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Home , Bacitracin, Polypeptide antibiotic, Xellia

Safety and Effectiveness of for IM Injection

Tatjana Anic-Milic, MD Director, Medical Affairs, R&D Pharmaceuticals, ApS

Antimicrobial Drugs Advisory Committee Meeting Silver Spring, April 26, 2019 Content

• Snapshot of published clinical data • Efficacy in approved indication • Selected alternate uses – Surgical site (SSI) prophylaxis – Local administration for the treatment of SSIs and serious – Oral administration • Safety overview – Literature data – FAERS data

AMDAC meeting, April 2019 26, – Data from Xellia Safety database

2 Bacitracin

• Polypeptide produced by licheniformis • Active against aureus, including MRSA, and most Gram +ve

– Also active against meningococci, gonococci, Treponema Bacitracin A pallidum and some protozoa • Susceptibility breakpoints not established C55-isoprenyl – Limited data on current susceptibility pattern pyrophosphate • MoA: synthesis inhibition I

P – Binding to the lipid carrier C55-isoprenyl pyrophosphate (IPP) – Inhibits IPP dephosphorylation and recycling, blocking the trafficking of peptidoglycan precursors Bactericidal or static activity, depending on concentration AMDAC meeting, April 2019 26, – and pathogen susceptibility 3 Bacitracin (cont.)

• Approved indication: – and empyema in infants caused by staphylococci shown to be susceptible to the drug • Daily Dose: – Infants < 2.500 g = 900 units/kg – Infants > 2.500 g = 1.000 units/kg • Frequency: – The daily dose may be administered in 2 or 3 doses per day. • Route of administration: – IM

• Safety: – Boxed warning due to

4 Bacitracin: Snapshot of published clinical data

Various infections (mainly SSTI) IM administration Endocarditis Pneumonia Pericarditis Lung Waterhouse-Friderichsen syndrome Legend: abscess Sepsis Case report or <10 pts 1945 1950 1960 1970 1980 1990 2000 2010 Non-compa- rative study Various infections (mainly SSTI) Peritonitis Local (excluding topical) (10-50 pts) CNS infection Non-compa- Empyema/Mediastinitis rative study Airways infection (inhalation) (51-100 pts) Sinusitis Non-compa- SSI rative study prophylaxis (>100 pts) Surgical site infection Comparative Osteomyelitis trial/study Amebic liver abscess UTI prophylaxis Bladder malakoplakia Randomized trial Amebiasis Enterogenic C. difficile diarrhea Balanti- cyanosis Oral diasis Randomized Infantile diarrhea MRSA diarrhea VREF decolonization double-blind Bacillary trial dysentery Enterobiasis Bacterial enteritis No details SSI prophylaxis Giardiasis available AMDAC meeting, April 26, 2019 (colorectal surgery) Gut decontamination Diverticular - (neutropenia) disease induced diarrhea 5

Efficacy in staphylococcal pneumonia and empyema in infants (approved indication) AMDAC meeting, April 26, 2019

6 Staphylococcal pneumonia and empyema in infants

• The effectiveness of IM bacitracin based on experts opinion derived from experience in routine practice • Koch & Donnell 1957 1 – 480 infants and children (2d to 15y) with staphylococcal infections “In the severe cases at least two and sometimes three drugs to which the organism was sensitive were used. together with erythromycin or bacitracin were the drugs most frequently used. With this plan of therapy only two of the 23 infants with pneumonia and empyema died in 1956; and in one of these the correct diagnosis was not made and the infant did not receive adequate antibiotic therapy.”

– Over 50 % of all staphylococcal infections are hospital-acquired. – In 92 % of hospital- acquired infection, the organism is resistant to , and in 74 % to . – There was good correlation between clinical response and antibiotic therapy selected on the basis of results of organism sensitivity tests done by the agar diffusion technique. 1 Koch & Donnell. Calif Med. 1957; 87: 313-6.

