Examples of Operational Need Stimulating Scientific Innovation

1. Examplesof Operational Need Stimulating Scientific Innovation Antibiotics and Pain Control

2. WW II Poole, 1944: �The greatest lesson learned from World War II may have been the benefit of the use of penicillin prophylactically in the surgical units close to the front.� - Poole LT: Army progress with penicillin. Br. J Surg 1944; 32: 110-111.- Poole LT: Army progress with penicillin. Br. J Surg 1944; 32: 110-111.

3. Korea Scott, 1954: �In any tactical situation where the casualty cannot reach the aid station until 4-5 hours or longer after wounding, antibiotic therapy by the aidman in the field is most desirable� - Scott R,: Care of the battle casualty in advance of the aid station. Presentation at Walter Reed Army Medical Center Conference on Recent advances in medicine and surgery based on professional medical experiences in Japan and Korea. 19 April 1954.- Scott R,: Care of the battle casualty in advance of the aid station. Presentation at Walter Reed Army Medical Center Conference on Recent advances in medicine and surgery based on professional medical experiences in Japan and Korea. 19 April 1954.

4. Vietnam Kell, 1991: �A single injection of a broad-spectrum antibiotic with a long half-life should be given prophylactically to personnel on the battlefield to provide bactericidal coverage from the earliest moment after injury occurs.� - Kell K: Characteristics of the ideal antibiotic for prevention of wound sepsis among military forces in the field. Review of Infectious Diseases 1991; 13 (Suppl 2): S164-169.- Kell K: Characteristics of the ideal antibiotic for prevention of wound sepsis among military forces in the field. Review of Infectious Diseases 1991; 13 (Suppl 2): S164-169.

5. Somalia Mabry, 2000: 4 of 5 open fractures of the tibia from gunshot wounds became infected. 2 of 2 open fractures of the femur became infected. In all, 15 wound infections in 58 casualties. 15 hour delay to definitive care, �Current US Army doctrine on prehospital care does not call for antibiotic administration by medics in the field��. Mabry RL, Holcomb JB, Baker AM, Cloonan CC, Uhorchhak JM, Perkins DE, Canfield AJ, Hagmann JH: United States Army Rangers in Somalia: An analysis of combat casualties in an urban battlefield. J Trauma 2000; 49: 515-529. Mabry RL, Holcomb JB, Baker AM, Cloonan CC, Uhorchhak JM, Perkins DE, Canfield AJ, Hagmann JH: United States Army Rangers in Somalia: An analysis of combat casualties in an urban battlefield. J Trauma 2000; 49: 515-529.

6. Why not?! Antibiotics not routinely given in the field by civilian pre-hospital personnel (EMT/paramedic model for medic training). Combat medics don�t typically see wound infections during the time they care for them � may not appreciate their devastating effect. Not a �sexy� topic. Ivory Tower arrogance�.

7. Increased Risk of Infectionin Trauma Patients Disruption of Mechanical Barriers Bacterial Contamination Local Wound Factors Invasive Interventions Impaired Resistance 1. Disruption of mechanical barriers - most obvious. 2. Bacterial Contamination Exogenous - carried into wound by the missile or clothing, debris or dirt Endogenous - GI Track - anywhere from the mouth to the anus, or from the vagina. ** Doesn't always "infect" - may simply �contaminate� - depends on the # bacteria and the environment. 3. Local wound factors - dead tissue, vascular supply, etc.. 4. Invasive TX - ET Tubes, trach tubes IV lines, urinary catheters, etc.... Inherent urgency - routine sterile precautions bypassed. 5. Impaired resistance - Defense mechanisms compromised with intravascular volume depletion. *** several series studying penetrating abdominal injuries - most significant factor predictive of post-op infection was the amount of blood transfusions required in the first 24 hours. **Tissue Oxygen Tension PMNLs require O2 to kill bacteria - therefore a patient is more resistant to infection when they are breathing a higher percentage of O2 (like hyperbaric chamber therapy). 1. Disruption of mechanical barriers - most obvious. 2. Bacterial Contamination Exogenous - carried into wound by the missile or clothing, debris or dirt Endogenous - GI Track - anywhere from the mouth to the anus, or from the vagina. ** Doesn't always "infect" - may simply �contaminate� - depends on the # bacteria and the environment. 3. Local wound factors - dead tissue, vascular supply, etc.. 4. Invasive TX - ET Tubes, trach tubes IV lines, urinary catheters, etc.... Inherent urgency - routine sterile precautions bypassed. 5. Impaired resistance - Defense mechanisms compromised with intravascular volume depletion. *** several series studying penetrating abdominal injuries - most significant factor predictive of post-op infection was the amount of blood transfusions required in the first 24 hours. **Tissue Oxygen Tension PMNLs require O2 to kill bacteria - therefore a patient is more resistant to infection when they are breathing a higher percentage of O2 (like hyperbaric chamber therapy).

