• Update on therapy in the gram-negative syndrome

MAJ RICHARD B. HECKER, Me, USA

Two multicenter controlled sion." The syndrome may be expressed by clinical trial~ of genetically engineered tachycardia, telllperature instability (fever or monoclonal antibodies dir~cted against en ~ hypothermia), tachypnea, and evidence of in­ dotoxin, a potent mediator of iriflamm~­ adequate organ perfusion that includes one or tion in the gram-negative sepsis syndrome, more of the follqwing: were recently reported in the medical lit­ • ratio of arterial partial pressure of oxygen erature. One of these antiendotoxin anti­ to forced fraction of inspired oxygen (Pa02/ bodies was derived from a murine (mouse) FI02) less than or equal to 280 (without un­ source, and the other antibody was de­ derlying cardiac or pulmonary disease); rived mainly from a human source (neba­ • elevated arterial lactate level; cumab [negative human monoclo­ • oliguria for at least 1 hour. nal antibodyD. This article reviews recent It is important to emphasize that the sepsis literature concerning' the use of these syndrome can be caused by gram-positive and agents in the treatment of gram-negative gram-negative bacteria, viral agents, patho­ sepsis syndrome. It also projects economic genic fungi, and rickettsia. Patients having assessment data regarding the use of ne­ this syndrome mayor may not have an organ­ bac~mab in the pnited States. ism identified on blood cultures.! (Key words: Gram-negative sepsis syn­ The gram-negative sepsis syndrome re­ drome, monoclonal antibody, antiendo­ mains o~e of the most challenging entities toxin antibody, genetic engineering) confronting physicians who care for critically ill patients. The patient who has sepsis syn­ The sepsis syndrome, as defined by Bone,! drome is essentially suffering from distribu­ is "sepsis with evidence of altered organ perfu- tive shock, which may progress clinically to multiple-organ failure. During the 1980s, sep­ Major Hecker is a staff physicilln, Anesthesiology Criti­ cal Care Medicine, Critical Care Service, Department ticemia ranked as the 14th leading cause of of Surgery, Brooke Army Medical Center, Fort Sam Hous­ death in the United States.2 Currently, the sep­ ton, Tex. sis syndrome remains a leading cause of death The opinions or assertions contained herein are the 3 private views of the author and are not to be construed in the intensive care unit (ICU) setting. Esti­ as reflecting the views of the Department of the Army mates place the cost of treatment of this syn­ or the Department of Defense. drome between $5 billion and $10 billion an­ The author has no commercial or proprietary interest nually. in Xomen or HA-IA, nor does he have any financial in­ terest (as consultant, reviewer, or evaluator) in Xomen­ Despite prompt initiation of surgical, anti­ E5 or HA-IA. biotic, or ICU therapy, the mortality rate of Reprint requests to MAJ Richard B. Hecker, MC , patients with the sepsis syndrome continues ATTN: HSHE-SDI, Critical Care Service, Department of Surgery, Brooke Army Medical Center, Fort Sam Hous­ to remain in the range of 25% to 75%. When ton, TX 78234-6200. acute renal failure occurs in addition to fail-

Review article • Hecker JAOA • Vol 92 • No 8 • August 1992 • 1017 ure of other organs, mortality exceeds 90%. Antiendotoxin immunomodulation Any modality that may intervene in the de­ therapy velopment of the sepsis syndrome would be a Murine IgM monoclonal antibody welcome addition to our therapeutic arsenal. The E5 IgM antiendotoxin monoclonal anti­ body was developed in the mouse model. A ran­ Overview domized, double-blind, placebo-controlled clini­ The sepsis syndrome is a generalized mani­ cal study7 evaluated the genetically manufac­ festation of the provoked immunologic re­ tured E5 antibody. All patients accepted into sponse of the host associated with failure to this study had evidence of a gram-negative in­ defend against microbiologic organisms. The fection and a systemic septic response. Patients host becomes susceptible to and entered into this study received two doses, 24 mounts a systemic response to this invasion hours apart, of either the E5 antibody (2 mg/ of microorganisms by