AMDAC meeting, April 26, 2019 „Chloramphenicol, bacitracin, novobiocin and erythromycin are the drugs of choice for therapy.” 7

Staphylococcal pneumonia and empyema in infants

• Published evidence of efficacy of IM bacitracin limited to expert opinions

“… some pediatricians employ the of bacitracin, 1000 units per kg per day, for the treatment of staphylococcal pneumonia in infants.“ 4

176 infants and children 2 Gourlay RH. with staphylococcal Can Med Assoc pneumonia and 35 with J. 1962; 87: 1101-5. empyema 75 infants and children with staphylococcal 3 Diamond EF. “For patients who were pneumonia GP. 1964;29: 107-9. desperately ill we did “The following drugs have been effective in treating not hesitate to use AMDAC meeting, April 26, 2019 septicemia due to S. aureus and unresponsive severe bacitracin infections: , kanamycin, ristocetin and 8 intramuscularly...“2 bacitracin.”3 Corroborating clinical data

• A case report on successful treatment of staphylococcal lung abscess with IM bacitracin in a 62-year old man 4

• Evidence of penetration into lungs after IM dosing, derived from efficacy in the treatment of lobar pneumonia in adults 5 – Retrospective study in 14 patients  Cure rate 86% – Pathogens: S. pneumoniae (10), hemolytic (1), both (2)

• Efficacy of intrapleural administration of bacitracin in children with empyema 4 Charet & Siegel. AMA Arch Intern Med. 1952; 90: 250-7. Study N Dose Volume Frequency Duration Outcome 5 Reisner et al. Ann (units) (mL) (days) (compared to historical data) Intern Med. 1951; Pryles 1958 6 7 5,000- 5-10 QD or BID 1-10 Not reported but likely favorable 34: 1232-42. 10,000 as it became routine 6 Pryles CV. Pediatrics. 1958; 21: 609-23. 7 Geley 1972 147 NS* NS NS NS ↓ Mortality: 5.7 vs 11.3% 7 Geley & Hartl. Prog 8 Pediatr Surg. 1972; Willital 1983 19 25,000* 1000** QD 11 ↓ Septicemia: 21 vs 65% 4: 29-61. ↓ Abscess formation: 0 vs 19% 8 Willital GH. Fortschr ↓ Re-surgery: 0 vs 19% Med. 1983; 101: ↓ Fibrosis: 21 vs 77% 1631-4. AMDAC meeting, April 26, 2019 NS: Not stated; *Administered in combination with ; **Irrigation/suction over 8 hours 9 Local administration of bacitracin

Intraventricular Intranasal Intracerebral Intrasinusal Epidural Inhalation Subdural Intrapleural Intrathecal Intrapericardial Intraosseous Intraperitoneal Regional perfusion Wound irrigation Intralesional Enteral & Oral Intravesical

A plentitude of routes have been exploited AMDAC meeting, April 26, 2019

10

Selected alternate uses • Surgical site infection (SSI) prophylaxis AMDAC meeting, April 26, 2019 11 SSI prophylaxis – Intraoperative use of

• SSIs represent a significant burden on the health care system – Approximately 500,000 occur annually in the US  Associated cost $10 billion

• One of the prophylactic measures is surgical wound irrigation with antibiotics – Divided opinions on this intervention due to the lack of high quality evidence

Guideline Recommendation regarding surgical wound irrigation with antibiotics ASHP/IDSA/SIS/ 9 9 Routine use cannot be recommended because of insufficient evidence Bratzler et al. Am J SHEA 2013 Health Syst Pharm. 2013; 70: 195-283. WHO 2016 10 Antibiotic incisional wound irrigation before closure should not be used 10 WHO. Global • Conditional strength of the recommendation due to the low quality of the evidence guidelines for the prevention of CDC 2017 11 No recommendation on antibiotic irrigation of intra-abdominal, deep or subcutaneous surgical site tissues because of uncertain trade-offs between the benefits and harms infection. 2016. 11 Berríos-Torres et al. • Antibiotic ointments, solutions, or powders should not be applied to the surgical incision JAMA Surg. 2017; 152: 784-91. Int. Orthopedic 12 Blom et al. J Consensus 2019 12 Antibiotic irrigation should not be performed in orthopedic surgery Arthroplasty. 2019; 34(2S): S131-8. AMDAC meeting, April 26, 2019 12 Surveys on surgical wound irrigation in clinical practice

