1、Examplesof Operational Need Stimulating Scientific InnovationAntibiotics and Pain ControlWW 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.”Korea Scott,1954:“In any tactical sit
2、uation 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”Vietnam Kell,1991:“A single injection of a broad-spectrum antibiotic with a long half-life should be given prophylactically to personnel on
3、the battlefield to provide bactericidal coverage from the earliest moment after injury occurs.”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 def
4、initive care,“Current US Army doctrine on prehospital care does not call for antibiotic administration by medics in the field”.Why not?!Antibiotics not routinely given in the field by civilian pre-hospital personnel(EMT/paramedic model for medic training).Combat medics dont typically see wound infec
5、tions during the time they care for them may not appreciate their devastating effect.Not a“sexy”topic.Ivory Tower arrogance.Increased Risk of Infectionin Trauma Patients Disruption of Mechanical Barriers Bacterial Contamination Local Wound Factors Invasive Interventions Impaired ResistanceGeneral Pr
6、eventive Measures Adequate and Timely Resuscitation Early Wound Care Antibiotics Tetanus Immune ProphylaxisAdequate and Timely Resuscitation A,B,Cs*Need to maintain a“nearly normal”arterial oxygen tension.Volume Expansion ConsiderationsEarly Wound Care Eliminate Dead Space fluid,blood Delayed Primar
7、y Closure(DPC)4-6 days Early Immobilization of Fractures Soft tissue damage Sterile Dressing contamination,desiccation Debridement excise devitalized tissue Irrigation high pressure,solutionAntibiotics Finite period of time in which infection can be prevented.Miles,Burke.How early,not how long.Fulle
8、n,et al.Both the timing and the choice are important.Thadepalli,et al.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 Ceft
9、riaxone Waterborne Ops Sea Water Vibrio Overwhelming Gm Neg sepsis 50%mortality Fresh Water-AeromonasOur EnvironmentOur EnvironmentTactical Field Care“What We Want in an Antibiotic”Heat/Cold Resistance“Fire and Forget”Long Shelf LifeSingle AgentDurable PackagingEasy PreparationBroad SpectrumMultiple
10、 ApplicationsThe 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.The EAST Practice Management Guidelines(cont)Looking mostly at Class 1 a
11、rticles:More successful regiments included:cefoxin clindamycin with gentamycin tobramycin with clindamycin cefotetan cefamandole aztreonam gentamycinThe 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
12、%,Cefaman36%Jones et al.Cefoxitin vs.Cefotetan No difference Fabian et al.Aztreonam vs.Gent.(both with Clinda)Aztr 3%,Gent13%Fabian et al.What about US?Recommendations Considering special needs:Most applications-Cefoxitin/Cefotetan can cover both ortho and gut trauma,fast,stable.Cefoxin gets edge wi
13、th storage Cefotetan longer half-life onset same For PCN-Allergic:Cipro&Clinda covers bothBUTWhy 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 less
14、ened torso injuries.Therefore,orals are appropriate for vast majority of casualties.Which Orals?Penicillins.Too many serious allergic reactions.Dosing requirements too frequent.Miss most Gram Negs.Which Orals?(cont.)Flouroquinolones Blood levels via PO route similar to IV dosing.Ciprofloxacin.Good v
15、s.Pseudomonas,but not vs.anaerobes.Levafloxacin.Better Gm Pos than Cipro,but still not good for anaerobes.Okay for pseudomonas.Which Orals?(cont.)Flouroquinolones(cont.).Trovafloxacin.Covers Gm pos,neg,and anaerobes.Hepatotoxicity with prolonged use.Absorption delayed by morphine.Moxifloxacin.Covers
16、 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.Recommendation for Oral Dosing Gatifloxacin.400mg PO QD for all penet
17、rating injuries who can take oral meds.Alternative Moxifloxacin 400 mg PO QD.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
