1、Examples of Operational Need Stimulating Scientific Innovation,Antibiotics and Pain Control,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.”,Korea,Scott, 1954: “In any tact
2、ical 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”,Vietnam,Kell, 1991: “A single injection of a broad-spectrum antibiotic with a long half-life should be given prophylactically to p
3、ersonnel on 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. 1
4、5 hour delay to definitive 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 t
5、ypically see wound infections during the time they care for them may not appreciate their devastating effect. Not a “sexy” topic. Ivory Tower arrogance.,Increased Risk of Infection in Trauma Patients,Disruption of Mechanical Barriers Bacterial Contamination Local Wound Factors Invasive Interventions
6、 Impaired Resistance,General Preventive Measures,Adequate and Timely Resuscitation Early Wound Care Antibiotics Tetanus Immune Prophylaxis,Adequate and Timely Resuscitation,A,B,Cs * Need to maintain a “nearly normal” arterial oxygen tension. Volume Expansion Considerations,Early Wound Care,Eliminate
7、 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,Antibiotics,Finite period of time in which infection can be prev
8、ented. Miles, Burke. How early, not how long. Fullen, 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
9、 Clostridial Recommended PCN, Rifampin, Metronidazole, or Ceftriaxone Waterborne Ops Sea Water Vibrio Overwhelming Gm Neg sepsis 50% mortality Fresh Water - Aeromonas,Our Environment,Our Environment,Tactical Field Care “What We Want in an Antibiotic”,Heat/ Cold Resistance,“Fire and Forget”,Long Shel
10、f Life,Single Agent,Durable Packaging,Easy Preparation,Broad Spectrum,Multiple Applications,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 pharmaco
11、kinetics & cost.,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 EAST Practice Management Guidelines (cont),Cefoxitin
12、 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.,What about US? Recommendations,Considering
13、 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,BUT,Why not orals?,No powder to reconstitute. Can carry a lot more. Broad Spect
14、rum / 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.,Which Orals?,Penicillins. Too many serious allergic reactions. Dosing
15、requirements too frequent. Miss most Gram Negs.,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.,Which Oral
16、s? (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
17、 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 penetrating injuries who can take oral meds.Alternative Moxifloxacin 400 mg PO QD.,Final Recommendations in Tactical
18、 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.,Review of Oral Antibiotic Choices to Replace Gatifloxacin,Kevin C. OCo
19、nnor, D.O. LTC, MC, USACommittee on Tactical Combat Casualty CareTampa,FL29 June 2006,Current Situation,Safety Overview,Serious Adverse Drug Effects have led to withdrawal of four quinolones: Temafloxacin (immunological reactions), Grepafloxacin (cardiotoxicity), Trovafloxacin (hepatotoxicity), Spar
20、floxacin (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 wer
21、e withdrawn for TdP and sudden death.,Frothingham R: Quinolone Safety and Efficacy More Important than Potency. Emerging Infectious Diseases 2004;10:156-57.Iannini PB, Kubin R, Reiter C, Tillotson G: Reassuring Safety Profile of Moxifloxacin. Clinical Infectious Diseases 2001; 32(4):1112-4.,2002 Rec
22、ommendation,“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 flo
23、uroquinolones: new weapons in the arsenal of opthalmic antibiotics. Am J Ophthalmol 2002; 133: 463-466,OConnor K, Butler F: Antibiotics in Tactical Combat Casualty Care 2002. Military Medicine 2002;168(11):911-914.,2002 Recommendation,Another study Moxifloxacin was almost as active as trovafloxacin,
24、 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
25、Clin Microbiol Inf Dis 2000; 19: 228-232.,OConnor K, Butler F: Antibiotics in Tactical Combat Casualty Care 2002. Military Medicine 2002;168(11):911-914.,2002 Recommendation,“Gatifloxacin is a good choice for single-agent therapy based on its excellent spectrum of coverage, good safety profile, and