984 orthopedic surgeons (2008) 13 186 orthopedic surgeons (2008) 14 Operating room nurses (2013) 15 wound irrigation Any orthopedic surgery

13 Petrisor et al. BMC Musculoskelet Disord. 2008; 9: 7. 164 infection 14 Tejwani & Immerman. Clin Orthop Relat prevention Res. 2008; 466: practitioners 2861-72. 16,17 15 Twomey C. Infection (2017) Control Today 2013; July 15 16 Edmiston et al. Am J Infect Control. 2017; 61 (37%) have 45: 1259-66. responded to the 17 https://www.survey questions about monkey.com/results/ antibiotic irrigation SM-8FST8KPF/ AMDAC meeting, April 26, 2019 in their facility 13 Clinical studies of bacitracin efficacy in SSI prophylaxis

1945 1950 1960 1970 1980 1990 2000 2010

ALL Legend: Case report or <10 pts Bacitracin/neomycin POWDER Wound Non-compa- spraying rative study Bacitracin/neomycin/ (POLYBACTRIN) (10-50 pts) Non-compa- Bacitracin rative study alone (51-100 pts) Non-compa- rative study (>100 pts) Wound irrigation Bacitracin/neomycin Bacitracin/polymyxin Comparative trial/study Other mode of Bacitracin/penicillin G/gentamycin Randomized Bacitracin/neomycin trial administration SC injection Bone cement (intracavital instillation) Randomized double-blind trial Bacitracin/neomycin/clindamycin (gut irrigation) No details available

AMDAC meeting, April 26, 2019 Bacitracin-soaked bioapsorbable sponge Bacitracin POWDER 14 SSI prophylaxis with bacitracin-containing sprays

Infection rate (%) Study N Type of surgery Intervention Test group Control a Maguire 1964 18 1200 Orthopedic Bacitracin/neomycin 2.25 4.75 18 19 Maguire WB. Gibson 1958 480 Neurosurgery POLYBACTRIN 0.4 7.2 Med J Aust. 1964; 2: 412-4. Forbes 1961 20 6419 General, orthopedic, POLYBACTRIN 2.0 4.3 19 urologic Gibson RM. Br Med J. 1958; Fielding 1965 21 851 General, gynecologic, POLYBACTRIN 0.9/12.8 b 3.8/16.1 b 1(5083): 1326-7. urologic 20 Forbes GB. Lancet. 1961; Schima 1976 22 278 Appendectomy, biliary, POLYBACTRIN c Significant reduction compared to 2(7201): 505-9.

colorectal no local antibiotic 21 Fielding et al. 23 Med J Aust. 1965; Longland 1971 300 Appendectomy POLYBACTRIN vs. 18 2 (tetracycline) 2: 159-61. (control) Tetracycline irrigation vs. 19 22 Schima E. Wien Klin No local antibiotic Wochenschr. 1976; 88: 397-8. Gow 1980 24 300 Various POLYBACTRIN vs. 20 9.8 23 Longland et al. irrigation Br J Surg. 1971; a No local antibiotic unless otherwise stated; b Clean/Contaminated procedures; c Sprayed into the open laparatomy wound 58: 117-9. 24 Gow et al. Positive outcome when each tissue layer was sprayed at wound opening and closing Chemotherapy. 1980; 26: 64-71. AMDAC meeting, April 26, 2019 In negative studies, the spray was administered prior to skin closure only 15 SSI prophylaxis with bacitracin irrigation solution (1)

Infection rate (%) Study N Type of surgery Intervention Test group Control

25 a Teng 1951 28 Neurosurgery Bacitracin 0 NA 25 Teng et al. Surg Gynecol Obstet. Savitz 1981 26 82 Neurosurgery b Bacitracin 0 NA 1951; 92: 53-63.

