New Antibiotics · drug therapy utilizing newer agents to treat MRSA - linezolid, daptomycin, or...
Transcript of New Antibiotics · drug therapy utilizing newer agents to treat MRSA - linezolid, daptomycin, or...
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New Antibiotics
Will Roland, MD
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FDA Approvals
• 2010 - ceftaroline
• 2011 - 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
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Ceftaroline(Teflaro)
• ABSSSIs and CABP
• 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
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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
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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
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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 combination-drug therapy utilizing newer agents to treat MRSA - linezolid, daptomycin, or tigecycline
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Fidaxomicin(Dificid)
• Nonabsorbed macrocyclic compound
• 1st 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
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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
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Louie , T. J., et al. (2011). "Fidaxomicin versus Vancomycin for Clostridium difficile Infection." New England Journal of Medicine 364(5): 422-431.
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FidaxomicinVA Restrictions
• One of the following:
• Pts w/ severe CDI w/ 2nd recurrence (previously received appropriate therapy i.e., vanc 125mg po QID for initial and 1st recurrence)– Alternatively option to prescribe vanc taper for 2nd
recurrence
• OR
• Pts w/ mild-moderate CDI with 3rd recurrence (who previously received appropriate therapy, i.e., metronidazole 500mg po TID for initial and 1st
recurrence and then vanc taper for 2nd recurrence)
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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
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Oritavancin
• 2 clinical trials demonstrated noninferioritycompared 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
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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
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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 - 30-60% of isolates of S. aureus– β-lactam after a short inpatient course of vancomycin,
telavancin, daptomycin may be a more acceptable cost-effective strategy
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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
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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
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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
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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
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Tedizolid(Sivextro)
• 2nd commercially available oxazolidinone abx– 1st 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
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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
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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
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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
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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
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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
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TelavancinCaveats
• Pts w/CrCl ≤50 mL/min treated w/ Telavancinfor 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 hrsafter Telavancin administration
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TelavancinCaveats
• 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
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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 2016. Published by Oxford University Press for the Infectious Diseases Society of
America. All rights reserved.
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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
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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
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Ceftolozane sulfate and Tazobactamsodium (Zerbaxa)
• Novel cephalosporin, w/ activity against P. aeruginosa, w/ extended spectrum beta-lactamase 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
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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
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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 2013
– 9 NDM-producing isolates - resistant to all β-lactams, aztreonam, aminoglycosides and fluoroquinolones
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Ceftolozane sulfate and Tazobactamsodium
• 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
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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
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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
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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
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Difference in clinical cure rates at test-of-cure (TOC) visit by renal function.
John E. Mazuski et al. Clin Infect Dis. 2016;62:1380-1389
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of
America.
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van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Combinations. Clin Infect Dis. 2016;63(2):234-241
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No commercial sensitivity testing for the top 6 below
• Research use only disk
• Surrogate
• Pharma-Supported Research lab
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Peramivir2009 Emergency Use
• ~ 1274 hospitalized pts Rxed w/ IV peramivirthru 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
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PeramivirPotential 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
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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
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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
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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
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IsavuconazoleMechanism of Action
• Inhibits cytochrome P450–dependent 14α-lanosteroldemethylation– 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
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IsavuconazoleDrug-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
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IsavuconazoleSide 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
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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
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Restricting Fluoroquinolone UseFDA
• 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
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On The Verge
• Solithromycin - next-generation IV/po fluoroketolide in Phase 3 studies for Rx of moderate to moderately-severe 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
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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, Gram-
negative, atypical and anaerobic bacteria
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References
• Burdette SD, Trotman R. Tedizolid: The First Once-Daily OxazolidinoneClass Antibiotic. Clin Infect Dis. 2015 Oct 15;61(8):1315-21
• Saravolatz LD, Stein GE. Oritavancin: A Long-Half-Life Lipoglycopeptide.Clin Infect Dis. 2015 Aug 15;61(4):627-32.
• Billeter M, Zervos MJ, Chen AY, Dalovisio JR, Kurukularatne C. Dalbavancin: a novel once-weekly lipoglycopeptide antibiotic. Clin Infect Dis. 2008 Feb 15;46(4):577-83
• van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Combinations. Clin Infect Dis. 2016 Apr 20.epub
• Center for Disease Dynamics, Economics & Policy. 2015. State of the World’s Antibiotics, 2015. 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, 2010–2015FDA-Approved Antibiotics, 2010-2015." Annals of Internal Medicine Online May 31,2016.
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References
• Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2011 May;52(9):1156-63.
• Louie , T. J., et al. (2011). "Fidaxomicin versus Vancomycin for Clostridium difficile Infection." New England Journal of Medicine 364(5): 422-431.
• 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, double-blind, phase 3, non-inferiority trial. The Lancet Infectious Diseases, Volume 14 , Issue 8 , 696 – 705
• Rubinstein, E., et al. (2011). "Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens." Clin Infect Dis 52(1): 31-40.
• 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 , 760-769
• 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): 83-88.