MILITARY MEDICINE, 168, 11:911.2003

Antibiotics in Tactical Combat Casualty Care 2002

Guarantor: CAFT Frank Butler. MC USNContributors: MAJ Kevin O'Connor, MC USA*; CAPT Frank Butler, MC USNf

Care of casualties in the tactical combat environment shouldinclude the use of prophylactic antibiotics for all openwounds. Cefoxitin was the antibiotic recommended in the1996 article "Tactical Combat Casualty Care in Special Oper-ations." The present authors recommend that oral gatifloxacinshould be the antibiotic of choice because of its ease of car-riage and administration, excellent spectrum of action, andrelatively mild side effect profile. For those casualties unableto take oral antibiotics because of unconsciousness, penetrat-ing abdominal trauma, or shock, cefotetan is recommendedbecause of its longer duration of action than cefoxitin.

Introduction

I nfections are an important cause of late morbidity and mor-tality in combat trauma. The need for early administration of

antibiotics was recognized 50 years ago. when Poole' stated that"the greatest lesson learned from World War II may have beenthe benefit of the use of penicillin prophylactically in the surgicalunits closest to the front." Scott- commented after the KoreanWar that "In any tactical situation where the casualty cannotreach the aid station until 4 or 5 hours or longer after wounding,antibiotic Uierapy by the aidman in the field is most desirable."Sepsis was the major cause of mortality in rear echelon hospi-tals during the Vietnam conflict, particularly in the setting ofextensive bums or penetrating trauma to the head or centralner\'ous system,-' Hell'' states that "a single injection of a broad-spectrum dmg with a long half-life should be given prophylac-tically to personnel on the battlefield to provide bactericidalcoverage from the earliest moment after injury occurs," Civiliantrauma care also includes the use of prophylactic antibiotics.One standard surgical text notes that "All injured patients un-dergoing an operation should receive preemptive antibiotic ther-apy."''

Despite these observations and the lessons of past conflictshowever, as recently as the 1993 Mogadishu action, antibioticswere not being used by U,S. combat medics,*"' Mabry et al,reported that four of the five open fractures of the tibia fromgunshot wounds sustained in this battle became infected. Bothopen fractures ofthe femur also became infected. In all. therewere 15 wound infections in 58 casualties, Mabry noted that•"current U.S, Army doctrine on prehospital care does not call forantibiotic administration by medics in the field," Why has thisseemingly simple step in battlefield trauma care been so difficultto implement?

One reason that the military has been slow to adopt thepractice of using battlefield antibiotics is that antibiotics are notroutinely given in civilian prehospital trauma care. One textnotes that "Antibiotics are widely utilized for the prophylaxis of

'Combat Appllcalions Group (ABN). Fort Bragg. NC.+Naval Special Warfare Command. Detachment Pensacola, Naval Hospilal

Pensacola, FL.This lîianuscript was received for review in September 2002, The revised manu-

script was accepted for publication in Febmarv' 2003,

infections in trauma care. It is emphasized that they should beapplied early, before an operation is earned out. to be of any use.So far. however, their prehospital use has not been validated."''The current edition of the American College of Surgeons-spon-sored Prehospilal Trawna Life Support Manual contains no men-tion of prehospital antibiotics in civilian care,* This practice isquite reasonable given the short transport times to the hospitalin most urban trauma centers.

Combat medical personnel who provide prehospital care fortheir wounded teammates on the battlefield, however, do sounder conditions profoundly different from those found in civil-ian emergency medical systems, The treatment strategies thatthey use need to take into account the prolonged delays toevacuation commonly encountered in combat operations. Therewas a 15-hour delay to definitive care for most casualties inMogadishu,^ Because of these differences, there has been arenewed call for antibiotics to be included in the care providedby combat medics when there is penetrating abdominal trauma.massive sofi tissue damage, a grossly contaminated wound, anopen fracture, or when a long delay until Casualty Evacuation isanticipated.^ In acknowledgment of the differences between thecivilian and the military prehospital settings, this recommenda-tion has now been included in the Prehospital Traunia Life Siip-poñ Manual for battlefield trauma, and it is clear that battlefieldantibiotics should be added to the care provided by combatmedics.'''