26 27 Savitz & Katz. Klein 1981 3261 Neurosurgery Bacitracin/neomycin 0.4 NA Neurosurgery. 1981; 9:142-4. Beckman 2015 28 539 Cranial shunt Bacitracin irrigation and 1 13 27 Klein et al. powder vs. irrigation alone Fortschr Med. 1981; Kartush 1988 29 236 Neurotologic Bacitracin vs. Bacitracin 0 IV only 9 99: 1262-4. IV vs. Combo 3 None 9 28 Beckman et al. J Neurosurg Pediatr. Combo vs. 2015; 16: 648-61. No prophylaxis 29 Kartush et al. Savitz 1998 30 50 Spinal Bacitracin/ 0 NA d Laryngoscope. 1988; 98: 1050-4. 31 c Michels 2003 2823 Spinal, cardiac Bacitracin/neomycin vs. 4.5 4.6 30 Savitz et al. Normal saline Surg Neurol. 1998; 50: 208-12. a b c NA: Not applicable; Contaminated and clean procedures; Clean contaminated and contaminated procedures only; Laminectomy, 31 Michels & Agger. coronary artery bypass and pacemaker implantation; d Bacitracin/polymyxin combo was tested to check if it can substitute streptomycin, which was withdrawn from the market Gundersen Lutheran Med J 2003; 2: 31-3. AMDAC meeting, April 26, 2019 Antibiotic solution was just rapidly flushed into the wound prior to closing 16 SSI prophylaxis with bacitracin irrigation solution (2)

Infection rate (%) Study N Type of surgery Intervention Test group Control Belzer 1973 32 354 Major surgery in renal Bacitracin/neomycin vs. 2.2 12 transplant patients No local antibiotic

33 a Burri 1980 7699 Various major and Bacitracin/neomycin vs. No difference 32 Belzer et al. minor procedures Taurolidine (1%) Am J Surg. 1973; 126: 180-5. Anglen 2005 34 400 Open fracture Bacitracin vs. 18 13 33 Burri et al. Aktuelle Castile soap Traumatol. 1980; 10: 65-72. Lawrence 2019 35 300 Pancreaticoduode- Bacitracin vs. 11 22 34 nectomy No perioperative bundle b Anglen JO. J Bone Joint Surg Am. 2005; Miller 2001 36 97 Pneumectomy c Bacitracin/penicillin G/ 0 13 87: 1415-22. gentamycin vs. 35 Lawrence et al. No local antibiotic J Am Coll Surg. 2019. pii: S1072- Wijewickrama 321 Endoscopic sinus Bacitracin-soaked 5.4 3.8 (p>0.05) 7515(19)30015-8. 2013 37 surgery bioabsorbable nasal sponge 36 Miller et al. Ann Thorac vs. 1 week of oral antibiotics Cardiovasc Surg. 2001; 7: 14-6. a b Numeric result not available; Additional prophylactic measures were introduced together with bacitracin (double-ring wound protector, 37 Wijewickrama et al. gown/glove and drape change before fascial closure, and a negative-pressure wound dressing); c Antibiotic solution was intraoperatively Am J Rhinol Allergy. instilled into the post-pneumectomy cavity and left in the chest. 2013; 27: 329-32. AMDAC meeting, April 26, 2019 Bacitracin employed at low concentration (33.3 units/mL) 17 Optimal strength and volume of bacitracin solution?

• Strength and volume varied Bacitracin irrigation solution Study across the studies Conc (units/mL) Volume (mL) – At least 50 units/mL Anglen 2005 33.3 3000-9000 required for efficacy based Beckman 2015 50 1000

on available data Miller 2001 50 1000 (instillation)

• Other variables to be taken Savitz 1998 50 NS (constant irrigation) into account Klein 1981 250 10-20

– Duration of irrigation Kartush 1988 250 200 (exposure time) Michels 2003 250 200 (splashed only) – Local susceptibility of target Teng 1951 500-1000 10 pathogens Pryles 1958 500-1000 50-100 (instillation) – Need for Gram –ve coverage Savitz 1981 1000 50 Lawrence 2019 NS 500 AMDAC meeting, April 26, 2019 NS: Not stated 18

Selected alternate uses • Local administration for the treatment of SSIs and serious infections AMDAC meeting, April 26, 2019 19 Bacitracin irrigation for device-related SSI