26、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.”,OConnor K, Butler F: Antibiotics in Tactical Comb
27、at Casualty Care 2002. Military Medicine 2002;168(11):911-914.,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),O
28、Connor K, Butler F: Antibiotics in Tactical Combat Casualty Care 2002. Military Medicine 2002;168(11):911-914.,Re-look,Safety Torsades de Pointes,Prolonged QT interval. Grepafloxacin and Sparfloxacin - withdrawn 1996-2001 crude rates for TdP Gatifloxacin 90x cipro Levofloxacin 18x cipro Gatifloxacin
29、 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 cr
30、ossover 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).,Frothingham R: Rates of torsades de pointes associated with ciprofloxacin, ofloxacin,
31、levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 2001:21:1468-72.Owens R., Amprose P: Torsades de pointes associated with fluoroquinolones. Pharmacotherapy 2002;22(5):663-672.Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R: Effects of three fluoroquinolones on QT interval in
32、 healthy adults after single doses. Clinical Pharmacological Therapeutics 2003;73:292-303.,Safety Dysglycemia Outpatient study,Gatifloxacin has been associated with both hypoglycemia and hyperglycemia. As compared to macrolides gatifloxacin was associated with an increase risk of hypoglycemia(Adjust
33、ed 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.,Park-Wyllie LY Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, Dresser L, Low DE, Mamdani MM: Outpa
34、tient gatifloxacin therapy and dysglycemia in older adults. New England Journal of Medicine 2006;354(13):1352-61.,Safety Dysglycemia In-patient study,Serum glucose 200 or 50 within 72hrs of receiving the drug. Levofloxacin, Gatifloxacin, Ciprofloxacin or Ceftriaxone Dysglycemia rates: Gatifloxacin 7
35、6 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
36、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, McKinnon PS, Peymann PJ, Kenton I, Septimus E, Okhuysen PC: A retrospective
37、 comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin or ceftriaxone. Pharmacotherapy 2005;25(10):1303-9.,Safety Dysglycemia,Phase II/III clinical trials database 14,731 patients (8474 moxifloxacin, 6257 comparators). No drug-related hyp
38、oglycemic 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) report
39、ed 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.,Gavin JR 3rd, Ku
40、blin R, Choudhri S, Kubitza D, Himmel H, Gross R, Meyer JM: Moxifloxacin and glucose homeostasis: a pooled-analysis of the evidence from clinical and postmarketing studies. Drug Safety 2004;27(9):671-86.,Efficacy Pseudomonas,Scheld favors ciprofloxacin for known or suspected Pseudomonas aeruginosa i
41、nfections. Favors moxifloxacin for infections in which Streptococcus pneumoniae is likely.,Scheld WM: Maintaining fluoroquinolone class efficacy: review of influencing factors. Emerging Infectious Diseases 2003;9:1-9.,Efficacy Respiratory and Abdominal Pathogens,Moxifloxacin, gatifloxacin, levofloxa
42、cin, 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
43、 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 infect
44、ions. When treating Pseudomonas aeruginosa, the earlier fluoroquinolones such as ciprofloxacin or ofloxacin are the substances of choice.,Wenzler S, Schmidt-Eisenlohr E, Daschner F: Comparative in vitro activities of three new quinolones and azithromycin against aerobic pathogens causing respiratory
45、 tract and abdominal wound infections. Chemotherapy 2004;50(1):40-2.,Efficacy Against 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.Moxifloxa
46、cin 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 ofloxac
47、in and ciprofloxacin.Moxifloxacin grepafloxacin = sparfloxacin 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;4
48、2:803-806. Frothingham R: letter, in response to Bellomo S: Quinolone Safety and efficacy (letter). Emerging Infectious Diseases 2005;11(6)985-6. Emerging Infectious Diseases 2005;11(6)986-7.,Efficacy Respiratory Pathogens / Gram-Positives,Comparison of in vitro activity of moxifloxacin, levofloxaci
49、n 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.,Lopez H, Sader H, Amabile C, Pedreira W, Munoz Bellido 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.,