For prophylaxis with antibiotics to be practical and effective,the regimen chosen must be as simple as possible, and theantibiotic should be administered as soon as possible after theinjury occurs. The antibiotic coverage has to be maintained atleast until surgical debridement has been performed.'' Coveragemust be appropriate for the organisms implicated in combatwound infections, Klein et al." noted that combatants in theYom Kippur War were treated with penicillin. The most commonorganism found in wound infections in that conflict was Pseudo-monas, comprising 25.6% of clinical isolates. Gram-negativebacilli were found to be 70,2% of isolates overall, ' ' Mabry et al.''also found that Pseudomonas and polymicrobial infections werea significant cause of morbidity after the Mogadishu action.Reports from the Russian experience in Afghanistan stated thatclostridial species remain an important pathogen on the modembattlefield.'^'^

The timing of administration is likewise important. Intramus-cular benzyl penicillin, begun within 1 hour of wounding, waseffective in preventing streptococcal infections in a pig model offragment wounds. If administration was delayed until 6 hoursai'ter wounding, however, the medication was not effective.'''

Cefoxitin (2 g intravenously] has previously been recom-mended for battlefield use.''-"^ This drug is an accepted mono-therapentic agent for empiric treatment of abdominal sepsis'^and provides good coverage for patients with penetrating ab-dominal trauma.'*^" Cefoxitin is effective against Gram-positive

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912 Antibiotics in Tactical Combat Casualty

aerobes (except some Enterococcus species) and Gram-negativeaerobes (except for some Pseudomonas species), it also has goodactivity against anaerobes (including Baderoides and Clostjid-ium species).'^ Cefoxitin is supplied as a dry powder, whichmust be reconstituted by the combat medic with 10 ml of sterilewater for injection before administration. It may be given as aslow intravenous push over 3 to 5 minutes.'^ Cefoxitin may alsobe given intramuscularly if necessar\', ' Additional doses shouldthen be administered at 6-hour intervals until the casualtyarrives at a treatment facility.

Gatifloxacin for Oral Antibiotic Prophylaxis

The logistical burden of reconstituting and injecting paren-terai medications makes the use of oral antibiotics an attractivealternative if feasible. In some casualties, oral antibiotics areclearly not an option (penetrating abdominal trauma, uncon-sciousness, shock). In patients without contraindications, how-ever, oral antibiotic prophylaxis is practical and appropriate.The United States Special Operations Command-sponsoredworkshop on Tactical Management of Urban Warlare Casualtiesheld in Tampa in December 1998 focused on the Battle of Mo-gadishu and identified a number of potential improvements inthe battlefield care of combat casualties. Participants in thisworkshop noted that an orally administered antibiotic wouldhave several advantages.''^ Giving antibiotics to a woundedteammate would require no more than swallowing a tablet witha sip of water from a canteen and wouid eliminate the need formLxing aiid parenterai administration. With a long-acting oralantibiotic, Special Operations (SOF) combat medics couid easilycarr\' an adequate supply of antibiotics for several days for theentire unit.

Penicillins are not a good choice in this setting because they:(1) cause too many severe allergic reactions, (2) require toofrequent dosing, and (3) are not active against most Gram-negative organisms. The fluoroquinolones. on the other hand,have an excellent spectrum of antibacterial action. Ciprofloxa-cin has good coverage against Pseudomonas species " but littleactivity against anaerobes,^"^' LevoOoxacin has more actionagainst Gram-positive organisms than ciprofloxacin. but it isless effective against Pseudomonas and is also not reliably ef-fective against anaerobes. Le\'ofloxacin has some activityagainst Pseudomonas and is indicated for urinary tract infec-tions caused by this organism. ^ Trovafloxacin is effectiveagainst Gram-positive. Grani-negative, and anaerobic organ-isms.-" Moxifloxacin and gatifloxacin are also fourth-generationfluoroquinolones that have an enhanced spectrum of acti\1ty.Trovafloxacin. gatifloxacin. and moxifloxacin yield low mini-mum inhibitory concentrations against most groups of anaer-obes.^'^^ One study found that moxifloxacin actiWty againstClostridium and Bacteroides species was in the same range asmetronidazole and superior to that of clindamycin, * Anotherstudy found that "In general, moxifloxacin was the most potentfluoroquinolone ibr Gram-positive bacteria while ciprofloxacin.moxifloxacin, gatifloxacin. and ievofloxacin demonstratedequivalent potency to Grani-negative bacteria."^^ A third studyfound that moxifloxacin was almost as active as trovafioxacin.as active as gatifloxacin, Emd more active than levofloxacin andciprofloxacin against the anaerobes tested (including Clostrid-ium species), ^ Blood levels of the fluoroquinolones achieved

with oral dosing are similar to those achieved with intravenousdosing: therefore, oral administration does not signiflcantly re-duce the bioavailablity of these agents.