• Salvage of the cardioverter defibrillator in patients with infected generator pocket 38 – Wide debridement of the pocket – Continuous irrigation with bacitracin (50 U/mL), neomycin (40 μg/mL) and polymyxin (100 U/L), at a rate of 40 mL/h for at least 5 days – Culture-specific systemic antibiotic therapy – Procedure successful in 4/4 patients

• Single-stage revision of acute periprosthetic Pathogen N Success (%) Staphylococcus 39 24 58 total knee infection (non-MRSA) – Polyethylene liner removal and synovectomy MRSA 5 20 – Irrigation with 3 L of each betadine, Dakin's solution, 38 Lee et al. Pacing Clin Pseudomonas 3 33 Electrophysiol. 1996; bacitracin (strength not stated) and normal saline Other pathogen 17 88 19(4 Pt 1): 437-42. – Implantation of the new polyethylene liner 39 Duque et al. J Negative culture 18 83 Arthroplasty. 2017; 32: 1280-84. AMDAC meeting, April 26, 2019 – Postoperative treatment with IV antibiotics Total 67 69 20

Bacitracin irrigation for other types of SSI

• Vascular graft infection in the groin 40 – Explantation of the graft and placement of “distal” and “proximal” drains into the wound – Continuous wound irrigation with 0.25% betadine for 48 h, followed by bacitracin (50 U/mL) for 72 h (infusion rate 0.3 mL/kg/h; continuous suction at proximal drain at 80 mmHg) – At least 6 weeks of IV antibiotics, followed by oral antibiotic suppression for life – 8/9 patients cured (the remaining one died of ischemic bowel)

• Median sternotomy infection 41 – Debridement of the mediastinum, placement of irrigation/ draining tubes, and primary wound closure with wire sutures – Irrigation of the mediastinum with bacitracin (50-500 U/ml), neomycin (1-2 mg/mL) and/or polymyxin B (500 U/L) – Continuous infusion at 41.5-100 mL/h for 6-22 days 40 Strider et al. • Two patients switched to intermittent instillation of 60 mL q4h or J Vasc Nurs. 2018; 100 mL q6h, respectively 36: 40-4. 41 Bryant et al. – 4/5 patients survived (one died from ruptured mycotic Ann Surg. 1969; 169: 914-20. AMDAC meeting, April 26, 2019 aneurysm of the aorta) 21

Local bacitracin in the treatment of CNS infections

Cure RoA N • Forty-three cases Diagnosis N described by Paul rate (%) Intrathecal 20 Epidural 12 Teng in the 1950’s Purulent meningitis 17 71 Brain abscess* 8 88 Intracerebral 9 Intraventricular 7 Epidural abscess with chronic 6 100 osteomyelitis of the scull Subdural 6 Injection into the 5 Infected craniotomy wound 4 100 craniotomy wound Infected laminectomy wound 8 100 Intracranial 2 *Two patients also had subdural empyema Topical (dressings) 8

A patient with multiple brain abscesses in spongioblastoma 42 Teng P. AMA Arch multiforme who received Neurol Psychiatry. intracerebral injections of 1950; 64: 861-77. 250,000 U bacitracin in total 43 Teng et al. Surg Gynecol Obstet. 1951; 92: 53-63. 44 Teng & Meleney Surgery. 1953; 33: 321-32. AMDAC meeting, April 26, 2019 22

Selected alternate uses • Oral administration for high priority pathogens AMDAC meeting, April 26, 2019 23 Treatment of C. difficile associated diarrhea (CDAD)

• Two randomized double-blind trials vs. vancomycin yielded similar results • Young et al., 1985 45 – 42 patients with microbiologically confirmed CDAD – Bacitracin 20,000 U vs. vancomycin 125 mg; both q6h over 7 days – Responders followed for 4 weeks; non-responders and those with symptomatic relapse switched to alternative treatment arm in the blinded manner and followed for 4 weeks Results: – No difference in clinical response Bacitracin Vanco Initial treatment p-value – Microbiologic response inferior to (N=21) (N=21) vancomycin but no difference in Clinical response (%) 76 86 NS the clinical relapse rate Negative stool culture (%) 52 81 0.021 – Non-responders tended to be also C. diff cytotoxin cleared (%) 53 83 0.044 refractory to alternative treatment Clinical relapse rate (%) 42 33 NS – Patients with clinical relapse also Microbiologic relapse (%) 50 50 NS 45 Young et al. relapsed after cross-over Gastroenterology. 1985; 89: 1038-45. AMDAC meeting, April 26, 2019 24 Treatment of C. difficile associated diarrhea (CDAD)