8. General Preventive Measures Adequate and Timely Resuscitation Early Wound Care Antibiotics Tetanus Immune Prophylaxis Overview SlideOverview Slide

9. Adequate and Timely Resuscitation A,B,C�s * Need to maintain a �nearly normal� arterial oxygen tension. Volume Expansion Considerations This is the order of precedence in care! 1. ABCs - obviously, an apneic patient needs immediate airway and ventilation, but a lesser degree of respiratory dysfunction may be more subtle. ** Need a "nearly normal" arterial oxygen tension. - Hypovolemia and decreased tissue perfusion Study - a non-lethal bacterial inoculum in the peritoneal cavity of rats was uniformly fatal when it followed an episode of shock. - therefore, volume expansion. This is the order of precedence in care! 1. ABCs - obviously, an apneic patient needs immediate airway and ventilation, but a lesser degree of respiratory dysfunction may be more subtle. ** Need a "nearly normal" arterial oxygen tension. - Hypovolemia and decreased tissue perfusion Study - a non-lethal bacterial inoculum in the peritoneal cavity of rats was uniformly fatal when it followed an episode of shock. - therefore, volume expansion.

10. Early Wound Care Eliminate Dead Space fluid, blood Delayed Primary Closure (DPC) 4 - 6 days Early Immobilization of Fractures Soft tissue damage Sterile Dressing contamination, desiccation Debridement excise devitalized tissue Irrigation high pressure, solution 2. Early Wound Care a) Sterile dressing - Tsherne et al. - **Infection rate was 4 times lower following open fracture when sterile dressing was maintained from the scene to the OR As long as wound is open - can dry out - more dead tissue b) Debridement - excise devitalized and damaged tissue. Removes some bacteria, but more importantly removes necrotic muscle, homogenized fat, blood, and foreign bodies that promote and nourish bacterial growth. c) If not debrided - at least use high pressure irrigation - Normal Saline, not antiseptic solutions. d) Eliminate dead space (fluid / blood) Hematoma - low in antibody and complement, and low O2 tension. Therefore, WBCs don't work right! e) When there is extensive contamination... ** Delayed Primary Closure (DPC), 4-6 days. f) Fractures - early immobilization - infection is directly related to soft tissue damage! *** Anything that can be done to enhance rather than to damage perfusion to local tissue is good! 2. Early Wound Care a) Sterile dressing - Tsherne et al. - **Infection rate was 4 times lower following open fracture when sterile dressing was maintained from the scene to the OR As long as wound is open - can dry out - more dead tissue b) Debridement - excise devitalized and damaged tissue. Removes some bacteria, but more importantly removes necrotic muscle, homogenized fat, blood, and foreign bodies that promote and nourish bacterial growth. c) If not debrided - at least use high pressure irrigation - Normal Saline, not antiseptic solutions. d) Eliminate dead space (fluid / blood) Hematoma - low in antibody and complement, and low O2 tension. Therefore, WBCs don't work right! e) When there is extensive contamination... ** Delayed Primary Closure (DPC), 4-6 days. f) Fractures - early immobilization - infection is directly related to soft tissue damage! *** Anything that can be done to enhance rather than to damage perfusion to local tissue is good!

11. Antibiotics Finite period of time in which infection can be prevented. Miles, Burke. How early, not how long. Fullen, et al. Both the timing and the choice are important. Thadepalli, et al. 3. Antibiotics a) Pioneering studies of Miles, et al. and Burke - then confirmed by Alexander & Altemeier, and Edlich - All showed that there is a finite period of time in which infection can be prevented. b) Maximum protection is provided when antibx given before bacterial contamination (i.e. dental prophylaxis) ** How early is what counts - in all trials looking at duration of antibx tx, the shorter durations have been as effective as the longer regimens **Dellinger 1986 In trauma patients, can't really give antibx "before", but -Fullen et al (1972) - 3 groups of penetrating abdominal trauma: 295 pts Pre-op, Inter-op, and Post-op -- Pre-op group was clearly superior. (7% vs. 30% total infection rate, 11% vs. 70% when colon had been disrupted!!) - Subsequent study, Thalapelli (1973) - 2 groups: 1. Gentamycin and cephalothin Excellent aerobic coverage, but no anaerobic coverage 2. Gentamycin and Clindamycin Good aerobic and anaerobic coverage ( 10% vs. 27% for total infections, 2% vs. 21% for anaerobes!!) ** Much lower infection rate in 2nd group. Therefore **both the timing and the choice of antibiotic is important. 3. Antibiotics a) Pioneering studies of Miles, et al. and Burke - then confirmed by Alexander & Altemeier, and Edlich - All showed that there is a finite period of time in which infection can be prevented. b) Maximum protection is provided when antibx given before bacterial contamination (i.e. dental prophylaxis) ** How early is what counts - in all trials looking at duration of antibx tx, the shorter durations have been as effective as the longer regimens **Dellinger 1986 In trauma patients, can't really give antibx "before", but -Fullen et al (1972) - 3 groups of penetrating abdominal trauma: 295 pts Pre-op, Inter-op, and Post-op -- Pre-op group was clearly superior. (7% vs. 30% total infection rate, 11% vs. 70% when colon had been disrupted!!) - Subsequent study, Thalapelli (1973) - 2 groups: 1. Gentamycin and cephalothin Excellent aerobic coverage, but no anaerobic coverage 2. Gentamycin and Clindamycin Good aerobic and anaerobic coverage ( 10% vs. 27% for total infections, 2% vs. 21% for anaerobes!!) ** Much lower infection rate in 2nd group. Therefore **both the timing and the choice of antibiotic is important.

