ANTIBIOTICS and RESISTANCE: NEW • I Have Nothing to Disclose

7/24/2018

DISCLOSURES

ANTIBIOTICS AND RESISTANCE: NEW • I have nothing to disclose. DRUGS TO HELP COMBAT THE PROBLEM

Anna-Kathryn Burch, M.D. Medical Director, Pediatric Antimicrobial Stewardship Palmetto Health Children’s Hospital PHUSC

CLINICAL CASE CLINICAL CASE

• Patient is a 17 year old with history of interstitial nephritis, etiology unknown. • In the background…Patient is receiving plasmapheresis and increased immunosuppression • required a cadaveric renal transplant at MUSC 7/2/14 • thymoglobulin, rituximab and abatacept per peds Nephrology • Patient was doing well until March 2018 when she began to experience kidney • 3/15-3/30/18: Urosepsis #1 with ESBL E.coli., Blood and Urine culture positive. rejection • Tx x 10 days with Ertapenem after clearing blood culture. • Kidney Bx 3/9/18 for pathology to prove GVHD • 4/4-4/17/18: Urosepsis #2 with ESBL E.coli (stable susceptibilities), blood and urine • Oh by the way, she admits she quit taking her immunosuppressive drugs after the culture positive. biopsy proved she was in rejection. • Patient had a PICU stay. • Patient had large hematoma in the bladder s/p kidney biopsy. • 4/4 ECHO neg, 4/8 RUS neg, 4/9 thoracic/lumbar MRI neg. • 3/10/18 clot removed via large bore foley • Tx x 14 days with Ertapenem after clearing blood culture.

CLINICAL CASE CLINICAL CASE

• readmitted 4/20/18 for line placement and plasmapheresis. • 5/29-6/18/18: Patient admitted with fever-dx with ESBL E.coli in urine and • 4/22-5/21/18: Urosepsis #3 with ESBL E.coli (stable susceptibilities), blood culture C.diff colitis. only positive as urine culture unfortunately no performed. • Patient tx with Ertapenem and Fidaxomicin x 14 days. • 4/24 ECHO neg • 5/31 MRI abd/pelvis was negative. • 4/26 MRI abdomen and pelvis showed subtle areas of delayed-diminished • Because ESBL E.coli and C.diff found in stool, patient underwent FMT 6/13/18. enhancement involving mid and lower aspect of left kidney which can be seen in the setting of pyelonephritis. • Repeat urine culture 6/15/18 was negative. • Tx x 4 weeks of IV ertapenem after clearing blood culture. • 6/22/18: Stool culture and stool c.diff s/p FMT performed. Stool is c.diff and ESBL E.coli positive.

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CLINICAL CASE ANTIBIOTIC RESISTANCE

• 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?????

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 WHAT IS ANTIMICROBIAL RESISTANCE? • 1927: • German Gerhard Domagk found that an industrial dye, prontosil rubrum, had antibacterial action against staphylococci and hemolytic streptococci • Ability of organisms to resist the effects of an antimicrobial • Sulfonamide was the first antimicrobial • Organisms change in some way that reduces or eliminates the effectiveness of drugs, • Received Nobel Prize chemicals, or other agents designed to cure or prevent infections • The microbes have a better survival rate • 1928: • continue to multiply causing more harm • 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 http://www.cdc.gov/drugresistance/community/anitbiotic-resistance-faqs.htm World Health Organization Report on Infectious Diseases, 2000

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ANTIMICROBIAL RESISTANCE 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

• Causal associations between antimicrobial use and the • Abuse, Overuse and Misuse of “… the microbes are educated to resist Antimicrobials penicillin and a host of penicillin-fast emergence of antimicrobial resistance • Increase in drug-resistant organisms organisms is bred out… In such cases the • Changes in antimicrobial use are paralleled by changes in prevalence of resistance • Primary cause is repeated and improper uses thoughtless person playing with penicillin is of antimicrobials morally responsible for the death of the • Increased pressure on physicians inevitably leads to "defensive" and unnecessary prescribing as a means of man who finally succumbs to infection with forestalling potential complications the penicillin-resistant organisms. I hope Fluoroquinolone Use • In North America it is estimated that physicians in both this evil can be averted.” Canada and the United States over-prescribe antibiotics by and Resistance Rates in PSA and Gram- 50% - Sir Alexander Fleming, NY Times June 1945 Negative Bacilli

