Continuous infusion of cefazolin is superior to intermittent dosing in decreasing infection after hemorrhagic shock

SCIENTIFIC PAPERS

Continuous Infusion of Cefazolin Is Superior to Intermittent Dosing in Decreasing Infection After Hemorrhagic Shock David H. Livingston, Mr), Ming Tao Wang, Mr), Newark, NewJersey

Standard doses of antibiotic administered by intermiuent infusions after hemorrhagic shock have decreased efficacy in combating infection. This study compared identical quantities of cefazolin administered after shock as intermittent doses or as continuous infusions in a subcutaneous abscess model. One hour after resuscitation from shock, rats were inoculated with 2 X 108 Staphylococcus aureus subcutaneously on the dorsum and divided into three groups: ( 1 ) control rats, which received no drug treatment; ( 2 ) rats in the intermittent group, which received cefazolin at either 3 0 or 60 mg/kg intraperitoneally, 3 0 minutes prior to inoculation, then every 8 hours for three doses, and (3) rats in the continuous infusion group, which received cefazolin at either 3 0 or 6 0 mg/kg intraperitoneally, 3 0 minutes prior to inoculation, followed by cefazolin, 9 0 or 180 mg/kg, intraperitoneally by continuous infusion more than 2 4 hours after inoculation. Seve n days after the inoculation, abscess number, diameter, and weight were measured. Rats that received either dosage of cefazolin intermittently had the same abscess rate after shock as control rats. Rats that received a continuous infusion of cefazulin at either dose had 56% fewer abscesses than control rats. Absce~s diameter and weight decreased with increasing quantities of cefazolin, and abscesses were always smaller in rats receiving the continuous infusion. There were no differences in peak subcutaneous cefazolin levels between the intermittent and continuous groups. Continuous infusion provided significantly more cefazolin to the tissue than an equivalent quantity of eefazolin delivered as intermittent doses. These data demonstrate that continuous infusion of cefazolin provided more antibiotic to the tissue and was superior to intermittent injection in reducing infection after hemorrhagic shock.

he optimum dose and interval of antibiotic administration can be predicted by the pharmacokinetic T properties of the class of antibiotic used, the species of

bacteria to be treated, and the presence or absence of a post-antibiotic effect [1-5]. For example, high peak levels should be sought for antibiotics that have dose-dependent bactericidal action, such as the aminoglycosides [1,2]. Antibiotic administration is rarely fine-tuned in clinical practice because standard doses of antibiotics given at proscribed intervals are usually effective in eradicating infection, and intact host defenses can compensate for small deficiencies in antimicrobial coverage. In situations in which host defenses are diminished, improvements in antibiotic dosing and delivery may be critically important. Reed and coworkers [6] demonstrated that increased doses of aminoglycosides were necessary to treat intensive care unit patients with serious infections. Bodey et al [7] found that continuous infusion of cefamandole was superior to intermittent doses in neutropenic cancer patients. Hemorrhagic shock has been shown to alter immune responses and diminish the efficacy of antibiotics against both gram-positive and gram-negative organisms [8,9]. The decrease in antimicrobial efficacy reported in these experiments was postulated to be due to the failure of local host defenses to eliminate the residual bacteria remaining after the administration of antibiotics. Increased doses of cephalosporins have been shown to be more effective than standard doses in decreasing infection after shock [9,10]. The optimal bactericidal action of the ~-lactam antibiotics reportedly occurs at approximately four times the minimal inhibitory concentration (MIC) for the infecting organism, and increasing the level of antibiotic does not improve bacterial killing [11]. Delivery of/3-1actam antibiotics by continuous infusion maintains bactericidal levels of the drug using standard doses. The current study compared equivalent quantities of cefazolin delivered by either continuous infusion or intermittent bolus administration in a model of subcutaneous abscess after shock. Continuous infusion of cefazolin was superior to intermittent dosing in decreasing abscess formation in rats subjected to hemorrhage. The advantage of continuous infusion was not evident in sham-operated animals and suggests that altering antibiotic delivery is important afFrom the Departmentof Surgery,Universityof Medicineand Dentis- ter hemorrhagic shock when host defenses may be imtry-New JerseyMedicalSchool,Newark,New Jersey. paired. Requests for reprints shouldbe addressedto DavidH. Livingston, MD, UniversityHospital C-384, 150 Bergen Street, Newark, New MATERIALS AND METHODS Jersey07103. Rats: Female Sprague-Dawley rats weighing 190 to Manuscript submitted August 4, 1992, and accepted in revised 220 g were obtained from Harlan Sprague-Dawley (Indiform October7, 1992. THE AMERICAN JOURNAL OF SURGERY VOLUME165 FEBRUARY1993 203

