a. Fluoroquinolones inhibit bacterial DNA synthesis by inhibiting DNA gyrase, which folds DNA into a superhelix in preparation for replication. The flu- oroquinolones exhibit a broad spectrum of activity, excellent oral absorp- tion and bioavailability, and are generally well tolerated (photosensitivity, cartilage and tendon damage). These are potent agents with an unfortu- nate propensity to develop resistance rapidly. Agents with both parenteral and oral formulations include ciprofloxacin, levofloxacin, and moxifloxacin (which has some anti-anaerobic activity). Fluoroquinolones are most active against enteric gram-negative bacteria, particularly the Enterobacteriaceae and Haemophilus spp. There is some activity against P. aeruginosa, S. maltophilia, and GPC. Activity against GPC is variable, being least for ciprofloxacin and best for moxifloxacin. Ciprofloxacin has been most active against P. aeruginosa, but rampant overuse of fluoroquinolones is rapidly causing resistance that may limit the future usefulness of these agents. Fluo- roquinolone use has been associated with the emergence of resistant E. coli, Klebsiella spp., P. aeruginosa, and MRSA. Fluoroquinolones prolong the QTc interval and may precipitate the ventricular dysrhythmia torsades de pointes, so electrocardiographic measurement of the QTc interval before and during fluoroquinolone therapy is important. Also, fluoroquinolones interact with warfarin to cause a rapid, marked prolongation of the International Nor- malized Ratio (INR), so anticoagulation must be monitored closely during therapy.
11.Cytotoxic antibiotics
a. Metronidazole is active against nearly all anaerobes, and against many pro- tozoa that parasitize human beings. Metronidazole has potent bacterici- dal activity against B. fragilis, Prevotella spp., Clostridium spp. (including C. difficile), and anaerobic cocci, although it is ineffective in actinomycosis.
Resistance remains rare. The drug penetrates well nearly all tissues, including neural tissue, making it effective for deep-seated infections and bacteria that are not multiplying rapidly. Absorption after oral or rectal administration is rapid and nearly complete. The T1/2of metronidazole is 8 hours, owing
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160 The Trauma Manual: Trauma and Acute Care Surgery
to an active hydroxy metabolite. Increasingly, intravenous metronidazole is administered every 8 to 12 hours in recognition of the active metabolite, but once-daily dosing is possible. No dosage reduction is required for renal insufficiency, but the drug is dialyzed effectively and administration should be timed to follow dialysis if twice-daily dosing is used. Pharmacokinetics in patients with hepatic insufficiency suggests a dosage reduction of 50% with marked impairment.
b.Trimethoprim-Sulfamethoxazole (TMP-SMX). Sulfonamides exert bacterio- static activity by interfering with bacterial folic acid synthesis, a necessary step in DNA synthesis. Resistance is widespread, limiting use. The addi- tion of sulfamethoxazole to trimethoprim, which prevents the conversion of dihydrofolic acid to tetrahydrofolic acid by the action of dihydrofolate reductase (downstream from the action of sulfonamides), accentuates the bac- tericidal activity of trimethoprim. The combination of TMP-SMX is active against S. aureus, S. pyogenes, S. pneumoniae, E. coli, P. mirabilis, Salmonella and Shigella spp., Yersinia enterocolitica, S. maltophilia, L. monocytogenes, and Pneumocystis jerovici. TMP-SMX is a TOC for infections caused by S. maltophilia and outpatient and sometimes inpatient treatment of infec- tions caused by CA-MRSA. A fixed-dose combination of TMP-SMX of 1:5 is available for parenteral administration. The standard oral formulation is 80:400 mg, but lesser and greater strength tablets are available. Oral absorp- tion is rapid and bioavailability is nearly 100%. Tissue penetration is excel- lent. Ten milliliters of the parenteral formulation contains 160:800 mg drug.
Full doses (150 to 300 mg TMP in 3 to 4 divided doses) may be given if creatinine clearance is>30 mL/min, but the drug is not recommended when the creatinine clearance is<15 mL/min.
12.Duration of therapy.The endpoint of antibiotic therapy is largely undefined, because quality data are few. If cultures are negative, empiric antibiotic ther- apy should be stopped in most cases within 48 to 72 hours. The morbidity of antibiotic therapy also includes allergic reactions; development of nosocomial superinfections, (e.g., fungal, enterococcal, and CDI) organ toxicity; reduced yield from subsequent cultures; and vitamin K deficiency with coagulopathy or accentuation of warfarin effect. If infection is evident, treatment is contin- ued as indicated clinically. Some infections can be treated with therapy last- ing 5 days or less. Every decision to start antibiotics must be accompanied by an a priori decision regarding duration of therapy. A reason to continue ther- apy beyond the predetermined endpoint must be compelling. Bacterial killing is rapid in response to effective agents, but the host response may not subside immediately. Therefore, the clinical response of the patient should not be the sole determinant. If a patient still has SIRS at the predetermined endpoint, it is more useful to stop therapy and re-evaluate for persistent or new infection, MDR pathogens, and non-infectious causes of SIRS than to continue therapy uninformed.
AXIOMS
■Choose the most narrow range (per pathogen suspected/known) and adequate antibiotic agent and dose possible; if broad therapy is needed in early severe infection, narrow therapy as soon as possible based on microbiologic data.
■Antibiotic prophylaxis short be done for short intervals—often, just prior to surgery alone.
■Duration of antibiotic therapy is driven by infection location, organism, and response;
there is no set interval.
■Hospital infections are best avoided with hand washing and bundled actions regarding catheters and care-–treating them is much harder and fraught with morbidity.
■Remove catheters and other indwelling devices as soon as possible, and do not treat all cultures as evidence of infection-–correlate the pathogen and the clinical condition to any treatment plan.
Chapter 14rInfections, Antibiotic Prevention, and Antibiotic Management 161 Suggested Readings
Barie PS. Multidrug-resistant organisms and antibiotic management. Surg Clin North Am 2012;92:345–
391.
Burton DC, Edwards JR, Horan TC, et al. Methicillin-resistant Staphylococcus aureus central line- associated bloodstream infections in US intensive care units, 1997–2007. JAMA 2009;301:727–736.
Centers for Disease Control and Prevention (CDC). Vital signs: Central line-associated blood stream infections–United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep 2011;60:243–
248.
Chlebicki MP, Safdar N. Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med 2007;35:595–602.
Darouiche RO, Wall MJ Jr, Itani KM, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical- site antisepsis. N Engl J Med 2010;362:18–26.
Gosselin RA, Roberts I, Gillespie WJ. Antibiotics for preventing infection in open limb fractures. Cochrane Database Syst Rev 2004;1:CD003764.
Kumar A, Zarychanski R, Light B, et al. Early combination antibiotic therapy yields improved sur- vival compared with monotherapy in septic shock: A propensity-matched analysis. Crit Care Med 2010;38:1773–1785.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360(13):1283–1297.
O’Grady NP, Chertow DS. Managing bloodstream infections in patients who have short-term central venous catheters. Cleve Clin J Med 2011;78:10–17.
Pronovost P. Interventions to decrease catheter-related bloodstream infections in the ICU: the Keystone Intensive Care Unit Project. Am J Infect Control 2008;36:S171.e1–e5.
Prospero E, Barbadoro P, Esposto E, et al.
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–1367.
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15 Trauma Pain Management
Donald M. Yealy