activating, producing, kg) or placebo. Of the 486 treated patients, 316 and/or releasing various potent mediators of (54%) had culture-confirmed gram-negative inflammation. The intense anti-inflammatory bacteremia. In the patients with documented response may then lead to multisystem organ gram-negative bacteremia, treatment with E5 dysfunction. These mediators of inflammation was found to be beneficial: The 30-day mor­ include the cytokines, particularly tumor ne­ tality in the treated group was 33% compared crosis factor, prostaglandins, interleukins, and with 43% in the group receiving the placebo. others. In caused by gram-negative In the E5-treated group, this finding repre­ organisms, endotoxin-specifically the lipid A sented a 42% reduction in the overall mortal­ portion of the moiety-has been implicated as ity reported at 30 days (P = .03). The group of the main trigger of the host's inflammatory 179 patients with gram-negative bacteremia response.4 in shock at initial presentation had no signifi­ Immunomodulation therapy with antibod­ cant difference in survival rate compared with ies directed against the lipid A portion of en­ the group receiving placebo. dotoxin is an innovative approach to the treat­ Regarding the safety of E5 administration, ment of the gram-negative sepsis syndrome. four patients treated with E5 had severe al­ Early studies using a rough mutant Escheric­ lergic reactions. Positive IgG antimurine an­ hia coli J5 immune polyclonal human antise­ tibody formation against E5 monoclonal anti­ rum demonstrated a protective effect in a.ni­ body was discovered in 86 (47%) of 182 patients mal models.5 Ziegler and coworkers6 studied who had received E5 antibody as part of their administration of J5 polyclonal human anti­ therapy. Interestingly, 13 (8%) of the 169 pa­ serum in patients with gram-negative infec­ tients who had received placebo also tested posi­ tions, and reported a reduction in mortality tive for antimurine IgG class antibody. among those patients having gram-negative bacteremia. They found the major disadvan­ Human IgM monoclonal antibody tages with the use of the J5 polyclonal antise­ Nebacumab is a human-derived IgM monoclo­ rum to include (1) risk of disease transmission, nal antibody that binds to the lipid A portion (2) variable specificity and affinity ofthe poly­ of endotoxin. Nebacumab is produced by the clonal antibodies, and (3) limited supply. stable heteromyeloma cell line A6(H4C5) that In an attempt to overcome the shortcomings was developed by Teng and colleagues.9 This identified with the use of polyclonal sera, mono­ genetically manufactured human monoclonal clonal IgM class antibodies against endotoxin antibody was evaluated in a randomized, dou­ that were derived from different sources were ble-blind, placebo-controlled clinical study.8 developed. Human clinical trials7,8 recently All patients entered in the study had a pre­ evaluated both a murine-origin monoclonal sumptive diagnosis of gram-negative sepsis IgM antibody (E5 [Xomen, Xoma Corporation, with hypotension or systemic manifestations Berkeley, Calif]) and a human-origin mono­ of infection (or both). Patients received either clonal IgM antibody (nebacumab [HA-1A, Cen­ a single 100-mg dose ofnebacumab or placebo. tocor, Inc, Malvern, PaD with differing results. Gram-negative bacteremia was confirmed in

1018 • JAOA • Vol 92 • No 8 • August 1992 Review article • Hecker 200 (37%) of543 treated patients. In this group tality of patients having the gram-negative sep­ of patients, the 28-day mortality was 45 (49%) sis syndrome without shock. Instead, this of 92 in the group receiving the placebo and study identified only a small subgroup of pa­ 32 (30%) ofl05 in the treated group. This find­ tients with end-organ failure who may bene­ ing represents a 39% reduction in overall mor­ fit from the E5 agent.ll Unfortunately, the de­ tality at 28 days (P = .014). In those bactere­ finitive paper regarding this study is not ex­ mic patients having evidence of shock, the pected to be published in the near future. group receiving placebo had a 28-day mortality Although an open-label study ofnebacumab of 57% (27/47) compared with the treated has not been