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7/24/2018
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ANTIBIOTICS AND RESISTANCE: NEW DRUGS TO HELP COMBAT THE
PROBLEM
Anna-Kathryn Burch, M.D.
Medical Director, Pediatric Antimicrobial Stewardship
Palmetto Health Children’s Hospital
PHUSC
DISCLOSURES
• I have nothing to disclose.
CLINICAL CASE
• Patient is a 17 year old with history of interstitial nephritis, etiology unknown.
• required a cadaveric renal transplant at MUSC 7/2/14
• Patient was doing well until March 2018 when she began to experience kidney rejection
• Kidney Bx 3/9/18 for pathology to prove GVHD
• Oh by the way, she admits she quit taking her immunosuppressive drugs after the biopsy proved she was in rejection.
• Patient had large hematoma in the bladder s/p kidney biopsy.
• 3/10/18 clot removed via large bore foley
CLINICAL CASE
• In the background…Patient is receiving plasmapheresis and increased immunosuppression
• thymoglobulin, rituximab and abatacept per peds Nephrology
• 3/15-3/30/18: Urosepsis #1 with ESBL E.coli., Blood and Urine culture positive.
• Tx x 10 days with Ertapenem after clearing blood culture.
• 4/4-4/17/18: Urosepsis #2 with ESBL E.coli (stable susceptibilities), blood and urine culture positive.
• Patient had a PICU stay.
• 4/4 ECHO neg, 4/8 RUS neg, 4/9 thoracic/lumbar MRI neg.
• Tx x 14 days with Ertapenem after clearing blood culture.
CLINICAL CASE
• readmitted 4/20/18 for line placement and plasmapheresis.
• 4/22-5/21/18: Urosepsis #3 with ESBL E.coli (stable susceptibilities), blood culture
only positive as urine culture unfortunately no performed.
• 4/24 ECHO neg
• 4/26 MRI abdomen and pelvis showed subtle areas of delayed-diminished
enhancement involving mid and lower aspect of left kidney which can be seen in
the setting of pyelonephritis.
• Tx x 4 weeks of IV ertapenem after clearing blood culture.
CLINICAL CASE
• 5/29-6/18/18: Patient admitted with fever-dx with ESBL E.coli in urine and
C.diff colitis.
• Patient tx with Ertapenem and Fidaxomicin x 14 days.
• 5/31 MRI abd/pelvis was negative.
• Because ESBL E.coli and C.diff found in stool, patient underwent FMT 6/13/18.
• Repeat urine culture 6/15/18 was negative.
• 6/22/18: Stool culture and stool c.diff s/p FMT performed. Stool is c.diff and ESBL
E.coli positive.
7/24/2018
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CLINICAL CASE
• 6/24/18: Urosepsis #4 with ESBL E.coli (stable susceptibilities) in blood and
urine cultures.
• Patient has been started on Ceftazidime/Avibactam for urosepsis and oral vancomycin
for c.diff colitis as she is now symptomatic.
•WHAT DO YOU DO WITH THIS
PATIENT?????
ANTIBIOTIC RESISTANCE
ANTIMICROBIAL HISTORY
• Ancient Egyptians used honey as a wound dressing
• Contains hydrogen peroxide and the stickiness of honey provided a wound dressing
• Ancient Serbia:
• old bread was pressed on wounds to help prevent infection
• many of the molds on the bread contained early, raw forms of penicillin
• 1640:
• John Parkington wrote about mold's effectiveness as an antibiotic
• 1877:
• Louis Pasteur determined that cultures of bacillus anthracis specked with penicillium notatum could not easily sustain growth
World Health Organization Report on Infectious Diseases, 2000
ANTIMICROBIAL HISTORY
• 1927:
• German Gerhard Domagk found that an industrial dye, prontosil rubrum, had antibacterial action against staphylococci and hemolytic streptococci
• Sulfonamide was the first antimicrobial
• Received Nobel Prize
• 1928:
• British Alexander Fleming observed the antibiotic effects of penicillin
• Penicillium notatum had destroyed staphylococcus bacteria in culture
• Penicillin was finally isolated in 1939
• early 1940s large scale fermentation processes were developed for the production of penicillin
World Health Organization Report on Infectious Diseases, 2000
WHAT IS ANTIMICROBIAL RESISTANCE?