Fourth-generation fluoroquinolones have an additional ben-efit in SOF casualties. Because SOF operations often entailimmersion in sea or fresh water, infections with pathogensfound in these emironmenls must be considered as wefl.Wounds contaminated ulth seawater are susceptible to infec-tions with Vibrio species. Gram-negative rods that can result inan overu'helming Gram-negative sepsis with a 50% mortalityrate.^' Contamination of wounds with fresh water may result ininfections with Aeromonas species, also a Gram-negative rod,^'The excellent Gram-negative coverage of fourth-generation fluo-roquinolones make them good choices in these circumstances.

In addition to the ease and the logistical advantages of oraladministration, the fluoroquinolones require less frequent dos-ing. Both moxifloxacin and gatifloxacin are given as a singledaily 400-mg dose. Imagine a SOF team with three seriouslywounded individuals that cannot be extracted for 48 hours. Tomaintain antibiotic coverage with cefoxitin (as pre\1ously rec-ommended) Ibr all three casualties would require 24 parenteraidoses-a quantity that SOF corpsmen and medics are not likelyto carry. In contrast, six tablets of one of the fluoroquinoloneswould suffice for the same period.

In contrast to the penicillins and the sulfa-based antibiotics,the fluoroquinolones also have an excellent safety profile. Areview in the October 1999 Mayo Clinic Proceedings stated thatthey are tolerated as well or better than any other class ofantibacterial agents.^" The best known toxic effect of the fluoro-quinolones has been the severe hepatotoxicity seen with trova-floxacin. but this was seen in only 140 patients of 2,5 mñlionprescriptions and was usually seen after long-term (more than28 days) use of the medication,^" Another disadvantage of trova-floxacin is that its absorption is delayed by morphine, which willoften be used on combat casualties. Gastrointestinal upset isseen in approximately 5% of patients treated with fluoroquino-lones. and mfld allergic reactions (rash, urticaria, and photo-sensitivity) are seen in 1% to 2% of patients. Mild central ner-vous system symptoms (headache and dizziness] are alsoencountered in 5% to 10% of patients treated with the fluoro-quinolones. '

Based on the discussion above, either moxifloxacin or gati-floxacin would be a good choice for an ora! antibiotic to use onthe battlefield, A cost comparison of these two agents performedby the Naval Hospital Pensacola pharmacy in August 2002found that the cost to the U.S. government for a single dose ofmoxifloxacin was S5,09. whereas a single dose of gatifloxacinwas only $1.86, This cost comparison is based on the Depart-ment of Defense-wide pricing schedules. Based on the muchlower cost of gatifloxacin with other factors being approximatelyequal, gatifloxacin emerges as the best choice for an oral anti-biotic. Use of an oral antibiotic means that gatifloxacin can becarried by individual combatants, if they have been trained in itsuse. and self-administered in the event of penetrating trauma.

One of the considerations in a medication chosen for use byground troops in the field is its ability to maintain its acti\'ity inhot and cold environments. The recommended storage temper-ature for gatifloxacin is 25T with 15X to 30T listed as theacceptable temperature range.'^ If true, this would limit the

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Antibiotics in Tactical Combat Casualty 913

drug's usefulness to ground combat troops. Correspondence onthis issue with the manufacturer, Brisi:ol-Myers Squibb, hasindicated that jfatifloxacin tablets packaged in polwinyl chlo-ride/poly\1nylidene chloride blisters have excellent stability at awider range of ambient temperatures with documented mainte-nance of efficacy for 260 weeks at temperatures of 30X andlower. Efficacy was maintained for 56 weeks at 4O''C/75% rela-tive humidity and for 27 weeks at 50X (P. Carpenter. J. Ber-gum. Bristol-Myers Squibb, unbpublished data).

