1. Does Receiving Rifampin Prior to Clearing MRSA Bacteremia Increase Antibiotic Resistance? MARIANA SAYKINA DOCTOR OF PHARMACY CANDIDATE 2016 WESTERN NEW ENGLAND UNIVERSITY

2. Objectives  Understand the risks of using Rifampin as monotherapy  Understand the indication of Rifampin in adjunctive therapy for MRSA infections  Recognize the role of Rifampin as adjunct therapy in MRSA bacteremia

3. Patient Presentation  HPI: 58 yo male with a diagnosis of primary CNS lymphoma, presents to BMC on 1/13/2016 14 days post biopsy (12/30/2015), with pain, purulent discharge from scalp incision, fever 101.3º F, mental status changes and leukocytosis of 22 k/ mm 3. CT scan in the ED revealed increased size of extra-axial right frontotemporal fluid collection new from previous scan. Patient was intubated due to mental status changes and is suspected to have infection s/p biopsy.  PMH : HTN, HLD, large B cell lymphoma (rituxan and methotrexate), asthma and seizure disorder  Home Meds : o Allopurinol 300 mg po daily o Amlodipine 5 mg po daily o Escitalopram 10 mg po daily o Lisinopril 10 mg po daily o Montelukast 10 mg po daily o Prochlorperazine 10 mg po daily o Simvastatin 10 mg po QHS

4. Patient Presentation  Lab Values: Hospital day 3  Vitals: BP 157/83, RR 24 bpm, T 101º F (T max 104º F)  Dry wt: 88.0 kg  Glucose: 160 mg/dL (92-196 mg/dL)  WBC: 10.5 k/mm 3  Hgb/Hct: 11g/dL / 33.4%  Micro:  Positive for MRSA- CNS abscess and blood on 1/13 (admission)  Treatment: o Pt received Vancomycin 2g every 12 hrs (1/13/2016) and Rifampin 600 mg (1/15/2016) in the SICU where he received deep wound debridement (1/13) and evacuation of subdural empyema (1/16).

5. Patient Presentation  Micro: o Positive for Serratia in the blood (1/20/2016; 7 th day of ICU stay) o Negative for MRSA (1/19/2016)  Treatment: o Rifampin 600 mg was stopped on 1/19/2016 after 5 doses in the SICU. o Continue Vancomycin 2 g every 12 hrs and added Zosyn 3.375 g every 8 hrs on 1/20/2016, transferred to MICU from SICU.

6. Patient Presentation  Summary: 58 yo male with large B-cell lymphoma s/p right frontal craniotomy. Presenting to BMC with pain and discharge from infected incision following the biopsy procedure. Pt was found to have MRSA in the CNS abscess and blood, which was cleared with vancomycin by 1/19/2016, but was then found positive for serratia in the blood on 1/20/2016.  Plan: o Continue patient on Zosyn and Vancomycin o Follow-up on cultures o Family meeting to inform of bad prognosis

7. Rifampin MOA: Inhibits bacterial RNA synthesis by binding to the beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription. Use:  Labeled Indications- Management of active tuberculosis in combination with other agents; elimination of meningococci from the nasopharynx in asymptomatic carriers  Off-Label - Brain abscess, empyema, and epidural abscess (MRSA) Rifampin. LexiComp, 2011.

8. Rifampin  According to IDSA guidelines regarding the treatment of MRSA infections, rifampin can be considered as adjunctive therapy to vancomycin in the treatment of brain abscess, empyema, or spinal epidural abscess.  Rifampin should only be used in combination with other antibiotics for S. aureus infections because resistance can develop rapidly with monotherapy.  It has been assumed that the favorable clinical results observed with rifampin combinations are due to the ability of rifampin to concentrate within phagocytic cells and kill intracellular staphylococci. Liu C, et al, 2011, 52(3):285-92. Fass RJ, et al. 1987; 31 (10): 1457-60

9. Treatment of Experimental Staphylococcal Osteomyelitis with Rifampin and Trimethoprim, Alone and in Combination.  Rifampin and trimethoprim were used alone and in combination in the treatment of chronic osteomyelitis due to S. aureus in rabbits.  Results: Trimethoprim or rifampin, administered alone for 14 days, were ineffective in sterilizing infected rabbit bones. The combination of rifampin plus trimethoprim was significantly more effective (P<0.005) than either agents given alone.  Staphylococci isolated from the bones of rabbits treated with rifampin alone or rifampin plus trimethoprim were uniformly resistant to rifampin, but retained their susceptibility to trimethoprim. Norden CW, et al. 1980; 17 (4): 591-4.