12. What Bugs? Yom Kippur War Pseudomonas � 25.6% isolates Gm Neg bacilli � 70% isolates overall Used penicillins Somalia Pseudomonas and polymicrobial Russian Afghanistan Experience Clostridial Recommended PCN, Rifampin, Metronidazole, or Ceftriaxone Waterborne Ops Sea Water � Vibrio Overwhelming Gm Neg sepsis � 50% mortality Fresh Water - Aeromonas Yom Kippur War -Klein RS, Berger SA, Yekutiel: Wound Infections during the Yom Kippur War. Ann Surg 1975; 182-15-21. Somalia Mabry RL, Holcomb JB, Baker AM, Cloonan CC, Uhorchhak JM, Perkins DE, Canfield AJ, Hagmann JH: United States Army Rangers in Somalia: An analysis of combat casualties in an urban battlefield. J Trauma 2000; 49: 515-529. Russian Afghanistan -Badikov VD, Krylov KM, Minnullin IP: Etiological structure and antimicrobial susceptibility of Clostridium in war wound infections. Antbiot Khimioter 1997 (Russian); 42: 33-35. -Badikov VD, Krylov KM, Minnullin IP: The microflora of gunshot and explosive mine wounds in victims delayed for a long time at the prehospital stage. Voen Med Zh 1996 (Russian); 317: 34-37. -Mellor SG, Cooper GJ, Bowyer GW: Efficacy of delayed administration of benzylpenicillin in the control of infection in penetrating soft tissue injuries in war. J Trauma 1996; 43 (Suppl): S128-S134. Yom Kippur War -Klein RS, Berger SA, Yekutiel: Wound Infections during the Yom Kippur War. Ann Surg 1975; 182-15-21. Somalia Mabry RL, Holcomb JB, Baker AM, Cloonan CC, Uhorchhak JM, Perkins DE, Canfield AJ, Hagmann JH: United States Army Rangers in Somalia: An analysis of combat casualties in an urban battlefield. J Trauma 2000; 49: 515-529. Russian Afghanistan -Badikov VD, Krylov KM, Minnullin IP: Etiological structure and antimicrobial susceptibility of Clostridium in war wound infections. Antbiot Khimioter 1997 (Russian); 42: 33-35. -Badikov VD, Krylov KM, Minnullin IP: The microflora of gunshot and explosive mine wounds in victims delayed for a long time at the prehospital stage. Voen Med Zh 1996 (Russian); 317: 34-37. -Mellor SG, Cooper GJ, Bowyer GW: Efficacy of delayed administration of benzylpenicillin in the control of infection in penetrating soft tissue injuries in war. J Trauma 1996; 43 (Suppl): S128-S134.

13. Our Environment

14. Our Environment

15. Tactical Field Care�What We Want in an Antibiotic� What do WE want? -As aboveWhat do WE want? -As above

16. The EAST Practice Management Guidelines The Journal of Trauma - March 2000 Meta-analysis - MEDLINE Search for 1976-1997 After discrimination - 39 articles for review 32 comparing outcome, 7 comparing pharmacokinetics & cost. EAST Practice Management Guidelines -as above Meta-analysis of 55 english-speaking references - eliminated letters to the editor, case reports, review articles.EAST Practice Management Guidelines -as above Meta-analysis of 55 english-speaking references - eliminated letters to the editor, case reports, review articles.

17. The EAST Practice Management Guidelines (cont) Looking mostly at Class 1 articles: More successful regiments included : cefoxin clindamycin with gentamycin tobramycin with clindamycin cefotetan cefamandole aztreonam gentamycin The 7 most successful regiments.The 7 most successful regiments.