completed, questions regarding group's mortality of 33% (18/54). This finding the analyses of the reported nebacumab con­ represents a 42% reduction in overall mortal­ trolled study have been raised.12,13 The main ity at 28 days (P = .017). No benefit of treat­ concerns center around the reported survival ment was found with the nebacumab antibody data on the 14th treatment day. The data sug­ in the 343 patients presenting with sepsis who gest that at day 14 there was no statistically were not subsequently proved to have a gram­ significant difference between the treated and negative bacteremia. Overall, the nebacumab placebo groupS.14 In addition, a representative therapy was well tolerated and no evidence of of the manufacturer has noted that the data antibody formation against nebacumab was regarding the efficacy of nebacumab in ani­ found. mal studies has not been consistently repro­ ducible over time and from laboratory to labo­ Comment ratory.14 p,.lthough a superficial review of the studies In a rebuttal to the foregoing concerns, ~valuating E5 and nebacumab suggests that Ziegler15 reaffirmed her opinion that the avail­ these studies are similar, in reality they are able studies provided consistent and compel­ quite different in design and entry criteria. ling evidence that nebacumab reduces mortal­ The number of doses given is different, the defi­ ity in patients having sepsis resulting from nition of shock is dissimilar, and the neba­ gram-negative bacteremia. Based on an evalu­ cumab-treated group had higher Acute Physi­ ation of the current data by the US Food and ologic Assessment/Chronic Health Evaluation Drug Administration (FDA), neither E5 nor (APACHE) II than did the E5-treated group, nebacumab has received a license for product suggesting that there were more severely ill marketing in the United States. On April 17, patients in the nebacumab study. Direct com­ 1992, the FDA requested that Centocor, Inc parison of the results of these two studies is design and conduct a second controlled clini­ not possible at this time. cal trial before any further decision can be In a commentary published in the same jour­ made regarding licensure ofnebacumab in the nal as the E5 study, BonelO suggests that a United States. At the present time, nebacumab head-to-head study of these agents is needed has been licensed for use in Europe based on before comparable results can be discussed. He the available data. also addressed ethical issues regarding the use of these very expensive products in the near Future directiOl~s and considerations future. In a similar article that followed the Different monoclonal antibodies specifically di­ nebacumab report, Wolff! argued for more in­ rected against other mediators of the sepsis tense investigation of the available monoclo­ syndrome are being developed and tested. An nal adjuncts for the treatment of the gram­ IgG monoclonal antibody against tumor ne­ negative sepsis syndrome. He went so far as crosis factor appears to be protective in ani­ to recommend that the polyclonal J5 be used mal models and is currently undergoing clini­ prophylactically in sepsis-prone patients such cal safety and pharmacokinetic studies. Also, as burn victims. a monoclonal antibody against interleukin-6 An analysis of the data in abstract form of is being investigated. Although a monoclonal the second study of the E5 monoclonal anti­ antibody against interleukin-1 has been body has failed to confirm a reduction in mor- evaluated, interleukin-1 is not now consid-

Review article • Hecker JAOA • Vol 92 . No 8 • August 1992 . 1019 ered to be a significant problem in sepsis. of this therapy will make patient selection for Although the recent clinical trials of mono­ recei ving these drugs one of the highest pri- clonal antibodies against endotoxin in the treat­ 0rities facing the clinician in the near future. ment of gram-negative bacteremia have been impressive, their role in the treatment of gram­ negative sepsis syndrome remains to be more References clearly defined. Fllrther studies should eluci­ 1. Bone RC: Sepsis, the sepsis syndrome, multi-organ failure: date the appropriate agent, the most effective A plea for comparable definitions. Ann Intern Med 1991;114:332- dose, the best dosing interval, whether or not 333. 