediate, linezolid-resistant, daptomycin-nonsusceptible strains Variable activity against Enterobacteriaceae

4 Ceftaroline Good activity against oral anaerobes IV 600 mg every 12 h Excreted by kidneys - dose adjust in renal failure Noninferiority compared w/ vancomycin in ABSSSIs Noninferiority compared w/ ceftriaxone in CABP Safety profile similar to that of comparator drugs in clinical trials

5 Ceftaroline Well tolerated - adverse effect profile similar to other cephalosporins Can be given IM w/o causing significant pain No controlled trials in pregnancy animal studies did not find adverse effects on offspring Category B designation for use in pregnancy Not known if it is excreted in breast milk Manufacturer recommends that caution administering ceftaroline to nursing women

6 Ceftaroline Acquisition cost $80/day - favorable comparisons to other newer agents for the treatment of ABSSSI and CABP More costly than other IV cephalosporins, fluoroquinolones and vancomycin Less expensive than single-drug or combinationdrug therapy utilizing newer agents to treat MRSA - linezolid, daptomycin, or tigecycline

7 Fidaxomicin (Dificid) Nonabsorbed macrocyclic compound 1 st antimicrobial agent approved by FDA for Rx of C. difficile in last 25 years Bactericidal - mechanism of action: inhibition of a RNA polymerase 200 mg po BID not inferior to vancomycin for Rx of CDI as determined by clinical response after 10 days of Rx

8 Fidaxomicin Superior to vancomycin for sustained response w/o recurrence 25 days after Rx completion Relatively spares the indigenous fecal microbiota AEs not observed in animal reproduction studies Limited systemic absorption - exposure to fetus expected to be low Not known if it is excreted in breast milk Manufacturer recommends that caution when administering to nursing women

9 Louie, T. J., et al. (2011). "Fidaxomicin versus Vancomycin for Clostridium difficile Infection." New England Journal of Medicine 364(5):

10 Fidaxomicin VA Restrictions One of the following: Pts w/ severe CDI w/ 2 nd recurrence (previously received appropriate therapy i.e., vanc 125mg po QID for initial and 1 st recurrence) Alternatively option to prescribe vanc taper for 2 nd recurrence OR Pts w/ mild-moderate CDI with 3 rd recurrence (who previously received appropriate therapy, i.e., metronidazole 500mg po TID for initial and 1 st recurrence and then vanc taper for 2 nd recurrence)

11

12 Oritavancin (Orbactiv) Lipoglycopeptide abx with multiple mechanisms of action Inhibiting peptidoglycan cell wall synthesis Disrupting bacterial cell membrane Highly active against common gram-positive pathogens MRSA, VISA, VRSA, VRE Single IV dose of 1200 mg over 3 hours in adult patients Terminal half-life of 393 hours, repeat dosing not required for ABSSIs Very slow elimination from tissue sites No dosing adjustments required for renal, hepatic insufficiency

13 Oritavancin 2 clinical trials demonstrated noninferiority compared w/ vancomycin in the treatment of ABSSSIs AEs similar to vanc in f/u for up to 60 days Liver enzyme elevation Occurrence of osteomyelitis Pregnancy Risk Factor C - AEs not observed in animal reproduction studies Not known if it is excreted into breast milk Manufacturer recommends caution when administered to a nursing woman

14 Oritavancin Pts should be monitored for osteomyelitis and alternate Rx given in case of confirmed or suspected osteomyelitis Attractive antibiotic to consider in the outpatient area Efficacy and safety in Rx of other sites of infection yet to be established

15 Oritavancin Can reduce outpatient infusion services and home care - improve patient satisfaction Acquisition cost ($2900) may ultimately limit its use Costs in healthcare frequently limited by acquisition costs - many other associated costs are fixed or not easily reduced Occurrence of MSSA % of isolates of S. aureus β-lactam after a short inpatient course of vancomycin, telavancin, daptomycin may be a more acceptable costeffective strategy

16 Oritavancin Has not been assessed in bacteremia or bone and joint infections Resolution of reimbursement, co-pay issues along w/ cost-benefit analyses of oritavancin vs other abx used for OPAT of ABSSSIs are needed Additional clinical experience w/ response to transition therapy from other regimens needed to further assess oritavancin's role in treatment of ABSSSIs