18. The EAST Practice Management Guidelines (cont) Cefoxitin vs. Clinda. & Gent. Both 24% Nichols et al. Cefoxitin vs. Tobra. & clinda. vs. Cefamandole Cefox 18%, T&C 29%, Cefaman36% Jones et al. Cefoxitin vs. Cefotetan No difference Fabian et al. Aztreonam vs. Gent. (both with Clinda) Aztr 3%, Gent13% Fabian et al. 1. Nichols (1984) compared cefoxitin to Clinda / Gent. - Both had an infection rate of ~24%, with 5 days of treatment. 2. Jones (1985) compared cefoxitin to tobra / clinda, and to cefamandol. - 96 pts. with colon injuries were equally distributed between the 3 groups. - concluded that both cefoxitin and tobra / clinda were superior to cefamandole. - only 48 hours treatment. 3. Fabian (1992) compared cefoxitin to cefotetan - 515 pts. - found no difference between agents or between 1 and 5 day courses. 4. Fabian also compared aztreonam to gentamycin (both with clindamycin for anaerobic coverage) - Aztreonam appeared superior, likely because dosing of the gentamycin was not appropriately adjusted for traumatic fluid/blood losses. *** One study (class 2) - Weiget (1993) compared ampicillin/sulbactam to cefoxitin - not valid, because twice as many patients in the amp/sulbactam group had their wounds left open (DPC).1. Nichols (1984) compared cefoxitin to Clinda / Gent. - Both had an infection rate of ~24%, with 5 days of treatment. 2. Jones (1985) compared cefoxitin to tobra / clinda, and to cefamandol. - 96 pts. with colon injuries were equally distributed between the 3 groups. - concluded that both cefoxitin and tobra / clinda were superior to cefamandole. - only 48 hours treatment. 3. Fabian (1992) compared cefoxitin to cefotetan - 515 pts. - found no difference between agents or between 1 and 5 day courses. 4. Fabian also compared aztreonam to gentamycin (both with clindamycin for anaerobic coverage) - Aztreonam appeared superior, likely because dosing of the gentamycin was not appropriately adjusted for traumatic fluid/blood losses. *** One study (class 2) - Weiget (1993) compared ampicillin/sulbactam to cefoxitin - not valid, because twice as many patients in the amp/sulbactam group had their wounds left open (DPC).

19. What about US?Recommendations Considering special needs: Most applications - Cefoxitin/Cefotetan can cover both ortho and gut trauma, fast, stable. Cefoxin gets edge with storage Cefotetan longer half-life onset same For PCN-Allergic: Cipro & Clinda covers both See my spreadsheet -as above ** half-life gives cefotetan a slight edgeSee my spreadsheet -as above ** half-life gives cefotetan a slight edge

20. BUT�

21. Why not orals? No powder to reconstitute. Can carry a lot more. Broad Spectrum / Rapid Absorption now available. Only hesitation would be: Penetrating Abd. Trauma. Unconsciousness. Shock. Body Armor has profoundly lessened torso injuries. Therefore, orals are appropriate for vast majority of casualties. Butler, O�ConnorButler, O�Connor

22. Which Orals? Penicillins. Too many serious allergic reactions. Dosing requirements too frequent. Miss most Gram Negs.

23. Which Orals? (cont.) Flouroquinolones � Blood levels via PO route similar to IV dosing. Ciprofloxacin. Good vs. Pseudomonas, but not vs. anaerobes. Levafloxacin. Better Gm Pos than Cipro, but still not good for anaerobes. Okay for pseudomonas. Cipro -Walker RC: The fluoroquinolones. Mayo Clinic Proceedings 1999; 74: 1030-1037. -Appelbaum PC: Quinolone activity against anaerobes. Drugs 1999; 58 Suppl 2: 60-64. Levo -Mosby�s General Rx 11th Edition. 2001. Quoted on MD Consult Website.Cipro -Walker RC: The fluoroquinolones. Mayo Clinic Proceedings 1999; 74: 1030-1037. -Appelbaum PC: Quinolone activity against anaerobes. Drugs 1999; 58 Suppl 2: 60-64. Levo -Mosby�s General Rx 11th Edition. 2001. Quoted on MD Consult Website.