18、 3-5 min.)or IM every 12 hours.Review of Oral Antibiotic Choices to Replace GatifloxacinKevin C.OConnor,D.O.LTC,MC,USACommittee on Tactical Combat Casualty CareTampa,FL29 June 2006Current SituationSafetyOverview Serious Adverse Drug Effects have led to withdrawal of four quinolones:Temafloxacin(immu
19、nological 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 200 or 50 within 72hrs of receiving t
20、he drug.Levofloxacin,Gatifloxacin,Ciprofloxacin or CeftriaxoneDysglycemia 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
21、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.Mohr JF
22、,McKinnon PS,Peymann PJ,Kenton I,Septimus E,Okhuysen PC:A retrospective comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin,levofloxacin,ciprofloxacin or ceftriaxone.Pharmacotherapy 2005;25(10):1303-9.SafetyDysglycemiaPhase II/III clinical trials database 14,731 pa
23、tients(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(grepafloxacin=sparfloxaci
24、n levofloxacin ofloxacin=ciprofloxacin.Reinert R.,Schlaeger J.,Lutticken R:Moxifloxacin:a comparison with other antimicrobial agents of in-vitro activity against Streptococcus pneumoniae.Journal of Antimicrobial Chemotherapy 1998;42:803-806.Frothingham R:letter,in response to Bellomo S:Quinolone Saf
25、ety and efficacy(letter).Emerging Infectious Diseases 2005;11(6)985-6.Emerging Infectious Diseases 2005;11(6)986-7.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.
26、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.Lopez H,Sader H,Amabile C,Pedreira W,Munoz Belli
27、do JL,Garcia Rodriquez JA,Grupo MSP-LA:In vitro activity of moxifloxacin against respiratory pathogens in Latin AmericaArticle in Spanish.Rev Esp Quimioter 2002;15(4):325-34.Comparison of Antibiotic SpectrumNotable differences(otherwise rated equally)MoxifloxacinE.faecium (Gm+)Clinical trials lackin
28、g 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 l
29、acking or 30-60%susc.LevofloxacinE.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.
30、C.difficile (anaerobe)Not effective clinically or 5Kotwal R,OConnor K,Johnson T,Mosely D,Meyer D,Holcomb J.“A Novel Pain Management Strategy for Combat Casualty Care during Operation Iraqi Freedom.”Annals of Emergency Medicine 44/2(August 2004):121-127.MAIN OUTCOME MEASURES Pain measured by verbal 0
31、-to-10 pain scale Pretreatment 15-minutes post-treatment 5-hours post-treatment Limitations Prefer visual analog pain scale Four data points missing at 5-hour mark Blunt trauma(fractures,dislocations,sprains)Kotwal R,OConnor K,Johnson T,Mosely D,Meyer D,Holcomb J.“A Novel Pain Management Strategy fo
32、r Combat Casualty Care during Operation Iraqi Freedom.”Annals of Emergency Medicine 44/2(August 2004):121-127.0.01.02.03.04.05.06.07.08.09.010.00 Min15 Min5 HrsTimeSubjective PainThe median pain rating at initial presentation was 7.0(Mean 7.18,SD 1.26,95%confidence interval CI 6.62 to 7.74,N=22).The
33、 median pain rating at 15 min following medication administration was 1.0(Mean 1.41,SD 1.74,95%CI 0.64 to 2.18,N=22),and the median pain rating at 5 hrs following medication administration was 0.5(Mean 1.00,SD 1.37,95%CI 0.32 to 1.68,N=18).Figure 1.Dot Plot of Effect of 1600 mcg OTFC on Subjective P
34、ainRESULTS 0 to 15 minutes Median verbal pain scores declined 6.0 points(p 0.001)0 minutes(median 7.0)15 minutes(median 1.0)15 minutes to 5 hours No difference in pain scores(p=0.157)15 minutes(median 1.0)5 hours(median 0.5)Indicates sustained action of intervention without need for re-dosing(19 of
35、22 needed no additional Rx)Side effects Pruritis(22.7%),nausea(13.6%),emesis(9.1%),LH(9.1%)1 patient with hypoventilation Kotwal R,OConnor K,Johnson T,Mosely D,Meyer D,Holcomb J.“A Novel Pain Management Strategy for Combat Casualty Care during Operation Iraqi Freedom.”Annals of Emergency Medicine 44/2(August 2004):121-127.