• Dudley et al., 1986 46

– 62 symptomatic patients tested positive for Bacitracin Vanco Initial treatment C. difficile toxin in stool (N=15) (N=15) – Bacitracin 25,000 U vs. vancomycin 500 mg Clinical response (%) 80 100 both q6h over 10 days Microbiologic response (%)* 30 71 – Patients followed-up during the At least 1 recurrence (%) 33 20 hospitalization and instructed to return in *Both stool culture and C. diff toxin in stool negative case of relapse – 1st recurrence treated with the same drug; Random effects meta-analysis 47 2nd recurrence with the opposite drug • Bacitracin clinically as effective as 46 Dudley et al. Arch – 30 patients evaluable for efficacy (others vancomycin and other drugs for CDAD Intern Med. 1986; excluding fidaxomicin and 146: 1101-4. mainly withdrawn due to negative culture) 47 Beinortas et al. 48 Lancet Infect Dis. – Comparable clinical response Bayesian network meta-analysis 2018; 18: 1035-44. Bacitracin comparable to 48 – Microbiologic response inferior to • Sridharan & (with or w/o ) and Sivaramakrishnan. vancomycin but no major difference in Drug Res (Stuttg). the clinical relapse rate but inferior to other drugs 2018. doi: 10.1055/ a-0645-1169. AMDAC meeting, April 26, 2019 25 Vancomycin-resistant E. faecium (VREF) decolonization

Microbiologic Microbiologic Study N Bacitracin dose Follow-up period response (%) relapse (%) O’Donovan 1994 49 8 25,000 U q6h/10 days Not stated 100 a 25 Chia 1995 50 8 25,000 U q12h/10 days Not stated 75 a,b 13 Mondy 2001 51 19 c 50,000 U q6h/10 days 10 weeks 33 vs. 33 a,d 50 vs. placebo Weinstein 1999 52 39 75,000 U q6h plus 100 mg 24 weeks e 100 vs 33 f 60 vs 63 doxycycline q24 h/10 days vs. no treatment

a Defined as no VREF in 3 weekly stool cultures after the 49 O'Donovan et al. treatment. Diagn Microbiol b Two courses were needed in one patient. Infect Dis. 1994; 18: c Twelve patients were evaluable for efficacy. 105-9. d In 5 of 8 non-responders (62%), VREF spontaneously 50 Chia et al. Clin Infect cleared from stool within 35 days. Dis. 1995; 21: 1520. e Rectal swab and stool culture performed at days 0, 7, 14, 51 Mondy et al. Clin then biweekly for 6 weeks, and monthly for 4 months. Infect Dis. 2001; 33: f No VREF in stool culture at the end of treatment. 473-6. 52 Weinstein et al. Clin Infect Dis. 1999; Short-term elimination only 29: 361-6. AMDAC meeting, April 26, 2019 26 Control of VREF bacteremia from intestinal source

• Despite a limited value of oral bacitracin for VREF decolonization in the gut, individual patients may greatly benefit from such treatment 53

• A 25-year-old patient with leukemia and neutropenia after chemotherapy developed VREF bacteremia • Catheters were changed multiple times, but blood cultures continued to grow VREF despite combinations of tigecycline, rifampin, quinupristin-dalfopristin, linezolid, and • An indium white blood cell scan revealed uptake consistent with focal pericecal colitis and a perirectal swab grew VREF • Oral bacitracin (25,000 units q6h) was introduced • Forty-eight hours later, stool cultures were negative for VREF as were blood cultures for the first time in 17 days 53 Tran et al. Clin Infect Dis. 2015; 60: 1726-8. AMDAC meeting, April 26, 2019 27