24. Which Orals? (cont.) Flouroquinolones (cont.). Trovafloxacin. Covers Gm pos, neg, and anaerobes. Hepatotoxicity with prolonged use. Absorption delayed by morphine. Moxifloxacin. Covers Gm pos, neg, and anaerobes. Good vs. Clostridium and Bacteroides � same range as metronidazole, and superior to clindamycin. QD dosing. Gatifloxicin. Covers Gm pos, neg, and anaerobes. Very similar to moxifloxacin, but less expensive. QD dosing. Trova Walker RC: The fluoroquinolones. Mayo Clinic Proceedings 1999; 74: 1030-1037. Moxi/Gati -Appelbaum PC: Quinolone activity against anaerobes. Drugs 1999; 58 Suppl 2: 60-64. Hoellman DB, Kelly LM, Jacobs MR, Appelbaum PC: Comparative antianaerobic activity of BMS 284756. Antimicrob Agents Chemother 2001; 45: 589-592. Seciale A, Musumeci R, Blandino G, Milazzo I, Caccamo F, Nicoletti G: Minimal inhibitory concentrations and time-kill determination of moxifloxacin against aerobic and anaerobic isolates. Int J Antimicrob Agents 2002; 19: 11-118. Mather R, Karenchak LM, Romanowski EG, Kowalski RP: Fourth generation flouroquinolones: new weapons in the arsenal of opthalmic antibiotics. Am J Ophthalmol 2002; 133: 463-466. Ackerman G, Schaumann R, Pless B, Claros MC, Goldstein EF, Rodloff: Comparative activity of moxifloacin in vitro against obligately anaerobic bacteria. Eur J Clin Microbiol Inf Dis 2000; 19: 228-232. - Ling ML, Tan PL: In vitro activity of moxifloxacin against local bacterial isolates. Ann Acad Med Singapore 2001; 6: 607-610 Trova Walker RC: The fluoroquinolones. Mayo Clinic Proceedings 1999; 74: 1030-1037. Moxi/Gati -Appelbaum PC: Quinolone activity against anaerobes. Drugs 1999; 58 Suppl 2: 60-64. Hoellman DB, Kelly LM, Jacobs MR, Appelbaum PC: Comparative antianaerobic activity of BMS 284756. Antimicrob Agents Chemother 2001; 45: 589-592. Seciale A, Musumeci R, Blandino G, Milazzo I, Caccamo F, Nicoletti G: Minimal inhibitory concentrations and time-kill determination of moxifloxacin against aerobic and anaerobic isolates. Int J Antimicrob Agents 2002; 19: 11-118. Mather R, Karenchak LM, Romanowski EG, Kowalski RP: Fourth generation flouroquinolones: new weapons in the arsenal of opthalmic antibiotics. Am J Ophthalmol 2002; 133: 463-466. Ackerman G, Schaumann R, Pless B, Claros MC, Goldstein EF, Rodloff: Comparative activity of moxifloacin in vitro against obligately anaerobic bacteria. Eur J Clin Microbiol Inf Dis 2000; 19: 228-232. - Ling ML, Tan PL: In vitro activity of moxifloxacin against local bacterial isolates. Ann Acad Med Singapore 2001; 6: 607-610

25. Recommendation for Oral Dosing Gatifloxacin. 400mg PO QD for all penetrating injuries who can take oral meds. Alternative � Moxifloxacin 400 mg PO QD. Butler, O�ConnorButler, O�Connor

26. Final Recommendations in Tactical Arena (2002) For all open combat wounds: Gatifloxacin 400mg by mouth once a day. If unable to take oral medications (shock, unconsciousness, penetrating abd. Injury): Cefotetan 2gm IV (slow push over 3-5 min.) or IM every 12 hours. Butler, O�ConnorButler, O�Connor

27. Review of Oral Antibiotic Choices to Replace Gatifloxacin Kevin C. O�Connor, D.O. LTC, MC, USA Committee on Tactical Combat Casualty Care Tampa,FL 29 June 2006

28. Current Situation

29. SafetyOverview Serious Adverse Drug Effects have led to withdrawal of four quinolones: Temafloxacin (immunological reactions), Grepafloxacin (cardiotoxicity), Trovafloxacin (hepatotoxicity), Sparfloxacin (cardiotoxicity). Gatifloxacin associated with dysglycemia. Tosufluxacin associated with immunological reactions. Gemifloxacin associated with high rate of rashes (esp. women <40yo). * More than 100 million prescriptions were written for terfenadine and astemizole were written before they were withdrawn for TdP and sudden death.

30. 2002 Recommendation �In general, moxifloxacin was the most potent fluoroquinolone for Gram-positive bacteria while ciprofloxacin, moxifloxacin, gatifloxacin, and levofloxacin demonstrated equivalent potency to Gram-negative bacteria.� Mather R, Karenchak LM, Romanowski EG, Kowalski RP: Fourth generation flouroquinolones: new weapons in the arsenal of opthalmic antibiotics. Am J Ophthalmol 2002; 133: 463-466

31. 2002 Recommendation Another study Moxifloxacin was almost as active as trovafloxacin, as active as gatifloxacin, and more active than levofloxacin and ciprofloxacin against the anaerobes tested (including Clostridium species) Ackerman G, Schaumann R, Pless B, Claros MC, Goldstein EF, Rodloff: Comparative activity of moxifloxacin in vitro against obligately anaerobic bacteria. Eur J Clin Microbiol Inf Dis 2000; 19: 228-232.