• Ability of organisms to resist the effects of an antimicrobial
• Organisms change in some way that reduces or eliminates the effectiveness of drugs,
chemicals, or other agents designed to cure or prevent infections
• The microbes have a better survival rate
• continue to multiply causing more harm
http://www.cdc.gov/drugresistance/community/anitbiotic-resistance-faqs.htm
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ANTIMICROBIAL RESISTANCE
• Selected Pressure
• Susceptible microbes are killed easily with antimicrobials leaving organisms that are resistant
• They can then pass on their resistance genes
• Replication
• Conjugation
• Plasmids carrying the genes jump from one organism to another
• “This process is a natural, unstoppable phenomenon exacerbated by the abuse, overuse and misuse of antimicrobials in the treatment of human illness and in animal husbandry, aquaculture and agriculture.”
World Health Organization Report on Infectious Diseases, 2000
ANTIMICROBIAL RESISTANCE
ANTIMICROBIAL RESISTANCE
• Abuse, Overuse and Misuse of Antimicrobials• Increase in drug-resistant organisms
• Primary cause is repeated and improper uses of antimicrobials
• Increased pressure on physicians inevitably leads to "defensive" and unnecessary prescribing as a means of forestalling potential complications
• In North America it is estimated that physicians in both Canada and the United States over-prescribe antibiotics by
50%
World Health Organization Report on Infectious Diseases, 2000
“… the microbes are educated to resist
penicillin and a host of penicillin-fast
organisms is bred out… In such cases the
thoughtless person playing with penicillin is
morally responsible for the death of the
man who finally succumbs to infection with
the penicillin-resistant organisms. I hope
this evil can be averted.”
- Sir Alexander Fleming, NY Times June 1945
ANTIMICROBIAL RESISTANCE
• Causal associations between antimicrobial use and the
emergence of antimicrobial resistance
• Changes in antimicrobial use are paralleled by changes in prevalence of resistance
Dellit TH et al. CID 2007
Fluoroquinolone Use and Resistance Rates in PSA and Gram-
Negative Bacilli
Neuhauser, M. M. et al. JAMA 2003
ANTIMICROBIAL RESISTANCE
• Causal associations between antimicrobial use and the emergence of antimicrobial resistance (cont)
• Resistance is more prevalent in health care-associated bacterial infections
• Patients with health care-associated infections caused by resistant strains are more likely than control patients to have prior antibiotic exposure
• Areas within hospitals with the highest rates of antimicrobial resistance also have the highest rates of antimicrobial use
• Increased length of exposure to antimicrobials increases the likelihood of colonization with resistant organisms
ANTIMICROBIAL RESISTANCE
• There is an association between development of antimicrobial resistance and
mortality
• Cosgrove et al CID 2003: Meta-analysis
• Patients with MRSA bacteremia had an increased risk of mortality compared to
patients with MSSA bacteremia
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ANTIMICROBIAL DEVELOPMENT VS. RESISTANCE
1st case MRSA reported 1961
FEWER DRUGS CREATED TO COMBAT ANTIBIOTIC RESISTANCE
WHAT ARE WE DOING ABOUT RESISTANCE
NEW DRUGS 2014-2017
Drug Indications Approval Date
Dalbavancin (Dalvance®) ABSSSI May 2014
Tedizolid (Sivextro®) ABSSSI June 2014
Oritavancin (Orbactiv®) ABSSSI August 2014
Ceftolozane/Tazobactam
(Zerbaxa®)
cUTI, cIAI December 2014
Ceftazidime/Avibactam
(Avycaz®)
cUTI, cIAI February 2015
Bezlotoxumab (Zinplava®) C.difficile Infection October 2016
Delafloxacin (Baxdela®) ABSSSI June 2017
Meropenem/Vaborbactam
(Vabomere®)
cUTI September 2017
Plazomicin (Zemdri®) cUTI June 2018
NEW GRAM-POSITIVE AGENTS
• Dalbavancin (Lipoglycopeptide – think long acting Vancomycin)
• Oritavancin (Lipoglycopeptide – think long acting Vancomycin)