Bacitracin safety AMDAC meeting, April 26, 2019 28 Bacitracin: Over 70 years of clinical experience

1945 1950 1960 1970 1980 1990 2000 2010 Various infections (mainly SSTI) IM administration Endocarditis Pneumonia Pericarditis Lung WaterhouseIM-Friderichsen use in syndrome adults ceased in the 1960’s due to nephrotoxicity abscess • Sepsis– In 1978, Eichenwald reported that adverse renal effects were rarely Various infections (mainly SSTI) 54 found when bacitracin was usedPeritonitis in early infancy (no detailsLocal (excluding provided) topical) CNS infection • Local administration, especiallyEmpyema/Mediastinitis surgical wound irrigation Airways infection Sinusitisfor SSI prophylaxis and treatment, gained acceptance SSI prophylaxis – According to recent surveys, around 20% of surgeons use bacitracin for this purpose Surgical site infection Osteomyelitis Amebic liver• abscessWidespread useUTI prophylaxis of topical bacitracinBladder malakoplakia products for the 54 Eichenwald & Amebiasistreatment andEnterogenic prevention of superficialC. difficile diarrhea infections Oral McCracken. J Pediatr. Balanti- cyanosis 1978 ; 93: 337-56. diasis Infantile diarrhea MRSAth diarrhea VREF decolonization – In 1992, bacitracin was the 7 most prescribed agent among the 55 https://www.the- Bacillary 55 dysentery Enterobiasis 34 million injury-related ER visitsBacterial enteritis dermatologist.com/c ontent/focus-on- SSI prophylaxis – Over 500 bacitracin-containing products currentlyGiardiasis listed on DailyMed bacitracin-- (colorectal surgery) year-2003 AMDAC meeting, April 26, 2019 Gut decontamination Diverticular Chemotherapy- (neutropenia) disease induced diarrhea 29 Side-effects of bacitracin IM treatment

• Nephrotoxicity 56-58 – Results from tubular and possibly glomerular injury – Manifests as uniform occurrence of proteinuria with casts, often associated with glycosuria in the post-absorptive state – Proteinuria is usually reversible, even with continuation of the treatment, but may progress to anuria and azotemia 56Michie et al. Surgery. 1949 ;26: 626-32. • A case of acute renal failure and death has been reported in 1954 59 57 Miller et al. J Clin – Proteinuria typically quickly resolves upon discontinuation of therapy but glomerular and Invest. 1950; 29: tubular function remain depressed over a period of weeks 389-95. 58 Meleney et al. Surg – Nephrotoxicity has been also reported after intraperitoneal instillation and mediastinal Gynecol Obstet. 1952; 94: 401-25. irrigation with bacitracin 60,61 59 Genkins & Bryer. J Am Med Assoc. 1954; • Pain at the injection site 58 155: 894-7. 60 Rywlin & Minovitch. – Minimized by addition of a South Med J. 1965; 58: 736-9. 58 • Loss of appetite, nausea and vomiting 61 Westerman EL. JAMA. 1983 ; – Occur occasionally 250(7):899. AMDAC meeting, April 26, 2019 30

