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Safety and Effectiveness of Bacitracin for IM Injection

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Safety and Effectiveness of Bacitracin for IM Injection Safety and Effectiveness of Bacitracin for IM Injection Tatjana Anic-Milic, MD Director, Medical Affairs, R&D Xellia 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 infection (SSI) prophylaxis – Local administration for the treatment of SSIs and serious infections – Oral administration • Safety overview – Literature data – FAERS data AMDAC meeting, April 2019 26, – Data from Xellia Safety database 2 Bacitracin • Polypeptide antibiotic produced by Bacillus licheniformis • Active against Staphylococcus aureus, including MRSA, and most Gram +ve bacteria – 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: peptidoglycan 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: – Pneumonia 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 nephrotoxicity 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 Chemotherapy- (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. Chloramphenicol 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 penicillin, and in 74 % to tetracycline. – 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 intramuscular injection 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 J. 1962; 87: pneumonia and 35 with 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: vancomycin, 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 Streptococcus (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 neomycin; **Irrigation/suction over 8 hours 9 Local administration of bacitracin Intraventricular Intranasal Intracerebral Intrasinusal Epidural Inhalation Subdural Intrapleural Intrathecal Intrapericardial Intraosseous Regional perfusion Intraperitoneal 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 antibiotics • 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 Open fracture 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/polymyxin (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
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