Gatiiloxacin is a good choice for single-agent therapy basedon its excellent spectrum of coverage, good safety profile, andonce-a-day dosing, Moxifloxacin would be an acceptable secondchoice, A third choice might be levofloxacin. but because levo-floxacin has only limited activity against anaerobes, anotherdmg must be added to achieve coverage against these organ-isms. The most active drugs for the treatment of anaerobicinfections are clindamycin and metronidazole.'" Relatively fewanaerobes are resistant to clindamycin and few. if any. areresistant to metronidazole.^^ Metronidazole has the additionaladvantage of having a less severe side effect profile than clinda-mycin,

Cefotetan Instead of Cefoxitin When ParenteralAntibiotics Are Needed

There are some casualties in whom the use of oral antibioticsis not advisable. An unconscious casualty is not able to take themedication. An individual in shock will have a reduced mesen-teric blood flow that might interfere with absorption of an oralagent. Casualties with penetrating abdominal trauma may havea mechanical disruption ofthe gastrointestinal tract that wouldimpede absorption of an oral antibiotic. Effective antibiotic pro-phylaxis is especially important in this group of patients. Onestudy of 338 patients with penetrating trauma to the abdomenwere reported by Dellinger et al.-'' Even in this civilian traumacenter setting. 24% of patients developed wound infections, andnine died as a result.

Use of cefotetan as an alternative lo cefoxitin as a battlefieldantibiotic was first proposed by O'Connor, ' Cefotetan is a sim-ilar medication with the same broad spectrum of action, butwith a longer half-life that allows every 12-hour dosing. Bothcefoxitin and cefotetan were recommended by Osmon'" as pro-phylactic agents for adults undergoing colorectal surgery and byConte' - for trauma victims with a ruptured viscus.

A meta-analysis on antibiotic prophylaxis in penetratingtrauma was published by Luchette et al.-*'' in 2000. The moresuccessful regimens included: cefoxitin. gentamicin with clin-damycin. tobramycin with clindamycin. ceibtetan, cefamandole,aztreonam. and gentamicin alone. Nichols et ai,- -' comparedcefoxitin to a gentamicin/clindamicin combination in penetrat-ing abdominal trauma and found them to be equivalent. Joneset al.'' compared cefoxitin. cefamandol. and a tobramycin/clin-damycin combination in patients with penetrating colontrauma. They concluded that both cefoxitin and the tohramy-cin/clindamycin combination were superior to cefamandole. In1992. Fabian et ai.' ^ compared cefoxitin with cefotetan directly.This study included 515 patients, and they found no differencein efficacy between the two agents.

Whereas cefoxitin and cefotetan appear to be equal in efficacy.the longer half-life and comparable cost make cefotetan a better

choice for use by combat corpsmen and medics. Cefoxitin re-mains a \aable alternative and a good second choice. With bothchoices, dry powders must be reconstituted manually with ap-propriate diluenls. Packaging that allowed for streamlined han-dling in tactical environments would represent an invaluableadvance in the military application of these products. Currentrecommendations for storage of cefotetan in the powder fomi arethat the vials not be stored at temperatures above 22"C (72''F)and that they be protected from light.'" Expanded storage andhandling guidelines for use in the field should be addressed withthe manufacturer should this agent be chosen for use by combatmedical personnel.

Antibiotics may be useful to prevent the development ofwound infections, but there is no guarantee that they will beeffective in all casualties. Wound infection is a function of thenumber and type of contaminating organisms, the amount ofdevitalized tissue, the presence of foreign bodies in the wound,and the delay to surgical care. Wounds with large quantities oforganisms, foreign bodies, or dead tissue may become infecteddespite the early use of antibiotics. The use of antibiotics forcombat trauma does not lessen the importance of timely surgi-cal treatment of the wound, and there should be no decreasedemphasis on Lhe need to obtain definitive care as soon as feasi-ble. In the event of a prolonged delay in evacuation, antibioticuse should be continued until the casualty reaches a medicaltreatment facility.

The widespread use of a particular antibiotic eventually pro-duces organisms that have developed a resistance to it. It iscommon practice to use antibiotics for a variety of minor upperrespiratory infections, and these infections are common in de-ployed troops. Should these recommendations be implementedby the military, the importance of avoiding the use of gatifloxa-cin for the treatment of minor infections in deployed troopsshould be emphasized to decrease the development of resistantorganisms.

Conclusion

We propose that prophylactic antibiotics be used by combatmedical personnel for all open combat wounds. Where there isno contraindication to the use of oral antibiotics. (1) gatifloxa-cin, 400 mg, by mouth once a day and (2) if unable to take oralmedications (shock, unconscious, or penetrating abdominal in-jury), cefotetan. 2 g. intravenously (slow push over 3-5 minutes)or intramuscularly every 12 hours.

Acknowledgments

The aiilhors thank COL John Holcomb. CAFT Roger Edwards,CDR Scott Fiinn, CDR JeffTimby. CDR Les Fenton. Dr, Dave Perlmaii,LT Ro^er Bunch, and LCDR Tony Capano for assistance in the prepara-tion of this article.

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