TREATMENT OF MULTIDRUG-RESISTANT ACINETOBACTER BAUMANII OSTEOMYELITIS WITH ADJUNCTIVE CONTINUOUS COLISTIN IRRIGATION LT Christina Jamros, DO (Associate) CDR Ryan Maves, MD (Fellow) CAPT Mary Bavaro, MD (Fellow) Department of Internal Medicine Naval Medical Center, San Diego, CA

Disclosure I have no relevant financial relationships with any commercial supporters.

The case 26-year-old man was transferred to the intensive care unit after a private plane crash. – bilateral closed femur and open tibia fractures – above the knee amputations and implanted hardware

Presentation Physical exam was concerning for soft tissue and bone infections at the surgical sites. – debridement – started cefazolin and gentamicin Fevers persisted and he developed pneumonia. – broadened to vancomycin, piperacillin- tazobactam, and ciprofloxacin

Cultures from bronchoalveolar lavage and wound debridement grew multidrug- resistant Acinetobacter baumanii complex. – initially susceptible to only colistin IV colistin, meropenem, and minocycline – persistent fever and purulent drainage from the surgical sites multiple surgical debridements and washouts application of wound vacuum- assisted closure (VAC) Source: Public Health Image Library Introducing …

Progress Initiated trial of continuous irrigation of colistin via his wound VAC. – wounds improved – normalization of inflammatory markers Subsequent testing revealed colistin/rifampin synergy.

Outcome Finally discharged on meropenem, colistin, and rifampin for 4 additional weeks. Transitioned to amoxicillin and doxycycline – chronic suppression of multidrug-resistant organism osteomyelitis due to retained hardware Seven years of follow-up – living independently with bilateral lower extremity prostheses

Discussion Multidrug-resistant organisms cause a variety of infections and are an economic burden. Associated with – increased length of hospitalization – healthcare costs $20 million a year additional costs $35 billion a year – mortality

Threat Report 2013

New antibacterial agents approved by the US Food and Drug Administration Boucher H W et al. Clin Infect Dis. 2013;cid.cit152 Bad bugs, need drugs

Then and now Challenge for newer uses of older drugs Devices for VAC instillation therapy

Colistin: The last resort Introduced in 1952 for the treatment of infections caused by Gram-negative bacilli including multidrug-resistant Acinetobacter baumannii Replaced in the 1970s with other antibiotics owing to its nephrotoxicity and neurotoxicity

Mechanism of action RIFAMPIN

Phoenix rising Citations in the PubMed from 1960 to 2011 using either the term 'colistin' or 'colistin resistance'.

Negative pressure wound therapy Since 1990s, advances in wound management VAC or negative pressure wound therapy combined with local antiseptic wound cleansing KCI V.A.C. Instill® Therapy Unit Instillation Therapy Combined with Negative Pressure Wound Therapy

How it works Back DA, et al. Int Wound J 2013; 10 (suppl. 1):32–42. Application of sub-atmospheric pressure to the local wound environment

A clinical example Wound VAC placement for a case of necrotizing fasciitis Back DA, et al. Int Wound J 2013; 10 (suppl. 1):32–42.

MEDLINE literature searches – negative pressure wound and instillation therapy from 1990 to 2013 (36 peer-reviewed citations) – randomized controlled trials from 2005 to 2012 wound care with bone involvement (27 publications) or soft-tissue wounds without bone participation (11 publications)

The future use of VAC instillation is not yet widespread and literature is limited there is a need for further studies – benefit using antiseptics (polyhexanide, acetic acid, povidone-iodine) – role for prophylactic use in contaminated wounds that cannot be closed primarily with surgical means

Navy medicine Acinetobacter baumanii complex infections were notorious during Operation Iraqi Freedom/Operation Enduring Freedom – hospital acquired – resistance deployed > nondeployed – Hawley JS et al. noted isolates developed resistance to colistin during testing – increasing cause of infection in personnel returning from overseas conflicts after care in deployed military hospitals

Military physicians face similar challenges More attention to unique treatment and preventive measures Camp Bastion 2009 Approved for training use by UK MOD

Lessons from the case In colistin-resistant infections, high minimum inhibitory concentrations may potentially be overcome through the direct application of high drug concentrations to the affected site. Synergy testing – expand the antibiotic spectrum – prevent the emergence of resistance

Thank you! Questions? Comments …

References Back DA, Scheuermann-Poley C, Willy C. Recommendations on negative pressure wound therapy with instillation and antimicrobial solutions – when, where and how to use: what does the evidence show? Int Wound J 2013; 10 (suppl. 1):32–42. Bassetti M. New treatment options against gram-negative organisms. Crit Care. 2011; 15(2): 215. Biswas, S et al. Colistin: An Update on the Antibiotic of the 21st Century. Expert Rev Anti Infect Ther. 2012; 10(8): Boucher, HW et al. Clin Infect Dis. 2013; 152. Calhoun, JH et al. Multidrug-resistant Organisms in Military Wounds from Iraq and Afghanistan. Clin Orthop Relat Res (2008) 466:1356–1362. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States. Atlanta: CDC, Centers for Disease Control and Prevention (CDC). Healthcare-associated infections. Atlanta: CDC, Conly JM, Johnston BL. Colistin: The Phoenix Arises. Can J Infect Dis Med Microbiol Sep-Oct; 17(5): 267–269. Saiman L. Clinical utility of synergy testing for multidrug-resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis: ‘the motion for’. Paed Resp Rev. 2007; 8: 249–255.