• Tedizolid (Oxazolidinone – think Linezolid like)
• Delafloxacin (Fluoroquinolone – think ciprofloxacin like)
DALBAVANCIN (DALVANCE®)
• Lipoglycopeptide
• Mechanism of Action
• Inhibits cross-linking of peptidoglycans
• Destabilizes cell wall, causing cell death
• Concentration dependent, bactericidal
• FDA approved indications: acute bacterial skin and skin structure infections (ABSSSI)
Roberts KD, et al. Pharmacotherapy 2015;35(10):935-948
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DALBAVANCIN (DALVANCE®)
• ABSSSI recommended Adult dose:
• Single-dose regimen:
• 1500mg IV x 1 dose
• Two-dose regimen:
• 1000mg IV day 1, followed by 500mg IV day 8
• Effective half-life: 8.5 hours
• No dose adjustment necessary with hemodialysis
• No adjustment for mild liver dysfunction
• Infused over 30 minutes
• Cost around $4500/course
• No home health, No PICC line
Roberts KD, et al. Pharmacotherapy 2015;35(10):935-948
DALBAVANCIN (DALVANCE®)
• Pediatric Dosing:
• phase 1, open-label, multicenter study to investigate the pharmacokinetics (PK) and safety of a single dose of intravenous dalbavancin in hospitalized pediatric subjects 3 months to 11 years of age
• the following age-dependent dosing regimen was found to achieve similar dalbavancin exposure to that in adults administered a 2-dose regimen:
• 6 to <18 years of age, 12 mg/kg (1000 mg maximum) on day 1, 6 mg/kg (500 mg maximum) on day 8
• 3 months to <6 years of age, 15 mg/kg (1000 mg maximum) on day 1, 7.5 mg/kg (500 mg maximum) on day 8
• following age-dependent regimen was found to match adult exposure after a single-dose (1500 mg):
• 6 to <18 years of age, 18 mg/kg (1500 mg maximum) on day 1
• 3 months to <6 years of age, 22.5 mg/kg (1500 mg maximum) on day 1
Pediatr Infect Dis J. 2017 Jul;36(7):645-653.
ORITAVANCIN (ORBACTIV®)
• Lipoglycopeptide
• Multiple Mechanisms of Action
• Inhibits cross-linking of peptidoglycans
• Destabilizes cell wall, causing cell death
• Disruption of bacterial membrane integrity
• Leads to depolarization, permeabilization and cell death
• Concentration dependent, bactericidal
• Only lipoglycopeptide that can cover VRE
• FDA approved indications: ABSSSI
Roberts KD, et al. Pharmacotherapy 2015;35(10):935-948
ORITAVANCIN (ORBACTIV®)
• ABSSSI recommended adult dose:
• 1200 mg IV once
• Terminal half-life: 8-10 days
• No adjustment for renal or hepatic impairment
• Infused over 3 hours
• Cost around $2900 per dose
• No home health, No PICC line
Roberts KD, et al. Pharmacotherapy 2015;35(10):935-948
ORITAVANCIN (ORBACTIV®)
https://clinicaltrials.gov/ct2/show/NCT02134301
DALBAVANCIN/ORITAVANCIN STEWARDSHIP
• Formulary should choose only one if possible simplify for practitioners
• Possible uses:
• If patient isn’t an ideal candidate for oral antibiotics
• Key Patient groups: lack of transportation, live to far from infusion center, poor follow
up
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TEDIZOLID (SIVEXTRO®)
• Member pf oxazolidinone class (similar to Linezolid)
• Prodrug: tedizolid phosphate—converted to in vivo active form by phosphatases
• Active against VRE
• Mechanism of Action
• Inhibits protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit, preventing the formation of 70S complex
• Why its unique:
• More potent activity against MDR gram-positive pathogens allows for lower amounts of drug to be given
• Phase 3 trial compared 6 days of tedizolid vs 10 days of linezolid
• May have less risk of adverse effects:
• MAO inhibition, bone marrow effects
• FDA approved indications: ABSSSI
Kisgen JJ, et al. Am J Health Syst Pharm. 2014 Apr 15;71(8):621-33
TEDIZOLID (SIVEXTRO®)
• ABSSSI recommended adult dose:
• 200 mg IV/PO daily for 6 days
• Adolescent Dosing:
• multicenter, open-label study, a single IV infusion (N = 10) or oral dose (N = 10) of
200 mg tedizolid phosphate was administered to adolescents already receiving
antibacterial treatment for presumed or documented infection.