LIVINGSTON AND WANG

TABLE

I

Abscess Number, Diameter, and Weight in Sham-Operated Rats

Group

Total Cefazolin Dose

Abscess Number

Abscess Diameter (mm)

Abscess Weight (mg)

Control INTER* CONI~

0 120 m g / k g 120 m g / k g

18/18 7/18 t 6/18 t

12.6 _+ 1.1 3.7 _+ 0.7 t 3.8 _+ 1.0 t

502 -+ 120 31 __- 18 t 36 --- 15t

All data mean -+ SD. *INTER indicates total cefazolin dose given to rats as four equally divided intermittent doses. tp <0.05 versus control. ~:CONTindicates continuous infusion of cefazolin given to rats as a bolus of 25% of the total dose followed by an infusion of the remaining 75% of the total dose over the next 24 hours.

TABLE II

Abscess Number, Diameter, and Weight in Rats After Shock

Group Control INTER* CONTw INTER CONT INTER

Total Cefazolin Dose

120 120 240 240 480

0 mg/kg mg/kg mg/kg mg/kg mg/kg

Abscess Number 18/18 18/18 10/18 t 24/24 15/24t 0/24

Abscess Diameter (ram) 14.8 7.1 5.2 5.3 3.8

_+ 2.7 _+ 1.7t~ ___1.4 + 0.8 t _+ 0.9 t --

Abscess Weight (mg) 722 170 56 93 61

_+ 423 _+ 94tr -+ 33 l_+ 41 t _+ 23t --

All data mean -+ SD. *INTER indicates total cefazolin dose given to rats as four equally divided intermittent doses. tp <0.05 versus Control. tp <0.05 versus CONT 120 mg/kg. w indicates continuous infusion of cefazolin given to rats as a bolus of 25% of the total dose followed by an infusion of the remaining 75% of the total dose over the next 24 hours,

anapolis, IN) and were acclimated to our facility for 1 week prior to experimentation. Animals were allowed free access to food and water and were not fasted prior to experimentation. Hemorrhagic shock: Rats were anesthetized with an intraperitoneal injection of ketamine hydrochloride (50 mg/kg) and xylazine hydrochloride (15 mg/kg). A rectal probe was inserted to monitor core body temperature, which was maintained at 37~ by a heating blanket. The right carotid artery was cannulated with polyethylene-90 tubing to monitor blood pressure and infuse fluids. Heparin (1,000 U/kg) was administered. Shock was induced by the gradual withdrawal of blood as previously described [10]. Briefly, rats were bled until a mean arterial pressure of 45 mm Hg was reached, which was maintained for 45 minutes. Animals were then resuscitated with their shed blood, and intravenous saline (1.5 times shed blood volume) was administered to restore blood pressure to pre-shock levels. Animals that underwent sham operations had their carotid artery exposed but not ligated. The mortality of this shock model is 15%, with all 204