32. 2002 Recommendation �Gatifloxacin is a good choice for single-agent therapy based on its excellent spectrum of coverage, good safety profile, and once-a-day dosing. Moxifloxacin would be an acceptable second choice. A third choice might be levofloxacin, but because levofloxacin has only limited activity against anaerobes, another drug must be added to achieve coverage against these organisms.�

33. 2002 Recommendation Recommendation for Oral Dosing Gatifloxacin. 400mg PO QD for all penetrating injuries who can take oral meds. (US Govt. cost August 2002 $1.86) Alternative � Moxifloxacin 400 mg PO QD. (US Govt. cost August 2002 $5.09) Butler, O�ConnorButler, O�Connor

34. Re-look

35. SafetyTorsades de Pointes Prolonged QT interval. Grepafloxacin and Sparfloxacin - withdrawn� 1996-2001 crude rates for TdP Gatifloxacin 90x cipro Levofloxacin 18x cipro Gatifloxacin 5x rate for levo Moxifloxacin � no US cases. (3 foreign cases) ?? Confidence Interval Gatifloxacin associated with highest rate of TdP, Moxifloxacin associated with lowest. BUT� - Preclinical and clinical trials indicate that levofloxacin, moxifloxacin, and gatifloxacin all prolong QT interval. Small crossover study, a single oral dose of moxifloxacin 800mg associated with greater QT interval prolongation (16-18 milliseconds) than ciprofloxacin 1500mg (2-5 milliseconds) or levofloxacin 1000mg (4-5 milliseconds).

36. SafetyDysglycemia � Outpatient study Gatifloxacin has been associated with both hypoglycemia and hyperglycemia. As compared to macrolides � gatifloxacin was associated with an increase risk of hypoglycemia (Adjusted Odds Ratio 4.3, 95% Confidence Interval). Levofloxacin was also associated with slightly increased risk (AOR = 1.5, 95% CI) No increased risk with moxifloxacin, ciprofloxacin, or cephalosporins.

37. SafetyDysglycemia � In-patient study Serum glucose >200 or <50 within 72hrs of receiving the drug. Levofloxacin, Gatifloxacin, Ciprofloxacin or Ceftriaxone Dysglycemia rates: Gatifloxacin 76 of 7540 pts. (1.01%) Levofloxacin 11 of 1179 pts. (0.93%) Ceftriaxone 14 of 7844 pts. (0.18%) Ciprofloxacin 0 of 545 pts. (0%) Of the 101 patients with dysglycemia, hypoglycemia occurred in 9 (9%) and hyperglycemia in 92 (91%). In the 17,108 patients receiving a fluoroquinolone or ceftriaxone, the rate of dysglycemia was greater in those receiving levofloxacin or gatifloxacin, than in those receiving Ceftriaxone. However, there was no statistically significant difference between levofloxacin and gatifloxacin.

38. SafetyDysglycemia Phase II/III clinical trials database 14,731 patients (8474 moxifloxacin, 6257 comparators). No drug-related hypoglycemic events in moxifloxacin group. Two drug-related hypoglycemic events with levofloxacin. One with trovafloxacin. Seven hyperglycemic events in moxifloxacin group (<.1%). One hyperglycemic events with comparators (<0.1%). Data from five moxifloxacin postmarketing studies (46,130 subjects) reported no episodes of hypoglycemia and two non-drug-related hyperglycemic episodes. Conclusion: Comprehensive analysis of datapool for moxifloxacin Phase II/III trials and post-marketing studies suggest that moxifloxacin administration has no relevant effect on blood glucose homeostasis.

39. EfficacyPseudomonas Scheld favors ciprofloxacin for known or suspected Pseudomonas aeruginosa infections. Favors moxifloxacin for infections in which Streptococcus pneumoniae is likely.

40. EfficacyRespiratory and Abdominal Pathogens Moxifloxacin, gatifloxacin, levofloxacin, and azithromycin compared. in-vitro susceptibility of common pathogens that cause respiratory tract and abdominal wound infections. 50 isolates each MRSA, E. faecalis, E. faecium, S. pneumoniae, S. pyogenes, E. coli, P. aeruginosa, & H. influenzae. Results: Moxifloxacin was most active substance vs. Gram-positive pathogens. Gatifloxacin most active vs. Pseudomonas. Moxifloxacin & Gatifloxacin comparable vs. E. coli and H. influenzae. Conclusions: Moxifloxacin and gatifloxacin display excellent activity vs. respiratory pathogens as well as nosocomial pathogens causing abdominal wound infections. When treating Pseudomonas aeruginosa, the earlier fluoroquinolones such as ciprofloxacin or ofloxacin are the substances of choice.