• Overall pharmacokinetics of tedizolid was similar after administration of a single oral
or IV 200 mg dose, and bioavailability was high.
• Exposure profiles were similar to those in adults.
Pediatr Infect Dis J. 2016 Jun;35(6):628-33
Kisgen JJ, et al. Am J Health Syst Pharm. 2014 Apr 15;71(8):621-33
TEDIZOLID STEWARDSHIP
• last-line treatment of ABSSSI when other options are not feasible
• Especially in patients who would otherwise be given PO linezolid but are restricted
due to drug interactions
• Will have a minimum role most likely
DELAFLOXACIN (BAXDELATM)
• Anionic fluoroquinolone
• Concentration-dependent bactericidal activity
• Mechanism of action
• Equally potent activity against topoisomerase IV and DNA gyrase
• More potent activity in acidic environments due to molecule having a weak acid
property
• FDA approved indications: ABSSSI
Cho JC, et al. Pharmacotherapy 2017 Oct 23
DELAFLOXACIN (BAXDELATM)
• Why its unique:
• Broad spectrum of activity against gram-negative, atypical, anaerobic and gram-positive
bacteria
• MRSA, PSA
• No QTc prolongation found in initial studies
• ABSSI recommended adult dose:
• 300 mg IV q 12 hours or 450 mg PO q 12 hours
• No pediatric clinical trials currently…
Cho JC, et al. Pharmacotherapy 2017 Oct 23
DELAFLOXACIN STEWARDSHIP
• Treatment of polymicrobial ABSSSI when all other IV or PO options are not
feasible (in adolescent populations)
• Will have a minimum role most likely
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NEW GRAM-NEGATIVE AGENTS
• Ceftolozane/Tazobactam (think cephalosporin with a friend—help against
Enterobacteriaceae ESBLs and resistant PSA)
• Ceftazidime/Avibactam (think cephalosporin with a friend—help against
Enterobacteriaceae KPCs and ESBLs)
• Meropenem-Vaborbactam (think help against Enterobacteriaceae KPCs and
ESBLs)
BETA-LACTAM RESISTANCE
Peds ASP conference June 1, 2017
CEFTOLOZANE/TAZOBACTAM (ZERBAXA®)
• Ceftolozane
• Cephalosporin with potent anti-pseudomonal activity
• Similar to ceftazidime--with a different side chain
• Destroyed by ESBLs and Carbapenemases
• Relatively stable vs Amp C
• Tazobactam
• Protects ceftolozane from many ESBLs and Cephalosporinases
• Not active against AmpC beta-lactamases or Carbapenemases
Zhanel GG et al. Drugs 2014;74:31-51.
CEFTOLOZANE/TAZOBACTAM (ZERBAXA®)
• Spectrum of Activity:
• Strong Against:
• Pseudomonas aeruginosa, including ceftazidime- and carbapenem-resistant strains
• Enterobacteriaceae, including many ESBL-producing strains
• Weak Against:
• Ceftazidime-resistant Enterobacter spp
• Carbapenemase-producing Enterobacteriaceae
• Gram-positive anything
• Gram-negative anaerobes
• Tazobactam does add anaerobic coverage, but it is weaker
Zhanel GG et al. Drugs 2014;74:31-51.