10. Advantages of Adjunct Rifampin Therapy  Rifampin has good oral bioavailability.  It penetrates cells, tissues and biofilms better than beta-lactam and glycopeptide antibiotics (the current mainstays of SAB treatment) and, therefore, in combination with these agents, may resolve serious S. aureus infections faster and more effectively.  It is cheap: o 300 mg oral capsules (60): $331.90 o 600 mg IV (1): $135.00 (LexiComp) Thwaites et al.; licensee BioMed Central Ltd. 2012. Rifampin. LexiComp, 2011.

11. The Disadvantages of Adjunct Rifampin Therapy  There are three important potential problems with using rifampicin for the treatment of S. aureus bacteremia: o Development of rifampicin-resistant bacteria o Interactions with other drugs o Hepatic toxicity Thwaites et al.; licensee BioMed Central Ltd. 2012.

12. Rifampin-Resistance in S. Aureus Bacteremia  Resistance can be acquired rapidly when rifampicin is used alone in treatment o Resulting from mutations in the drug’s binding site  The frequency with which rifampicin resistance develops during the combination therapy of SAB is difficult to assess from the published literature, varying from three non-randomised studies of serious S. aureus infections to other smaller case series. Thwaites et al.; licensee BioMed Central Ltd. 2012

13. Adjunctive Use of Rifampin for the Treatment of S. aureus Infections  A systematic review of the literature was done to identify in vitro, animal, and human investigations that compared single antibiotics therapy and in combination with rifampin against S. aureus  The effect of rifampin therapy was often inconsistent  The quality of data reporting in these investigations was often suboptimal  Few human studies have addressed the role of adjunctive rifampin therapy  Further adequately powered investigations are needed Perlroth J, et al. 2008;168(8):805-819.

14. Clinical Features of Heteroresistant Vancomycin- Intermediate S. aureus Bacteremia versus Those of MRSA Bacteremia  A total of 27 case patients with hVISA bacteremia were compared with 223 control patients with MRSA bacteremia.  The median duration of bacteremia among patients with hVISA was significantly longer than that among patients with MRSA (12 vs. 2 days; P=.005)  Patients with hVISA had a greater prevalence of complications, such as endocarditis (18.5% vs. 3.6%; P=.007) and osteomyelitis (25.9% vs. 7.2%, respectively; P=.006).  Rifampin resistance emerged more frequently among hVISA isolates than among MRSA isolates (44% vs. 5.9%; P<.001).  No significant difference in mortality existed between the two groups. Maor Y, et al. (2009) 199 (5): 619-624.

15. Conclusion  In vitro results of interactions between rifampin and other antibiotics are method dependent and often do not correlate with in vivo findings.  Adjunctive rifampin use seems promising in the treatment of clinical hardware infections or osteomyelitis, but more definitive data are lacking regarding the use of adjunctive Rifampin therapy in MRSA bacteremia.  Further adequately powered investigations are needed.

16. References 1. Rifampin. Online, Hudson, Ohio: Lexi-Comp, Inc.; January 29, 2011. Accessed February 4, 2015. 2. Liu C, Bayer A, Cosgrove SE, et al, “Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children: Executive Summary,” Clin Infect Dis, 2011; 52(3):285-92. 3. Fass RJ, Helsel VL. In vitro antistaphylococcal activity of pefloxacin alone and in combination with other antistaphylococcal drugs. Antimicrob Agents, 1987; 31 (10): 1457-60. 4. Norden CW, Keleti E. Treatment of experimental staphylococcal osteomyelitis with rifampin and trimethoprim, alone and in combination. Antimicrob Agents Chemother, 1980; 17 (4): 591-4. 5. Thwaites G, Auckland C, Barlow G, et al. Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial; licensee BioMed Central Ltd. 2012. 6. Perlroth J, Kuo M, Tan J, et al. Adjunctive Use of Rifampin for the Treatment of Staphylococcus aureus Infections: A Systematic Review of the Literature. Arch Intern Med. 2008;168(8):805-819. 7. Maor Y, Hagin M, Belausov N, et al. Clinical Features of Heteroresistant Vancomycin- Intermediate Staphylococcus aureus Bacteremia versus Those of Methicillin-Resistant S. aureus Bacteremia. J Infect Dis. (2009) 199 (5): 619-624.