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deaths occurring within 24 hours after shock. Animals that died were not included in the final analysis. Experimental design: One hour after the completion of the shock or sham procedure, the dorsal fur of the rats was clipped, and the back was painted with povidoneiodine solution. Six separate sites on each animal were injected subcutaneously with 0.3 mL of the bacterial suspension (2 • 108 Staphylococcus aureus per injection). Prior to inoculation, the rats were allocated to one of the following three treatment groups: (1) Control: no further drug treatment; (2) Intermittent: cefazolin sodium was given intraperitoneally at a dose of either 30, 60, or 120 mg/kg, 30 minutes before bacterial inoculation, then 8, 16, and 24 hours after inoculation, and (3) Continuous: cefazolin 30 or 60 mg/kg, intraperitoneally, 30 minutes before inoculation. After rats in this group were inoculated, a 0.5-cm laparotomy incision was made, and an osmotic pump (Alzet model 1003D, Alza Corporation, Palo Alto, CA) that was primed according to the manufacturer's instructions to deliver 90 mg (for the 30-mg group) or 180 mg (for the 60-mg group) of cefazolin over a 24-hour time period was implanted intraperitoneally. The laparotomy incision was closed in layers using absorbable sutures. The osmotic pumps were explanted with the rats receiving ketamine/xylazine anesthesia, 24 to 36 hours after insertion, as per the manufacturer's guidelines to prevent osmotic rupture. Seven days after inoculation, rats were killed, a dorsal incision was made, and the skin and abscesses were reflected away from the underlying musculature. Abscesses were measured in situ with a micrometer, and the abscess diameter was calculated from the average of two measurements done at 90 ~. Abscesses were dissected free from the skin, excised, and weighed. Subcutaneous tissue cefazolin concentrations were determined in all animals 60 minutes after the initial antimicrobial dose. In addition, antibiotic pharmacokinetic studies were performed in additional animals as follows: (1) animals that received intermittent doses (n = 4) were anesthetized and received 30 mg/kg cefazolin intraperitoneally. Subcutaneous tissue was excised at 0.5, 1, 2, 4, and 6 hours for determination of the concentration of cefazolin, and (2) animals that received continuous infusion (n -- 4) received cefazolin 30 mg/kg, intraperitoneally, followed by the intraperitoneal placement of an osmotic pump with 90 mg/kg (flow rate 3.75 mg/kg/h). Subcutaneous tissue was excised at 0.5, 1,4, 8, 12, 18, and 24 hours. All pharmacokinetic studies were replicated. The tissue concentration of cefazolin was determined by agar diffusion using Bacillus subtilis, ATCC strain 6633 (DIFCO, Detroit, MI), as the indicator organism. The limit of detection of this assay for cefazolin is 0.5 ug/g tissue. This study was reviewed and approved by the Animal Care and Use Committee of the New Jersey Medical School. Statistical analysis: The number of abscesses was compared using Fisher's exact test. Mean abscess diameter and weight were calculated only for the abscesses that were measurable, and the groups were compared using a

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INFECTION AFTER HEMORRHAGIC SHOCK

30

40

BOLUS CEFAZOLIN 30mg/kg IP

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BOLUS CEFAZOLIN 30mg/kg IP THEN CEF 90mg/kg BY PUMP

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TIME (HRS}

TIME (HRS) Figure 1. Tissue cefazolin (CEF) levels after the administration of a bolus of 30 mg/kg intraperitoneally (n = 4). Area under the curve (AUC) above the minimal inhibitory concentration (MIC) is 4,145/~g/g 9 min. Total AUC for 4 doses is 16,580 #gig 9 min. Conc -- concentration; IP = intraperitoneally.

Figure 2. Tissue cefazolin (CEF) levels after the administrationof a

two-way analysis of variance followed by the TukeyHSD multiple comparison of means (SPSS/PC+, SPSS Inc., Chicago, IL). Differences in tissue concentrations of cefazolin were assessed using Student's t-test. Significance was predetermined as p <0.05.

intermittent dosing in sham-operated rats (Table I). In contrast, cefazolin administered continuously at 30 mg/kg/8 h after hemorrhagic shock was significantly better in decreasing abscess number and diameter than the same quantity of cefazolin given in divided doses (Table II). Abscess diameter and weight were also reduced to levels similar to those observed in sham-operated rats receiving intermittent cefazolin. Increasing the quantity of cefazolin administered by continuous infusion to 60 mg/kg/8 h resulted in a further decrease in abscess diameter without decreasing the abscess rate. Mean (4- SD) peak tissue levels of cefazolin at all doses of antibiotic were significantly greater than the MIC for the staphylococci used (30 mg/kg -- 32 4- 4 /~g/g; 60 mg/kg = 66 4- 5 ~tg/g; 120 mg/kg = 87 4- 12 /~g/g; MIC -- 1.0 ~tg/mL). There was no difference in the mean peak tissue cefazolin levels between shock or shamoperated rats receiving continuous or intermittent cefazolin. The administration of cefazolin as a bolus dose (30 mg/kg) followed by a continuous infusion (90 mg/kg over 24 hours) resulted in significantly more drug being present in the tissue (Figure 1) than the identical quantity of cefazolin given as four bolus doses (Figure 2).