Neuhauser, M. M. et al. JAMA 2003 World Health Organization Report on Infectious Diseases, 2000 Dellit TH et al. CID 2007

ANTIMICROBIAL RESISTANCE ANTIMICROBIAL RESISTANCE

• Causal associations between antimicrobial use and the emergence of • There is an association between development of antimicrobial resistance and antimicrobial resistance (cont) mortality • Resistance is more prevalent in health care-associated bacterial infections • Cosgrove et al CID 2003: Meta-analysis • Patients with health care-associated infections caused by resistant strains are • Patients with MRSA bacteremia had an increased risk of mortality compared to more likely than control patients to have prior antibiotic exposure patients with MSSA bacteremia • 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

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ANTIMICROBIAL DEVELOPMENT VS. FEWER DRUGS CREATED TO COMBAT RESISTANCE ANTIBIOTIC RESISTANCE

1st case MRSA reported 1961

WHAT ARE WE DOING ABOUT NEW DRUGS 2014-2017 RESISTANCE

Drug Indications Approval Date Dalbavancin (Dalvance®) ABSSSI May 2014 Tedizolid (Sivextro®) ABSSSI June 2014 Oritavancin (Orbactiv®) ABSSSI August 2014 Ceftolozane/Tazobactam cUTI, cIAI December 2014 (Zerbaxa®) Ceftazidime/Avibactam cUTI, cIAI February 2015 (Avycaz®) Bezlotoxumab (Zinplava®) C.difficile Infection October 2016 Delafloxacin (Baxdela®) ABSSSI June 2017 Meropenem/Vaborbactam cUTI September 2017 (Vabomere®) Plazomicin (Zemdri®) cUTI June 2018

NEW GRAM-POSITIVE AGENTS DALBAVANCIN (DALVANCE®)

• Dalbavancin (Lipoglycopeptide – think long acting Vancomycin) • Lipoglycopeptide • Oritavancin (Lipoglycopeptide – think long acting Vancomycin) • Mechanism of Action • Tedizolid (Oxazolidinone – think Linezolid like) • Inhibits cross-linking of peptidoglycans • Delafloxacin (Fluoroquinolone – think ciprofloxacin like) • 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®) DALBAVANCIN (DALVANCE®)

• ABSSSI recommended Adult dose: • Pediatric Dosing: • Single-dose regimen: • 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 • 1500mg IV x 1 dose • the following age-dependent dosing regimen was found to achieve similar dalbavancin exposure to that in adults • Two-dose regimen: administered a 2-dose regimen: • 1000mg IV day 1, followed by 500mg IV day 8 • 6 to <18 years of age, 12 mg/kg (1000 mg maximum) on day 1, 6 mg/kg (500 mg maximum) on day 8 • Effective half-life: 8.5 hours • 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 • No dose adjustment necessary with hemodialysis • following age-dependent regimen was found to match adult exposure after a single-dose (1500 mg): • No adjustment for mild liver dysfunction • 6 to <18 years of age, 18 mg/kg (1500 mg maximum) on day 1 • Infused over 30 minutes • 3 months to <6 years of age, 22.5 mg/kg (1500 mg maximum) on day 1 • Cost around $4500/course • No home health, No PICC line

Roberts KD, et al. Pharmacotherapy 2015;35(10):935-948 Pediatr Infect Dis J. 2017 Jul;36(7):645-653.