CEFTOLOZANE/TAZOBACTAM (ZERBAXA®)
• Pediatric Dosing at PHR:
• Neonatal: 18 mg/kg IV q 8 hours
• Each 18 mg/kg ceft/taz=12 mg ceftolozane/kg per dose
• General: 27 mg/kg IV q 8 hours
• Each 27 mg/kg ceft/taz=18 mg ceftolozane/kg per dose
• CF: 54 mg/kg IV q 8 hours
• Each 54 mg/kg ceft/taz=36 mg ceftolozane/kg per dose
CEFTOLOZANE/TAZOBACTAM STEWARDSHIP
• Helpful against ESBL Enterobacteriaceae and Resistant PSA
• Has not been very helpful in our CF population
• Will have a moderate/major role most likely in GNR Infections
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CEFTAZIDIME/AVIBACTAM (AVYCAZ®)
• Ceftazidime
• Third-generation antipseudomonal cephalosporin
• Susceptible to ESBL and KPC enzymes, but not porin channel changes that affect
carbapenems
• Avibactam
• Novel beta-lactamase inhibitor not based on beta-lactam structure
• Active against ESBLs, KPC-type and OXA-48 carbapenemases
• Not active against metallo-beta lactamases
CEFTAZIDIME/AVIBACTAM (AVYCAZ®)
• Spectrum of Activity:
• Strong Against:
• Many gram-negative bacilli
• PSA
• Enterobacteriaceae producing KPC and ESBL enzymes
• Weak Against:
• Gram-positive organisms
• GNRs producing metallo-beta-lactamases (NDM)
• Gram-negative anaerobes
• Avibactam does not add anaerobic coverage (unlike tazobactam)
• Doesn’t help with Acinetobacter
CEFTAZIDIME/AVIBACTAM (AVYCAZ®)
• Pediatric Dosing at PHR:
• 62.5 mg/kg IV q 8 hours
• Each 62.5 mg/kg ceftaz/avi=50 mg ceftaz/kg per dose
CEFTAZIDIME/AVIBACTAM STEWARDSHIP
• Helpful against ESBL and KPC producing Enterobacteriaceae
• Has been very helpful in our CF population
• Will have a major future role most likely in GNR Infections
MEROPENEM/VABORBACTAM (VABOMERE®)
• Meropenem
• Potent antipseudomonal carbapenem with broad spectrum
• Resistant to destruction from ESBLs, cephalosporinases
• Vaborbactam
• Boronic acid beta-lactamase inhibitor
• Active against ESBLs, KPCs but not metallo-beta-lactamases (NDM)
• Doesn’t add activity against resistant PSA
Toussaint K, Gallagher JC. Ann Pharmacother 2015;49:86-98
MEROPENEM/VABORBACTAM (VABOMERE®)
• Spectrum of Activity:
• Strong Against:
• Many gram-negative bacilli
• Carbapenem-susceptible Pseudomonas aeruginosa
• Enterobacteriaceae producing KPC and ESBL enzymes
• Weak Against:
• Carbapenem-resistant PSA
• GNRs producing metallo-beta-lactamases (NDM) or OXA-enzymes
Shaeles DM. Ann NY Acad Sci 2013;1277:105-114
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MEROPENEM/VABORBACTAM (VABOMERE®)
• Pediatric Dosing:
• In trials for PK/PD data in children
MEROPENEM/VABORBACTAM STEWARDSHIP
• Helpful against ESBL and KPC producing Enterobacteriaceae
• Hopefully will be helpful in our CF population but we have not used this at
PHR yet
PLAZOMICIN (ZEMDRITM)
• Neoglycoside
• next-generation aminoglycoside
• Mechanism of Action
• Inhibits bacterial protein synthesis
• Exhibits dose-dependent bactericidal activity
• Activity against:
• ESBL Enterobacteriaceae
• fluoroquinolone-resistant and aminoglycoside-resistant GNB
• GNB-expressing Amp C cephalosporinases, carbapenemases, and metallo-beta-lactamases (NDM)
• not Proteus species or strains with aminoglycoside-resistant methylase genes (eg, ArmA, RmtC)