17 Dalbavancin (Dalvance) Lipoglycopeptide w/ broad spectrum against virtually all important gram-positive pathogens Exception of vana expressing VRE Potent bactericidal agent against drug-resistant staphylococci Animal models and clinical trials - demonstrated efficacy in Rx of SSTIs Prolonged half-life of 181 h - allows for convenient once-weekly dosing

18 Dalbavancin No data to suggest clinical superiority over β - lactam abx or linezolid for infections due to susceptible organisms No sufficient data on Rx of pneumonia or bone and joint infections to draw conclusions about it s clinical usefulness for these indications Noninvolvement w/ cytochrome p450 system makes drug-drug interactions unlikely

19 Dalbavancin No serious AEs in early clinical trials Prolonged half-life - unique challenge should AEs occur Pregnancy Implications AEs have been observed in animal reproduction studies Long half-life should be considered when evaluating potential exposure to the fetus. Not known if it is excreted into breast milk Manufacturer recommends caution when administered to a nursing woman

20 Tedizolid (Sivextro) 2 nd commercially available oxazolidinone abx 1 st in class that is dosed qd Activity against wide range of gram-positive pathogens Approved to treat ABSSSIs 2 randomized controlled phase 3 trials: 6 days of tedizolid (200 mg once daily) - noninferior to 10 days of linezolid (600 mg twice daily) Differs from linezolid in incidence of GI and hematologic side fx Lacks drug interactions w/ SSRIs Conditions other than ABSSSI currently being evaluated

21 Tedizolid PO and IV tedizolid costs $235 per day. Branded IV linezolid (Zyvox) is currently $288 per day, oral $246 per day Generic intravenous linezolid relatively cheap The apparent lack of interactions with SSRIs can be a significant benefit

22 Tedizolid Pregnancy Risk Factor C AEs observed in animal reproduction studies Not known if it is excreted into breast milk Manufacturer recommends caution when administered to a nursing woman

23 Tedizolid Lack of an interaction between tedizolid and SSRIs are currently lacking clinical confirmation, as no patients in ESTABLISH-1 and -2 were on concomitant SSRIs due to the black-box warning with the comparator, linezolid Postmarketing data will need to be collected to clarify this clinical entity, as serotonin syndrome is rare and could not be studied prospectively

24 Tedizolid Linezolid does maintain certain advantages over tedizolid to date in FDA indications for: Pneumonia (nosocomial and community acquired) Complicated skin and skin structure infections (including diabetic foot infections without concomitant osteomyelitis) Uncomplicated skin and skin structure infections VRE Some physicians comfortable w/ prolonged courses of linezolid w/ close clinical monitoring Longest use of tedizolid to date is 21 days in healthy subjects

25

26 Telavancin (Vibativ) Approved (2009) for treatment of adults w/ HABP/VABP caused by susceptible isolates of S. aureus when alternative treatments are not suitable 05/09/16 FDA approval to expand the product's label to include data describing the treatment of pts w/ concurrent S. aureus bacteremia in HABP/VABP Approved for the treatment of adult pts w/ complicated skin & skin structure infections caused by susceptible isolates of Gram-positive bacteria

27 Telavancin Caveats Pts w/crcl 50 ml/min treated w/ Telavancin for HABP/VABP - increased mortality observed versus vancomycin Need to monitor renal fnx thruout therapy IV unfractionated heparin is contraindicated w/ Telavancin administration due to artificially prolonged aptt test results for up to 18 hrs after Telavancin administration

28 Telavancin Caveats Avoid in pregnancy AEs in animal developmental outcomes have been observed Women of childbearing age should have serum pregnancy test Not recommended during pregnancy unless potential benefit to mother outweighs possible risk to fetus Not known if it is excreted into breast milk Manufacturer recommends caution when administered to a nursing woman

29

30

31 Clinical decision tree to predict a bacteremic patient's likelihood of infection with an extended-spectrum β-lactamase (ESBL) producing organism at the time of organism genus and species identification. Katherine E. Goodman et al. Clin Infect Dis. 2016;cid.ciw425 The Author Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

32 Ceftolozane/tazobactam (Zerbaxa) Ceftazidime/avibactam (Avicaz) 2 novel β-lactam/β-lactamase combination abx Active against MDR gram-negatives including P. aeruginosa Ceftazidime/avibactam - active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases Avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases

33 Ceftolozane/tazobactam (Zerbaxa) Ceftazidime/avibactam (Avicaz) Both only available as IV - dosed TID in pts w/ normal renal function Clinical trials - noninferiority to comparators of both agents when used in Rx of cutis and complicated IAIs (w/ metronidazole) Results from pneumonia studies - not yet been reported Antimicrobial stewardship - essential to preserve activity

34 Ceftolozane sulfate and Tazobactam sodium (Zerbaxa) Novel cephalosporin, w/ activity against P. aeruginosa, w/ extended spectrum betalactamase inhibitor cutis caused by E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa Combo w/ metronidazole for ciai caused by E. cloacae, E. coli, K. oxytoca, K. pneumoniae, P. mirabilis, P. aeruginosa, B. fragilis, Strep anginosus, Strep constellatus, Strep salivarius

35

36

37 Metallo-β-lactamases Diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs including carbapenems Exception - monobactams Not inhibited by mechanism-based inhibitors such as clavulanate, sulbactam, or tazobactam

38 New Delhi Metallo-beta-lactamase-1 (NDM-1) 1st found in K. pneumoniae isolate from Swedish pt in India in 2008 Died despite colistin EID Volume 19, Number 6 June NDM-producing isolates - resistant to all β- lactams, aztreonam, aminoglycosides and fluoroquinolones

39

40 Ceftolozane sulfate and Tazobactam sodium Pregnancy Risk Factor B - AEs observed in some animal reproduction studies Tazobactam crosses the placenta Not known if ceftolozane or tazobactam are excreted into breast milk Manufacturer recommends caution if administered to a nursing woman

41 Ceftazidime/avibactam (Avicaz) Avibactam - novel, non β-lactam β-lactamase inhibitor that restores the in vitro activity of the established extended-spectrum antipseudomonal cephalosporin, ceftazidime, against Ambler class A, class C, and some class D β-lactamase producing pathogens

42

43 Ceftazidime/avibactam In phase 2 trials - effective and well tolerated in pts w/ ciai (in combo w/ metronidazole) and cutis Based on these data - approved by FDA for Rx of ciai (in combo w/ metronidazole) and cutis (including pyelonephritis) in adults w/ limited or no alternative Rx options

44 Ceftazidime/avibactam Pregnancy Implications AEs not been observed in animal reproduction studies conducted with ceftazidime AEs observed in some animal reproduction studies conducted with avibactam. Ceftazidime is excreted in breast milk Not known if avibactam is excreted in breast milk Manufacturer recommends caution when administering ceftazidime and avibactam to breast-feeding women

45

46 Difference in clinical cure rates at test-of-cure (TOC) visit by renal function. John E. Mazuski et al. Clin Infect Dis. 2016;62: The Author Published by Oxford University Press for the Infectious Diseases Society of America.

47

48 van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-lactam/β-lactamase Combinations. Clin Infect Dis. 2016;63(2):

49 No commercial sensitivity testing for the top 6 below Research use only disk Surrogate Pharma-Supported Research lab

50

51

52 Peramivir 2009 Emergency Use ~ 1274 hospitalized pts Rxed w/ IV peramivir thru the EUA program during the pandemic Mostly critically ill, white adults w/ underlying medical conditions who had been treated initially w/ oral oseltamivir and subsequently treated late in the clinical course with peramivir for ~ 1 wk Hard to interpret results

53 Peramivir Potential Indications N/V/D, or other GI sensitivity Requiring IV for rehydration or other meds Pts preferring a single-dose Rx administered by a healthcare provider Pts who otherwise cannot be prescribed oral or inhaled, multi-dose therapies

54 Peramivir Pregnancy Risk Factor C AEs observed in some animal reproduction studies Information related to the use of peramivir in pregnancy is limited Based on information from one case, the pharmacokinetics of peramivir may be changed with pregnancy

55 Peramivir Untreated influenza - associated with increased risk of AEs to the fetus and increased risk of complications or death to the mother Neuraminidase inhibitors are currently recommended for the treatment or prophylaxis of influenza in pregnant women and women up to 2 weeks postpartum Not known if peramivir is excreted into breast milk Manufacturer - decision to breast-feed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother

56 Isavuconazole (Cresemba) Extended spectrum triazole with activity against yeasts, molds, dimorphic fungi Approved for treatment of invasive aspergillosis and mucormycosis Advantages Availability of a water-soluble IV formulation Excellent bioavailability of the oral formulation Predictable pharmacokinetics in adults