RESULTS Inoculation of 2 • 108 S. aureus in control animals without shock resulted in the formation of large and discrete abscesses in all animals (Table I). Hemorrhagic shock produced a trend toward slightly larger, heavier lesions, although the increase was not statistically significant. This experiment did not evaluate the effect of hemorrhagic shock on untreated infection. Rather, the bacterial inoculum was purposely chosen to be large, in order to best evaluate antimicrobial therapy. Increasing the bacterial inoculum above 2 X 108 produced overlying skin necrosis without increasing abscess size. This feature was noted in 16 of 18 abscesses in control rats after shock compared with 4 of 18 abscesses in sham-operated animals, which showed that shock increased the virulence of untreated infection. Intermittent doses of cefazolin at 30 mg/kg successfully decreased the number of abscesses and their mean diameter by 71% (both p <0.05) in sham-operated animals compared with control rats (Table I). After hemorrhagic shock, the same dose of cefazolin failed to decrease the number of abscesses (Table 1I). Abscess diameter and weight were also significantly greater than those observed in sham-operated rats receiving intermittent cefazolin (p <0.05). Increasing the intermittent dose of cefazolin to 60 mg/kg resulted in a further decrease in abscess diameter and weight, again without changing the number of abscesses. Eradication of infection (0 of 24 abscesses) was observed only when the total intermittent dose of cefazolin was increased to 480 mg/kg. Continuous infusion of cefazolin was not better than

bolus dose of 30 mg/kg intraperitoneally followed by planned continuous infusion of 90 mcj/kg/24 h (n = 4). Actual infusion of the drug may have been lower. The area under the curve (AUC) is 24,440 /~g/g 9min, which is significantly greater (p <0.05) than the total AUC for intermittent CEF. Conc = concentration; IP = intraperitoneally.

COMMENTS The therapeutic efficacy of the/~-lactam antibiotics correlates with the amount of antibiotic present at the site of bacterial infection [2-4]. Unlike the aminoglycoside or quinolone antibiotics, increasing the quantity of the/3lactam antimicrobial agent above a threshold quantity, usually 4 to 5 times the MIC, does not result in increased bactericidal action [11]. The need to maintain bactericidal levels of antibiotic makes continuous infusion the best method of delivery. The efficacyof continuous infusion of ~-lactam antibiotics has been demonstrated both experimentally and clinically [7,12]. These reports suggest that the advantages of continuous-infusion antibiotics com-

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LIVINGSTONAND WANG

pared with intermittent infusions are apparent when the infections occur in immunodeficient hosts or in locations where antibiotics penetrate poorly. Roosendaal et a l [12] demonstrated that 70 times less ceftazidime was needed to produce equivalent survival rates in neutropenic rats subjected to experimental pneumonia when the drug was given by continuous infusion rather than by intermittent administration. Continuous-infusion penicillins and cephalosporins have also been shown to be superior to intermittent doses in eradicating both gram-positive and gram-negative bacterial infections after complement depletion and granulocytopenia [13,14]. Previously, we have demonstrated that, after hemorrhagic shock, seven times more antibiotic, administered by intermittent dose, was needed to achieve a similar reduction in infection than what was observed in sham-operated animals [9,10]. This study demonstrated the superiority of continuous infusion of cefazolin over its intermittent administration in decreasing staphylococcal abscesses after hemorrhagic shock. In this model of hemorrhagic shock, a standard dose of cefazolin administered to sham-operated rats resulted in a 60% reduction in abscess formation. In contrast, the same dose of cefazolin administered to rats with shock resulted in no decrease in the abscess number. The abscesses present in animals with shock treated with a standard dose of cefazolin were also significantly larger than those of similarly treated sham-operated rats. No differences in peak tissue cefazolin levels between the shamoperated and shock groups were found. The pharmacokinetic studies indicate that cefazolin levels were greater than four times the MIC 6 hours after the administration of a 30 mg/kg dose of cefazolin (Figure 2). The reported post-antibiotic effect of the cephalosporins to staphylococci is approximately 1.5 to 2.5 hours [1]; therefore, the 8-hour dosing interval should have been sufficient to provide adequate antimicrobial coverage after hemorrhagic shock. Increasing the dose of intermittent cefazolin to 60 mg/kg after shock resulted in twice the peak tissue level as the 30 mg/kg dose without affecting the number and size of the abscesses. This finding is compatible with the pharmacokinetic properties of cephalosporins, which demonstrate maximum bactericidal capacity just above the MIC level of the bacteria. Increasing the concentration of the drug above the threshold level does not increase bacterial killing [11]. Continuous infusion of a standard quantity of cefazolin (120 mg/kg/d) significantly decreased the number and size of the abscesses compared with intermittent dosing after hemorrhagic shock. The decrease in abscess number and size was similar to that measured in shamoperated rats given intermittent cefazolin, 30 mg/kg every 8 hours. In contrast, continuous infusion of cefazolin did not reduce abscess formation in sham-operated animals. This finding is comparable with other studies that have not shown a benefit of continuous-infusion antibiotics in normal animals [12,15]. In studies using normal mice, Vogelman and coworkers [11] demonstrated that the maximum bactericidal efficacy of cefazolin against S. aureus in a thigh-infection model occurred when the drug 206