62 Netland et al. Source Reaction Bacitracin RoA Neurosurgery. 1987; • Bacitracin has a skin sensitizing 62 21: 927-8. Netland 1987 Anaphylaxis Wound irrigation 63 (laminectomy) Sprung et al. Anesth potential Analg. 1990; 71: 430-3. Sprung 1990 63 Anaphylactic Wound irrigation 64 Carver et al. – Allergic contact dermatitis and Anesthesiology. 2000; shock (nephrectomy) 93: 578-9. anaphylactic-type reactions may Carver 2000 64 Anaphylaxis Bacitracin-soaked 65 Blas et al. Anesth Analg. occur after topical dosing shunt tubing 2000; 91: 1027-8. 66 Antevil et al. J Bone Blas 2000 65 Anaphylaxis Mediastinal Joint Surg Am. 2003; irrigation 85-A(2): 339-42. • Anaphylaxis has been also 67 Freiler et al. Ann Allergy Antevil 2003 66 Anaphylactic Wound irrigation Asthma Immunol. 2005; reported after tissue irrigation shock (arthroplasty) 95: 389-93. 68 Greenberg et al. or implantation of bacitracin- Freiler 2005 67 Anaphylaxis Wound irrigation J Clin Anesth. 2008; (pacemaker change) 20: 294-6. soaked implants 69 Damm S. Am J Health Greenberg Cardiac arrest Wound irrigation Syst Pharm. 2011; – All reactions occurred in the OR 68: 323-7. 2008 68 (spinal fusion) allowing for timely intervention 70 Caraballo et al. Damm 2011 69 Anaphylaxis Wound irrigation Ann Allergy Asthma Immunol. 2017; – All resolved w/o sequelae (3 cases) (cardiac surgery) 119: 559-60. – A history of skin reaction to Caraballo Anaphylaxis Bacitracin-soaked 71 Burnett et al. J Clin 2017 70 scleral buckle Anesth. 2018; 46: 35-3. topical bacitracin was present in 72 Desai & Castells. Burnett 2018 71 Anaphylactic Wound irrigation Ann Allergy Asthma some of the patients 72 Immunol. 2019; 122: AMDAC meeting, April 26, 2019 Desai 2019 shock (breast surgery) 217-8. 31 FAERS data

• 637 reports related to bacitracin were identified for the time period from 1969 (FAERS inception) through Dec 31, 2018  49 years in total – 216 (33.9%) events were classified as serious • The reports related to Bacitracin for Injection cannot be always distinguished from those associated with topical bacitracin products – To capture those most likely related to systemic and local administration the focus was put on immune system disorders and renal/urinary disorders Immune system disorders = 37 reports Renal/urinary disorders = 9 reports* Anaphylactic reaction (25), anaphylactoid reaction (11) Renal failure (4), pollakiuria (2), acute kidney injury (1), and anaphylactic shock (1) renal tubular necrosis (1), renal tubular disorder (1), anuria (1) and urinary tract disorder (1)

FAERS: The FDA Adverse Event

AMDAC meeting, April 26, 2019 Reporting System 32 *more than 1 syndrome may occur in 1 report, therefore the sum of syndromes exceeds nr. of reports Data from Xellia Safety database

• Xellia’s Bacitracin for Injection USP (50,000 units/vial) has been authorized in the US since 25-Aug-2014 [ANDA 203177]

• Since launch on 30-Sep-2014, approximately 2.5 million units have been sold

• As of 11-Mar-2019, two ICSRs were recorded in the Safety database – Both ICSRs originated from the literature and were related to “Bacitracin ointment” • In both the cases, patient received bacitracin ointment for scalp irritation secondary to seborrhea and mild folliculitis, and developed xanthoma, hair color change, and hypersensitivity. Causal role of bacitracin was confounded with other co-suspect drugs (polymyxin B, neomycin and selenium sulfide). – No cases were reported for bacitracin used in the labelled indication – No cases were reported for off-label use or lack of efficacy

• Based on the evaluation of the safety data and the benefit-risk analysis, current risk-benefit ratio for Bacitracin for Injection USP (50,000 units/vial)

remains unchanged ICSR: Individual Case

AMDAC meeting, April 26, 2019 Safety Report 33

Conclusion AMDAC meeting, April 26, 2019 34 Conclusion

• Risk-benefit ratio for Bacitracin for Injection USP remains positive under conditions and limitations listed in the current Prescribing Information – Published data related to efficacy in approved indication are limited, however, there is no evidence that any of the newer agents outperforms bacitracin efficacy in infants with staphylococcal pneumonia and empyema – In the era of MDR/XDR pathogens, bacitracin may still be a life-saving treatment option in individual patients

• Alternate uses, in particular wound irrigation for SSI prophylaxis or treatment, merit further optimization and standardization of current practices in terms of indication, dose (concentration in irrigation solution) and mode of administration – Available data indicate that wound irrigation with bacitracin is generally safe; anaphylaxis may occur but is extremely rare AMDAC meeting, April 26, 2019 35