57 Isavuconazole Mechanism of Action Inhibits cytochrome P450 dependent 14α-lanosterol demethylation Essential for fungal cell membrane ergosterol synthesis This blockade produces methylated sterols in the fungal membrane - accumulation of ergosterol toxic precursors in the cytoplasm, which leads to cell death Side arm of the active isavuconazole molecule allows greater avidity for the binding pocket in the fungal CYP51 protein, conferring broader antifungal spectrum even to pathogens resistant to other azoles

58 Isavuconazole Drug-Drug Interactions Substrate for CYP3A4 - inhibitors of this enzyme lead to increased levels of isavuconazole Rifampin, carbamazepine, long-acting barbituates Should not be used with this antifungal Moderate inhibitor of CYP3A4 Higher levels of sirolimus, tacrolimus, cyclosporine Serum levels need to be monitored Minimal effect on CYP2C9 and CYP2C19, No dosage adjustment of warfarin and omeprazole Overall compared with voriconazole and posaconazole Isavuconazole seems to have fewer drug-drug interactions

59 Isavuconazole Side Effects Relatively safe and well tolerated Most common N/V/D, rarely have led to discontinuation <15% - HA, rash, peripheral edema No voriconazole side effects - visual disturbances, hallucinations, photosensitivity

60 Isavuconazole Liver enzymes should be monitored Infusion reactions in a few pts - acute respiratory distress, chills, dyspnea, hypotension Recommend in-line filter be used for infusion Pregnancy Risk Factor C AEs observed in animal reproduction studies Not known if it is excreted into breast milk Breast-feeding not recommended by manufacturer

61 Restricting Fluoroquinolone Use FDA Serious side f/x ass. w/ fluoroquinolones generally outweigh benefits for pts w/ acute sinusitis, acute bronchitis, uncomplicated UTIs who have other Rx options Tendons, muscles, joints, nerves, CNS Fluoroquinolones should be reserved for those who do not have alternative Rx options

62

63

64

65

66 On The Verge Solithromycin - next-generation IV/po fluoroketolide in Phase 3 studies for Rx of moderate to moderatelysevere CABP and urethritis Fusidic acid bacteriostatic protein synthesis inhibitor used topically being investigated for IV/oral use Delafloxacin fluoroquinolone more active (lower MIC90) than other quinolones against MRSA In contrast to other fluoroquinolones, which are zwitterionic, delafloxacin has an anionic character, which results in a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic ph

67 On The Verge Lefamulin pleuromutilin in Phase 2 studies Inhibits bacterial growth by binding to specific site on the bacterial ribosome Brilacidin - novel defensin mimetic in Phase 2 studies Omadacycline aminomethylcycline derived from tetracyclines in Phase 3 IV/po qd w/activity against Gram-positive, Gramnegative, atypical and anaerobic bacteria

68 References Burdette SD, Trotman R. Tedizolid: The First Once-Daily Oxazolidinone Class Antibiotic. Clin Infect Dis Oct 15;61(8): Saravolatz LD, Stein GE. Oritavancin: A Long-Half-Life Lipoglycopeptide. Clin Infect Dis Aug 15;61(4): Billeter M, Zervos MJ, Chen AY, Dalovisio JR, Kurukularatne C. Dalbavancin: a novel once-weekly lipoglycopeptide antibiotic. Clin Infect Dis Feb 15;46(4): van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-lactam/β-lactamase Combinations. Clin Infect Dis Apr 20.epub Center for Disease Dynamics, Economics & Policy State of the World s Antibiotics, CDDEP: Washington, DC. Deak, D., et al. (2016). "Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration Approved Antibiotics, FDA-Approved Antibiotics, " Annals of Internal Medicine Online May 31,2016.

69 References Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis May;52(9): Louie, T. J., et al. (2011). "Fidaxomicin versus Vancomycin for Clostridium difficile Infection." New England Journal of Medicine 364(5): Moran, Gregory J et al. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, doubleblind, phase 3, non-inferiority trial. The Lancet Infectious Diseases, Volume 14, Issue 8, Rubinstein, E., et al. (2011). "Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens." Clin Infect Dis 52(1): Maertens, Johan A et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. The Lancet, Volume 387, Issue 10020, Humphries, R. M. and J. A. Hindler (2016). "Emerging Resistance, New Antimicrobial Agents but No Tests! The Challenge of Antimicrobial Susceptibility Testing in the Current US Regulatory Landscape." Clinical Infectious Diseases 63(1):