level exceeded the MIC for 55% of the dosing interval. Maintaining the level for more than 55% of the interval had no further effect. These results suggest that a longer time period above the MIC may be necessary after hemorrhagic shock when host defenses are diminished. Tissue levels of cefazolin were maintained between 16 and 18 #g/g after a 30 mg/kg bolus of cefazolin and the continuous infusion of 30 mg/kg/8 h (Figure 1). Although the osmotic pumps should have provided a steady state of cefazolin for 24 hours, bioassay results indicated that they apparently delivered the drug for only 18 hours. Since the explanted pumps were not examined for residual cefazolin, it is not known whether the full 90 mg/kg dose of cefazolin was delivered. Thus, a lower dose of drug over a shorter period of infusion than we anticipated may have been administered. In summary, continuous infusion of cefazolin was superior to twice as much cefazolin administered intermittently after hemorrhagic shock. The ability to use standard quantities of antibiotic delivered by continuous infusion avoids the need for large and potentially toxic bolus doses. The administration of #-lactam antibiotics by continuous infusion may also prove useful in other situations in which host defenses may be abnormal and infection remains a significant problem despite the use of antimicrobials, such as penetrating abdominal trauma or nosocomial pneumonia.

This provocath~e paper demonstrates that continuous antibiotic infusion, after a primary or loading dose, may be more effective than the normal practice of intermittent infusion. There are still a few areas in which antibiotics can be meaningfully studied in the clinical setting; this may well be one of them if these data are confirmed by other laboratories. REFERENCES 1. Craig WA, Ebert SC. Killingand regrowthof bacteria in vitro."a review. Scand J Infect Dis 1991; 74 Suppl: 63-70. 2. Drusano GL. Role of pharmacokineticsin the outcomeof infections. Antimicrob Agents Chemother 1988; 32: 289-97. 3. Legget JE, Ebert S, Fantin B, Craig WA. Comparative doseeffect relations at severaldosing intervals for beta-lactam, aminoglycoside,and quinoloneantibioticsagainst gram-negativebacilliin murine thigh-infectionand pneumonitis models. Scan J Infect Dis 1991; 74 Suppl: 179-84. 4. RoosendaalR, Bakker-WoudenbergIAJM. Impact of the antibiotic dosage schedule on efficacyin experimentallung infections. Scan J Infect Dis 1991; 74 Suppl" 155-62. 5. Schentag J J, Smith IL, Swanson D J, et al. Role for dual individualization with cefmenoxime. Am J Med 1984; 77 Suppl 6A: 43-50. 6. Reed R II, Wu A, Miller-Crotchett P, Crotchett J, Fischer R. Pharmacokinetic monitoring of nephrotoxicantibiotics in surgical intensive care patients. J Trauma 1989; 29: 1462-70. 7. Bodey GP, Ketchel SJ, Rodriguez V. A randomized study of carbenicillin plus cefamandoleor tobramycin in the treatment of febrile episodes in cancer patients. Am J Med 1979; 67: 608-16. 8. LivingstonDH, Malangoni MA. An experimentalstudy of susceptibilityto infectionafter hemorrhagicshock. Surg GynecolObstet 1988; 168: 138-42. 9. Livingston DH, Malangoni MA. Increased antibiotic dosing decreases polymicrobial infection following hemorrhagic shock.

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Surg Gynecol Obstet (In press). 10. LivingstonDH, Shumate C, Malangoni MA, Polk HC Jr. More is better: antibiotic management after hemorrhagic shock. Ann Surg 1988; 208: 451-60. 11. VogelmanB, GundmundssonS, LeggetJ, TurnidgeJ, Ebert S, Craig W. Correlationof antimicrobialpharmacokineticparameters with therapeutic efficacyin an animal model. J Infect Dis 1988; 158: 831-47. 12. Roosendaal R, Bakker-WoudenbergIAJM, van der Berg J, Michel M. Therapeutic efficacyof continuousversus intermittent administrationof ceftazidimein an experimentalKlebsiella pneumoniae pneumonia in rats. J Infect Dis 1985; 152: 373-83.