41. EfficacyAgainst Gram-Positives Older flouroquinolones (i.e. ciprofloxacin) � limited ability to cover Gram-positive bacteria. Cipro MIC90 for S. pneumonia is 1-4 mg/L, while the maximum concentrations in serum are 2-3 mg/L. Moxifloxacin had the highest in-vitro activity vs. S. pneumonia (MIC90=0.25 mg/L; MIC range 0.06-0.25 mg/L) The MIC90 values were one dilution lower than those obtained with sparfloxacin and grepafloxacin. Three dilutions lower than those obtained with levofloxacin. Four dilutions lower than those of ofloxacin and ciprofloxacin. Moxifloxacin > grepafloxacin = sparfloxacin > levofloxacin > ofloxacin = ciprofloxacin.

42. EfficacyRespiratory Pathogens / Gram-Positives Comparison of in vitro activity of moxifloxacin, levofloxacin and six other antibiotics frequently used for URIs. 1563 isolates S. pneumonia, S. pyogenes, S. aureus, H. influenzae, and M. catarrhalis. 21 centers in 10 Latin American countries Findings: Moxifloxacin was the most active compound vs. all the species included. Moxifloxacin was 2 � 4 fold more active than levofloxacin vs. gram positive bacteria.

43. Comparison of Antibiotic SpectrumNotable differences (otherwise rated equally) Moxifloxacin E. faecium (Gm+) Clinical trials lacking or 30-60% susc. S. aureus (MRSA) (Gm+) Usually effective clinically or >60% susc. S. (X.) maltophilia (Gm-) Usually effective clinically or >60% susc. Actinomycetes (anaerobe) Usually effective clinically or >60% susc. B. fragilis (anaerobe) Clinical trials lacking or 30-60% susc. C. difficile (anaerobe) Clinical trials lacking or 30-60% susc. Levofloxacin E. faecium (Gm+) Not effective clinically or <30% susc. S. aureus (MRSA) (Gm+) Not effective clinically or <30% susc. S. (X.) maltophilia (Gm-) Clinical trials lacking or 30-60% susc. Actinomycetes (anaerobe) (No data available) B. fragilis (anaerobe) Not effective clinically or <30% susc. C. difficile (anaerobe) Not effective clinically or <30% susc.

44. Costs Levofloxacin (Levoquin�) 500mg $1.95 per dose � DoD pricing Moxifloxacin (Avelox�) 400mg $1.22 per dose � DoD pricing

45. Recommendation Replace Gatifloxacin 400mg x 1 with Moxifloxacin 400mg x1 taken orally for all combat wounds.

46. Tactical Field Care - Antibiotics Recommended for all open wounds Use PO moxifloxacin 400 mg a day if able If casualty is unconscious, has an abdominal wound, or is in shock: Cefotetan 2 gm slow IV push (over 3-5 minutes) or IM every 12 hours O�Connor K, Butler F. �Antibiotics in Tactical Combat Casualty Care 2003.� Military Medicine 168/11 (November 2003): 911-914. NOW - Ertapenam 1gm IV / IM qD (recent change)

49. Introduction �Pain is a more terrible lord of mankind than even death itself.� -Albert Schweitzer.

50. �Oligoanalgesia� Term coined in 1989 by Wilson and Pendleton. The phenomena that care-givers often fail to either recognize or appropriately treat pain.

51. Pain As Interpreted by the Casualty �It is, of course, a complete myth that a standard cause produces a standard pain�� - Patrick Wall Wall PD. Pain: The Science of Suffering. London: Weidenfeld & Nicolson; 1999 �It is, of course, a complete myth that a standard cause produces a standard pain. However the myth affects the reactions of patients, medical staff, and friends alike. If you walk into an accident and emergency department with a broken wrist, you are matching the pain you feel with the pain you expect to feel with a broken wrist. They rarely match. You may be astonished if it does not hurt. You feel additionally miserable if your pain reduces you to a helpless, weeping wretch. The nurses and doctors instantly spot that you have a wrist at a strange angle, make a diagnosis and assign you to a category. For them, a broken wrist comes with an appropriate package of pain and deserves a fixed protocol of action. You as an individual may be anxious, terrified, drunk, or sad, but for them you become �the broken wrist in cubicle 6��.�.�It is, of course, a complete myth that a standard cause produces a standard pain. However the myth affects the reactions of patients, medical staff, and friends alike. If you walk into an accident and emergency department with a broken wrist, you are matching the pain you feel with the pain you expect to feel with a broken wrist. They rarely match. You may be astonished if it does not hurt. You feel additionally miserable if your pain reduces you to a helpless, weeping wretch. The nurses and doctors instantly spot that you have a wrist at a strange angle, make a diagnosis and assign you to a category. For them, a broken wrist comes with an appropriate package of pain and deserves a fixed protocol of action. You as an individual may be anxious, terrified, drunk, or sad, but for them you become �the broken wrist in cubicle 6��.�.