2. Voelker R: As medical technology advances, so does septice­ prophylactic use is efficacious, or if there is a mia. American Medical News March 9, 1992, P 3. benefit to using multiple-monoclonal antibody 3. Increase in national hospital discharge survey rates for sep­ therapy. Monoclonal antibodies appear to have ticemia-United States, 1979-1987. MMWR 1990;39:31-34. the ability to modulate the systemic response 4. Wolff SM: Monoclonal antibodies and the treatment of gram­ negative bacteremia and shock. N Engl J Med 1991:39:31-34. to gram-negative infection, but our control of 5. Ziegler EJ, Douglas H, Sherman JE, et al: Treatment of E these interventions in regard to the benefit to coli and Klebsiella bacteremia in agranulocytic animals with the patient must also be addressed. to a UDP-gal epimerase-deficient mutant. J Immu­ Nebacumab has been released for general nol1973;111:433-438. 6. Ziegler EJ, McCutchan JA, Fierer J, et al: Treatment of gram­ use in The Netherlands with a patient cost of negative bacteremia and shock with human antiserum to a mu­ $3750 per dose. The number of patients in tant Escherichia coli. N Engl J Med 1982;307:1225-1230. whom sepsis develops in the United States is 7. Greenman RL, Schein RM, Martin MA, et al: A controlled clinical trial ofE5 murine monoclonal IgM antibody to endotoxin estimated to be 400,000 annually. Assuming in the treatment of gram-negative sepsis. JAMA 1991;266:1097- that entry criteria for the 1991 controlled ne­ 1102. bacumab study would be strictly followed, then 8. Ziegler EJ, Fischer CJ, Sprung CL, et al: Treatment of gram­ negative bacteremia and septic shock with HA-1A human mono­ 36% of these patients could be expected to bene­ clonal antibody against endotoxin. N Engl J Med 1991;324:429- fit from instituting therapy. Schulman and col­ 436. leagues16 studied the cost-effectiveness of us­ 9. Teng NNH, Kaplan HS, Hebert JM, et al: Protection against gram-negative bacteremia and endotoxemia with human mono­ ing nebacumab predicted on 400,000 cases of clonal IgM antibodies. Proc Natl Acad Sci USA 1985;82:1790- sepsis. They found that if all patients in whom 1794. presumed gram-negative sepsis is diagnosed 10. Bone RC: Monoclonal antibodies to endotoxin: New allies were to be treated with a single dose of neba­ against sepsis? JAMA 1991 ;266:1125-1126. 11. Wenzel RP, Bone R, Fein A, et al: Results of a second double­ cumab, the annual cost would be $2.3 billion blind, randomized, controlled trial of antiendotoxin antibody or $24,100 per year of life saved. If a reliable E5 in gram-negative sepsis. Program and Abstracts of the 31 st test to confirm early gram-negative bactere­ Interscience Conference on Antimicrobial Agents and Chemo­ therapy, Chicago, September 29--October 2, 1991. Washington, mia could be marketed, then the annual cost DC, American Society for Microbiology, 1991, p 294 (extended would be reduced to $1.3 billion, or $14,900 abstract). per year of life saved. 12. Wenzel RP: Anti-endotoxin monoclonal antibodies-A sec­ ond look. N Engl J Med 1992;326: 1151-1153. Summary 13. Warren HS, Danner RL, Munford RS: Anti-endotoxin mono­ clonal antibodies. N Engl J Med 1992;326:1153-1157. Current monoclonal immunotherapy directed 14. Open Meeting of the Vaccines and Related Biological Prod­ against the gram-negative sepsis syndrome ap­ ucts Advisory Committee, September 4, 1991. Vol!. Bethesda, Md , Food and Drug Administration, 1991, p 50. (Obtained pears promising. The application of this tech­ through the Freedom of Information Act.) nology is expensive, labor-intensive (leu care), 15. Ziegler EJ, Smith CR: Anti-endotoxin monoclonal antibod­ and industry-driven. The addition of these ies. N Engl J Med 1992:326:1165. agents to our therapeutic armamentarium 16. Schulman KA, Glick HA, Rubin H, et al: Cost-effectiveness of HA-1A monoclonal antibody for gram-negative sepsis. Eco­ with the possibility of reducing morbidity in nomic assessment of a new therapeutic agent. JAMA our ICUs is exciting. The anticipated expense 1991;266:3466-3471.

lO20 • JAOA • Vol 92 • No 8 • August 1992 Review article • Hecker