ORITAVANCIN (ORBACTIV®) ORITAVANCIN (ORBACTIV®)

• Lipoglycopeptide • ABSSSI recommended adult dose: • Multiple Mechanisms of Action • 1200 mg IV once • Inhibits cross-linking of peptidoglycans • Terminal half-life: 8-10 days • Destabilizes cell wall, causing cell death • No adjustment for renal or hepatic impairment • Disruption of bacterial membrane integrity • Leads to depolarization, permeabilization and cell death • Infused over 3 hours • Concentration dependent, bactericidal • Cost around $2900 per dose • Only lipoglycopeptide that can cover VRE • No home health, No PICC line • FDA approved indications: ABSSSI

Roberts KD, et al. Pharmacotherapy 2015;35(10):935-948 Roberts KD, et al. Pharmacotherapy 2015;35(10):935-948

DALBAVANCIN/ORITAVANCIN ORITAVANCIN (ORBACTIV®) 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

https://clinicaltrials.gov/ct2/show/NCT02134301

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TEDIZOLID (SIVEXTRO ®) TEDIZOLID (SIVEXTRO ®)

• Member pf oxazolidinone class (similar to Linezolid) • ABSSSI recommended adult dose: • Prodrug: tedizolid phosphate—converted to in vivo active form by phosphatases • 200 mg IV/PO daily for 6 days • Active against VRE • Mechanism of Action • Adolescent Dosing: • Inhibits protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit, preventing the formation of 70S complex • multicenter, open-label study, a single IV infusion (N = 10) or oral dose (N = 10) of • Why its unique: 200 mg tedizolid phosphate was administered to adolescents already receiving • More potent activity against MDR gram-positive pathogens allows for lower amounts of drug to be given antibacterial treatment for presumed or documented infection. • Phase 3 trial compared 6 days of tedizolid vs 10 days of linezolid • Overall pharmacokinetics of tedizolid was similar after administration of a single oral • May have less risk of adverse effects: or IV 200 mg dose, and bioavailability was high. • MAO inhibition, bone marrow effects • FDA approved indications: ABSSSI • Exposure profiles were similar to those in adults.

Kisgen JJ, et al. Am J Health Syst Pharm. 2014 Apr 15;71(8):621-33 Kisgen JJ, et al. Am J Health Syst Pharm. 2014 Apr 15;71(8):621-33 Pediatr Infect Dis J. 2016 Jun;35(6):628-33

TEDIZOLID STEWARDSHIP DELAFLOXACIN (BAXDELATM)

• last-line treatment of ABSSSI when other options are not feasible • Anionic fluoroquinolone • Especially in patients who would otherwise be given PO linezolid but are restricted • Concentration-dependent bactericidal activity due to drug interactions • Mechanism of action • Will have a minimum role most likely • 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) DELAFLOXACIN STEWARDSHIP

• Why its unique: • Treatment of polymicrobial ABSSSI when all other IV or PO options are not • Broad spectrum of activity against gram-negative, atypical, anaerobic and gram-positive feasible (in adolescent populations) bacteria • Will have a minimum role most likely • 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

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NEW GRAM-NEGATIVE AGENTS BETA-LACTAM RESISTANCE

• 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)

Peds ASP conference June 1, 2017

CEFTOLOZANE/TAZOBACTAM CEFTOLOZANE/TAZOBACTAM (ZERBAXA®) (ZERBAXA®)

• Ceftolozane • Spectrum of Activity: • Strong Against: • Cephalosporin with potent anti-pseudomonal activity • Pseudomonas aeruginosa, including ceftazidime- and carbapenem-resistant strains • Similar to ceftazidime--with a different side chain • Enterobacteriaceae, including many ESBL-producing strains • Destroyed by ESBLs and Carbapenemases • Weak Against: • Relatively stable vs Amp C • Ceftazidime-resistant Enterobacter spp • Tazobactam • Carbapenemase-producing Enterobacteriaceae • Gram-positive anything • Protects ceftolozane from many ESBLs and Cephalosporinases • Gram-negative anaerobes • Not active against AmpC beta-lactamases or Carbapenemases • Tazobactam does add anaerobic coverage, but it is weaker

Zhanel GG et al. Drugs 2014;74:31-51. Zhanel GG et al. Drugs 2014;74:31-51.