• Activity against P. aeruginosa and Acinetobacter baumannii remains limited
Clinical Infectious Diseases, Volume 56, Issue 12, 15 June 2013, Pages 1685–1694
Expert Review of Anti-infective Therapy, 10:4,459-473
OTHER AGENTS IN GNR PIPELINE
Agent Class Company Notes
Imipenem/Relebactam Carbapenem-beta-
lactamase Inhibitor
Merck
Cefiderocol Siderophore
Cephalosporin
Shionogi Novel mechanism
that relies on active
iron transport
“Trojan Horse”
CEFIDEROCOL:USING IRON AS A TROJAN HORSE
NON-ANTIBIOTIC OPTIONS FOR TREATMENT OF MDR ORGANISMS
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FECAL MICROBIOTA TRANSPLANT (FMT)
• FMT has been used in adults (and children) for c.diff colitis with very good
cure rates
• Can FMT be used to help eradicate MDR GNR that colonize the GI tract???
FECAL MICROBIOTA TRANSPLANT (FMT)
• 34 year old had recurrent UTI preventing her from receiving a kidney/pancreas transplant.
• Combined fecal microbiota transfer and antibiotic treatment prevented recurrences of urinary tract infections with multidrug-resistant (MDR) Pseudomonas aeruginosa, but it failed to eradicate intestinal colonization with MDR Escherichia coli.
FECAL MICROBIOTA TRANSPLANT (FMT)
• Treated 15 patients carrying ESBL-producing Enterobacteriaceae(ESBL-EB) with FMT.
• Seven patients underwent a second FMT after 4 weeks when ESBL-EB remained
• total number of 22 transplants
• The objective was decolonization of ESBL-EB.
• Three out of 15 (20%) patients were ESBL-negative at 1, 2 and 4 weeks after the first transplant
• Six out of 15 (40%) were negative after the second transplant.
• Comparison of fecal microbiota at baseline and 4 weeks after FMT revealed restoration of microbial diversity after FMT and a microbial shift towards donor composition.
BMC Res Notes. 2018; 11: 190.
FECAL MICROBIOTA TRANSPLANT (FMT)
• Twenty-five FMTs were performed in 20 participants who were colonized by a median of 2 (range, 1–4) strains of antibiotic resistant bacteria (ARB).
• 40% had neutropenia
• The primary endpoint was reached in 15/25 (60%) of the FMTs and more frequently in cases in which there was no periprocedural use of antibiotics (79% vs 36%, P < .05).
• 15/20 (75%) participants experienced complete ARB decolonization.
• There were no severe adverse events.
• The microbiota composition analysis revealed higher abundance of Barnesiellaspp., Bacteroides, and Butyricimonas and greater bacterial richness in the fecal material, resulting in eradication of Klebsiella pneumoniae compared with nonresponders.
FECAL MICROBIOTA TRANSPLANT (FMT)
• Palmetto Health Children’s Hospital:
• N=1
• FMT 6/13/18 for ESBL E.coli colonization and C.diff infection
• 6/22/18: Stool culture and stool c.diff s/p FMT performed.
• Stool is c.diff and ESBL E.coli positive.
• Patient started on antibiotics 2 days later for urosepsis #4
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PHAGE THERAPY
• 2015, 69 year old male on vacation in Egypt developed pancreatitis (with pseudocyst) with a MDR Acinetobacter
• Treated with meropenem, tigecycline and colistin
• Airlifted home to UCSD—bacteria is now resistant to all antimicrobials
• His wife (an infectious disease epidemiologist and director of the UC San Diego Global Health Institute) searched for a way to save him.