52. Fundamentals Reassurance Distraction Immobilization

53. Types of Medications Non-Opioids Acetaminophen NSAIDs Other Sedative Hypnotics Dissociatives Opioids Full agonists Partial agonists Mixed

54. OpioidsGeneral 1680 A.D. ��among the remedies it has pleased Almighty God to give man to relieve his sufferings, none is so universal and so efficacious as opium.� -Syndenham Jaffee JH, Martin WR: Opioid analgesics and antagonists. In Gilman AG. Wall TW, Neis AS, et al (eds): The pharmacologic basis of therapeutics, ed 8, New York, 1993, McGraw-Hill.

55. OpioidsGeneral 2002 A.D. ��among the remedies it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opioid derivatives�� - O�Connor Today, SOMA, 2002

56. OpioidsGeneral Drugs of choice for severe pain Adverse effects Respiratory depression Sedation/lightheadedness Nausea/vomiting Constipation Tolerance Dependence Unlike NSAIDs, NO ceiling for analgesic effectiveness, except those imposed by adverse reactions. When comparing occurrence and severity of side effects � can easily make the case that opioids are safer than NSAIDs. Tolerance to analgesic effects common, tolerance to adverse effects as well, with the exception of constipation � where tolerance does not occur. Dependence � after several weeks Perry, 1982 � No cases of new drug addiction in 10,000 patients treated in burn units.Unlike NSAIDs, NO ceiling for analgesic effectiveness, except those imposed by adverse reactions. When comparing occurrence and severity of side effects � can easily make the case that opioids are safer than NSAIDs. Tolerance to analgesic effects common, tolerance to adverse effects as well, with the exception of constipation � where tolerance does not occur. Dependence � after several weeks Perry, 1982 � No cases of new drug addiction in 10,000 patients treated in burn units.

57. OpioidsFull Agonists Morphine related Morphine Hydromorphone Oxymorphone Heroin Codeine related Codeine Oxycodone Hydrocodone Dihydrocodeine Synthetic Meperidine Fentanyl Methadone Proproxyphene Levorphanol Tramadol

58. OpioidsFull Agonists � Long Acting Morphine Standard of comparison Onset: IV: 4-6 min Duration: 2-3 hours Onset: IM: 20-60 min Duration: 4-5 hours Long Acting Morphine is the standard of comparison for strong parenterals. Also available orally or rectally. 0.1-0.2mg/kg IV, IM, SC. Onset after IM is 20-60min, duration 4-5 hrs. IV onset 4-6 min, duration 2-3 hrs. Traditional dosing based on weight � in fact, there is NO correlation between pt. Wt. and opioid requirement. The best clinical predictor is age. Avg. 24 hr requirement MS for pts over 20yo is 100 minus age in years. **Assume most combatants between 20-40 � (i.e. 24 � would be 76mg). At 8 x 3 hr dosing = 9mg � at 12 x 2hr dosing = 6.3. Long Acting Morphine is the standard of comparison for strong parenterals. Also available orally or rectally. 0.1-0.2mg/kg IV, IM, SC. Onset after IM is 20-60min, duration 4-5 hrs. IV onset 4-6 min, duration 2-3 hrs. Traditional dosing based on weight � in fact, there is NO correlation between pt. Wt. and opioid requirement. The best clinical predictor is age. Avg. 24 hr requirement MS for pts over 20yo is 100 minus age in years. **Assume most combatants between 20-40 � (i.e. 24 � would be 76mg). At 8 x 3 hr dosing = 9mg � at 12 x 2hr dosing = 6.3.

59. Patient Controlled Analgesia Patient Titration Element of Control Less total medication used Much improved patient satisfaction / sense of pain relief provided

60. Oral Pain Medications Provide pain relief without altered mental status Many combat wounds without bony injuries only mild-moderate pain Non-narcotics meds preserve combatant ability of casualty

61. Tactical Field Care - PAIN: Analgesia as Necessary If Able to Fight - Use oral meds Meloxicam (Mobic�) � 15mg PO QD Rofecoxib (Vioxx�) (original recommendation) - 50 mg per day No platelet inhibition No sulfa reactions Acetaminophen � (Tylenol� 8hr Bi-layer) 1300 mg NO decrease in mental status as a result of these medications

62. Combat Pill Pack

63. Tactical Field Care - Analgesia as Necessary If Unable to Fight Morphine 5 mg IV/IO Reassess in 10 minutes Repeat dose q10min as necessary to control severe pain Monitor for respiratory depression Promethazine 25 mg IV/IO/IM q4h (for pain and nausea) (New Rec � only PRN�)

64. Oral Transmucosal Fentanyl Citrate

65. OTFC

66. DESIGN, SETTING, and PATIENTS

67. MAIN OUTCOME MEASURES

69. RESULTS