13. Bakker-Woudenberg IAJM, van der Berg JC, Fontijne P, Michel MF. Efficacyof continuousversusintermittentadministration of penicillin G in Streptococcus pneurnoniae pneumonia in normal and immunodeficientrats. Eur J Ciin Microbiol 1984; 3: 131-5. 14. Gerber AU, Craig WA, Brugger H, Feller C, Vastola A, Brandel J. Impact of dosingintervalson activityof gentamicinand ticareillin against Pseudornonas aeruginosa in granulocytopenic mice. J Infect Dis 1983; 142: 910-7. 15. LeggetJ, Fantin B, Ebert S, et al. Comparativeantibioticdoseeffect relations at several dosing intervals in murine pneumonitis and thigh-infectionmodels. J Infect Dis 1989; 159: 281-91.

EDITORIAL COMMENT

Wahid Naziri, MD,Louisville,Kentucky Livingston and Wang have focused attention on a new era in the use of antibiotics through their careful and wellcontrolled experiments. They compared identical quantities of cefazolin administered after hemorrhagic shock as intermittent doses or as continuous infusions in an animal model of subcutaneous abscess. These investigators compared tissue drug concentrations and the size and number of subcutaneous abscesses in rats subjected to hemorrhagic shock and control rats. Animals in both the continuous infusion and the intermittent injection groups were given equal doses of total antibiotic, ranging from 120 mg/kg to 480 mg/kg. All treated animals received a pre-infection bolus or priming dose. Based on their data, Livingston and Wang concluded that continuously administered antibiotics produced significantly fewer and smaller subcutaneous abscesses in the rats subjected to hemorrhagic shock. These data represent potentially important developments in the clinical application of antibiotics, especially in patients who sustain hemorrhagic shock. Current applicability and effectiveness of antibiotic therapy in prophylaxis and treatment of specific infection have both reached a clinical plateau. A practical challenge to clinicians is the development of a more effective means of utilizing currently available antibiotics. Continuous infusion of antibiotics may enhance their efficacy. The number of patients needed in order to perform a clinical trial demonstrating a statistically significant improvement in the treatment of infecFrom the Departmentof Surgery,University of Louisville,Louisville,Kentucky.

tion by a specific antibiotic protocol makes such an undertaking almost prohibitive, both logistically and fmandally. To assess the efficacy of an antibiotic protocol, it is necessary to use animal models of surgical infection. If results are positive and replicable, then empiric human clinical trials can be undertaken based on the results of the animal expe"rlments. Multiple, widely used, clinically relevant animal models of infection are available. One such model is the subcutaneous abscess model, used by Livingston and Wang, in which Staphylococcus aureus is injected into the subcutaneous tissue of rats. Another relevant model is the thigh suture model, in which Klebsiella pneumonia absorbed onto cotton suture is placed in the thigh muscle of mice, producing a lethal infection. Another surgically pertinent model of infection is the cecal ligation and puncture (CLP) model of intra-abdominal abscess in mice, which is accomplished by ligating and puncturing the cecum to allow limited fecal spillage. Well-formed intra-abdominal abscesses develop in CLP-treated mice in 7 days. All of these models have been used extensively, and the results from each are usually similar. The study by Livingston and Wang is well designed and carefully executed. They demonstrate a statistically significant reduction in the size and number of subcutaneous abscesses in rats subjected to shock and treated with continuous infusions of cefazolin compared with animals treated intermittently. Other factors, however, besides continuous infusion, which led to higher and more continuous tissue concentrations of cefazolin, may also have

contributed to the good results obtained in this study. First, all treated rats received bolus or priming doses of antibiotics prior to bacterial injection, perhaps making this study more relevant in the context of prophylaxis than in the treatment of infection. Second, the dose of cefazolin recommended for use in humans is 15mg/ kg. The doses used in this study ranged from 30 mg/kg to 120 mg/kg, which is two to eight times greater than the recommended dose for humans. The results of this study confirm previous work by Livingston et al (Ann Surg 1988; 208: 2: 451-60), in which they demonstrated that the efficacy of antibiotic treatment for shock was improved when drugs were used in very high doses. All of the aformentioned factors could have contributed to the good results seen in the current study. Despite the failue to control for these factors, this is an excellent study, one that is important and thought provoking. The continuous infusion of antibiotics may well enhance the effectiveness of currently available agents. This work also underscores the need for a clinically relevant animal model of surgical infection in the study of antibiotic therapy, especially since funding for large-scale human clinical trials of high-dose antibiotic therapy may prove prohibitive. Another obstacle may be approval by the U.S. Food and Drug Administration for a clinical trial utilizing very high doses of antibiotic. Finally, ethical and medicolegal considerations surrounding such a clinical thai have to be resolved. In the meantime, route and rate of infusion may be important to study.

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