• A colleague mentioned a friend had traveled to Tblisi, Georgia to undergo “phage therapy” for a difficult condition and had been “miraculously cured.”
• 3 Research teams in the US had phages that matched his Acinetobacter
• eIND from FDA
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY
• Phages (Bacteriophages) are viruses that solely and selectively target and kill
bacteria.
• Have been shown to effectively fight off and kill multi-drug resistant bacteria
• In theory, when all antibiotic medication fails, bacteriophages could still
succeed in killing the bacteria before the infection could kill the person.
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY HISTORY
• Frederick Twort
• 1915
• bacteriologist from England
• first to suggest that it was a virus that was responsible for previous observations of a "factor" that killed bacteria
• Felix d'Herelle
• 1917
• microbiologist at the Institut Pasteur in Paris
• picked up where Twort left off and first proposed phages as a therapy for human infections
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY HISTORY
• The first known therapeutic use of phages occurred in 1919
• d'Herelle and several hospital interns ingested a phage cocktail to check its safety
• gave it to a 12-year-old boy with severe dysentery
• symptoms cleared up after a single dose
• he fully recovered within a few days
• d'Herelle didn't publish findings until 1931
PHAGE THERAPY HISTORY
• Eli Lilly produced phages for human use in the US
• In the 1940s
• marketed to treat a range of bacterial infections
• Invention of antibiotics = Phage therapy fell out of favor in the U.S. and most of Europe
• Russia, Poland and the Republic of Georgia —
• antibiotics not as easily accessed
• phage therapy and commercial production continued
• phage studies continued to be non-randomized and uncontrolled
• data was lacking to show that phage therapy was effective
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
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PHAGE THERAPY HISTORY
• Western scientists "re-discovered" phage therapy in the 1980s.
• Growing threat of antibiotic-resistant bacterial strains has continued to further
interest in phage therapy as a potential alternative
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY
• Benefits
• Very specific about the bacteria they infect
• Damage to other bacteria or human cells is minimal
• Risk of resistance is low
• Bacteria can eventually shed the surface receptors that phages use to dock and enter the cells
• If resistance occurs, researchers can find new phages that work
• nearly inexhaustible supply of phages in nature
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY
• Risks
• phage therapy testing has largely been observational, or conducted in small, non-
randomized trials
• What are the short and long term side effects???
• Septic shock due to bacteria releasing endotoxins when broken up by phages
• not widely reported through the many decades of phage therapy in Eastern
Europe
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY
• Risks continued
• Transduction: phages are able to transfer DNA from one bacterium to another
• Phage manipulation and engineered introduction could theoretically introduce new
virulence factors or toxins to already pathogenic bacteria, or convert non-
pathogenic bacteria into pathogens.
• pre-selecting phages that have been carefully screened for toxins and virulence
factors
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY IN USA
• IPATH-Center for Innovative Phage
Applications and Therapeutics
• first bacteriophage therapy center in North
America
• UCSD
• https://medschool.ucsd.edu/som/medicine/d
ivisions/infectious-diseases/research/center-
innovative-phage-applications-and-
therapeutics/Pages/default.aspx
https://medschool.ucsd.edu/som/medicine/divisions/infectious-diseases/research/center-innovative-phage-applications-and-therapeutics/Pages/default.aspx
PHAGE THERAPY
• Palmetto Health Children’s Hospital:
• N=1 (hopefully)
• Patient’s strain of ESBL E.coli has been sent to Adaptive Phage Therapeutics (APT)
• If phage cocktail is identified, it will take 4+ weeks to make
• Then we will have to have to be approved by the FDA via an eIND
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SUMMARY
• Antibiotic Resistance is real
• At least 50% of antimicrobials prescribed in North America are unnecessary
• 80% of all antibiotics used in the US are given to animals
• Antimicrobial Stewardship is here to stay
• JCAHO, CDC, President Executive Order
• Not a lot of new antibiotics are coming out of the drug pipeline
• We are turning to century old treatments for pan resistant bacteria
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