CEFTOLOZANE/TAZOBACTAM CEFTOLOZANE/TAZOBACTAM (ZERBAXA®) STEWARDSHIP

• Pediatric Dosing at PHR: • Helpful against ESBL Enterobacteriaceae and Resistant PSA • Neonatal: 18 mg/kg IV q 8 hours • Has not been very helpful in our CF population • Each 18 mg/kg ceft/taz=12 mg ceftolozane/kg per dose • Will have a moderate/major role most likely in GNR Infections • 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

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CEFTAZIDIME/AVIBACTAM (AVYCAZ ®) CEFTAZIDIME/AVIBACTAM (AVYCAZ ®)

• Ceftazidime • Spectrum of Activity: • Strong Against: • Third-generation antipseudomonal cephalosporin • Many gram-negative bacilli • Susceptible to ESBL and KPC enzymes, but not porin channel changes that affect • PSA carbapenems • Enterobacteriaceae producing KPC and ESBL enzymes • Avibactam • Weak Against: • Gram-positive organisms • Novel beta-lactamase inhibitor not based on beta-lactam structure • GNRs producing metallo-beta-lactamases (NDM) • Active against ESBLs, KPC-type and OXA-48 carbapenemases • Gram-negative anaerobes • Avibactam does not add anaerobic coverage (unlike tazobactam) • Not active against metallo-beta lactamases • Doesn’t help with Acinetobacter

CEFTAZIDIME/AVIBACTAM CEFTAZIDIME/AVIBACTAM (AVYCAZ ®) STEWARDSHIP

• Pediatric Dosing at PHR: • Helpful against ESBL and KPC producing Enterobacteriaceae • 62.5 mg/kg IV q 8 hours • Has been very helpful in our CF population • Each 62.5 mg/kg ceftaz/avi=50 mg ceftaz/kg per dose • Will have a major future role most likely in GNR Infections

MEROPENEM/VABORBACTAM MEROPENEM/VABORBACTAM (VABOMERE®) (VABOMERE®)

• Meropenem • Spectrum of Activity: • Potent antipseudomonal carbapenem with broad spectrum • Strong Against: • Resistant to destruction from ESBLs, cephalosporinases • Many gram-negative bacilli • Vaborbactam • Carbapenem-susceptible Pseudomonas aeruginosa • Boronic acid beta-lactamase inhibitor • Enterobacteriaceae producing KPC and ESBL enzymes • Active against ESBLs, KPCs but not metallo-beta-lactamases (NDM) • Weak Against: • Doesn’t add activity against resistant PSA • Carbapenem-resistant PSA • GNRs producing metallo-beta-lactamases (NDM) or OXA-enzymes

Toussaint K, Gallagher JC. Ann Pharmacother 2015;49:86-98 Shaeles DM. Ann NY Acad Sci 2013;1277:105-114

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MEROPENEM/VABORBACTAM MEROPENEM/VABORBACTAM (VABOMERE®) STEWARDSHIP

• Pediatric Dosing: • Helpful against ESBL and KPC producing Enterobacteriaceae • In trials for PK/PD data in children • Hopefully will be helpful in our CF population but we have not used this at PHR yet

PLAZOMICIN (ZEMDRI TM) OTHER AGENTS IN GNR PIPELINE

• Neoglycoside Agent Class Company Notes • next-generation aminoglycoside Imipenem/Relebactam Carbapenem-beta- Merck • Mechanism of Action lactamase Inhibitor • Inhibits bacterial protein synthesis • Exhibits dose-dependent bactericidal activity Cefiderocol Siderophore Shionogi Novel mechanism Cephalosporin that relies on active • Activity against: iron transport • ESBL Enterobacteriaceae • fluoroquinolone-resistant and aminoglycoside-resistant GNB “Trojan Horse” • 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

CEFIDEROCOL: NON-ANTIBIOTIC OPTIONS FOR USING IRON AS A TROJAN HORSE TREATMENT OF MDR ORGANISMS

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FECAL MICROBIOTA TRANSPLANT (FMT) 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???

• 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) FECAL MICROBIOTA TRANSPLANT (FMT)

• Twenty-five FMTs were performed in 20 participants who were • Treated 15 patients carrying ESBL-producing Enterobacteriaceae(ESBL-EB) with FMT. colonized by a median of 2 (range, 1–4) strains of antibiotic • Seven patients underwent a second FMT after 4 weeks when ESBL-EB remained resistant bacteria (ARB). • 40% had neutropenia • total number of 22 transplants • The primary endpoint was reached in 15/25 (60%) of the FMTs and more frequently in cases in which there was no periprocedural use • The objective was decolonization of ESBL-EB. of antibiotics (79% vs 36%, P < .05). • Three out of 15 (20%) patients were ESBL-negative at 1, 2 and 4 weeks after the • 15/20 (75%) participants experienced complete ARB decolonization. first transplant • There were no severe adverse events. • The microbiota composition analysis revealed higher abundance • Six out of 15 (40%) were negative after the second transplant. of Barnesiellaspp., Bacteroides, and Butyricimonas and greater bacterial richness in the fecal material, resulting in eradication • Comparison of fecal microbiota at baseline and 4 weeks after FMT revealed of Klebsiella pneumoniae compared with nonresponders. restoration of microbial diversity after FMT and a microbial shift towards donor composition.

BMC Res Notes. 2018; 11: 190.

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 PHAGE THERAPY HISTORY

• Phages (Bacteriophages) are viruses that solely and selectively target and kill • Frederick Twort bacteria. • 1915 • Have been shown to effectively fight off and kill multi-drug resistant bacteria • bacteriologist from England • first to suggest that it was a virus that was responsible for previous observations of a • In theory, when all antibiotic medication fails, bacteriophages could still "factor" that killed bacteria succeed in killing the bacteria before the infection could kill the person. • 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

PHAGE THERAPY HISTORY PHAGE THERAPY HISTORY

• The first known therapeutic use of phages occurred in 1919 • Eli Lilly produced phages for human use in the US • d'Herelle and several hospital interns ingested a phage cocktail to check its safety • In the 1940s • • gave it to a 12-year-old boy with severe dysentery 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 • symptoms cleared up after a single dose • Russia, Poland and the Republic of Georgia — • he fully recovered within a few days • antibiotics not as easily accessed • d'Herelle didn't publish findings until 1931 • 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 PHAGE THERAPY

• Western scientists "re-discovered" phage therapy in the 1980s. • Benefits • Growing threat of antibiotic-resistant bacterial strains has continued to further • Very specific about the bacteria they infect interest in phage therapy as a potential alternative • 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

PHAGE THERAPY PHAGE THERAPY

• Risks • Risks continued • phage therapy testing has largely been observational, or conducted in small, non- • Transduction: phages are able to transfer DNA from one bacterium to another randomized trials • Phage manipulation and engineered introduction could theoretically introduce new • What are the short and long term side effects??? virulence factors or toxins to already pathogenic bacteria, or convert non- pathogenic bacteria into pathogens. • Septic shock due to bacteria releasing endotoxins when broken up by phages • pre-selecting phages that have been carefully screened for toxins and virulence • not widely reported through the many decades of phage therapy in Eastern factors Europe

PHAGE THERAPY IN USA PHAGE THERAPY

• IPATH-Center for Innovative Phage • Palmetto Health Children’s Hospital: Applications and Therapeutics • N=1 (hopefully) • first bacteriophage therapy center in North • Patient’s strain of ESBL E.coli has been sent to Adaptive Phage Therapeutics (APT) America • If phage cocktail is identified, it will take 4+ weeks to make • UCSD • Then we will have to have to be approved by the FDA via an eIND • 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

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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