LEADING ART ICLE
Drugs 43 (5): 629-636, 1992 00 12-6667/92/0005-0629/$04.00/0 © Adis International Limited. All rights reserved. DRUl140
Infectious Disease Therapy in the 1990s Where are we Heading?
M. Rozenberg-Arska and M.R. Visser Department of Clinical Microbiology and Laboratory of Infectious Diseases, University Hospital Utrecht, Utrecht, The Netherlands
Although effective antimicrobial agents have been in use for more than 50 years, patients still die from infection. Remarkable progress has been made in the prevention and treatment of infectious diseases and in the development of more potent, safer and more broadly active antimicrobial agents. Considerable efforts have also been made to enhance or restore human immune responses against pathogenic and opportunistic microorganisms. Why, then, do antimicrobial drugs fail in some patients with severe infections and how should we treat such infections in the future? Antimicrobial treatment may fail for several reasons: antibiotics may be administered too late; the infecting microorganism(s) may be resistant to the agent used; despite adequate antimicrobial therapy leading to efficient killing of microorganisms, released microbial products may cause damage to essential physiological mechanisms; or the patient's immune defences may be inadequate to provide the support that antimicrobial therapy requires. With regard to the first point, it is important to establish a specific microbial diagnosis and initiate the appropriate antimicrobial therapy as rapidly as possible. New techniques, such as probes and polymerase chain reaction for detection of microbial RNA or DNA, may be able to detect pathogens in the early stage of disease and small amounts of infectious particles (Polin 1985).
1. Antimicrobial Therapy Because microorganisms are developing resistance to the available antimicrobials there is still a need for new and more active drugs (Neu 1991). 1.1 Antibacterial Agents At present, there are probably sufficient effective drugs against bacteria, especially those of a Gram-negative nature. However, some microorganisms in patients with chronic, progessive diseases requiring prolonged therapy (e.g. patients with cystic fibrosis) may cause therapeutic problems in future because of increasing resistance to all available agents. Problems with Gram-positive bacteria may arise because of the development of resistance to vancomycin (Woodford et al. 1991). 1.2 Antifungal Agents Potent and efficacious drugs are needed in the treatment of fungal infections. The therapy of choice in severe systemic fungal infections, especially in neutropenic patients, remains amphotericin B. However, failures are still numerous, as are relapses (Meunier 1988). Moreover, administration of this drug has been associated with major adverse effects and toxicity (Sabra & Branch 1990). To increase the therapeutic index of amphotericin B and diminish the toxicity, new modes of admin-
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istration of this agent have been used, such as encapsulation in liposomes (Meunier 1989). This new form of drug administration will probably be applied to other drugs in order to avoid toxicity and to allow the use of much higher doses.
ation therapy with other antiviral drugs or with biological agents such as interferon and 'Y-g1obulin for augmentation of the treatment and possibly for the prevention of the emergence of resistant strains (Baba et al. 1984; Hoofnagle et al. 1986; Lok et al. 1988; Rasmussen et al. 1984; Reed et al. 1988).
1.3 Antiviral Agents In comparison with the wealth of antibacterial agents available only a few specifically antiviral drugs are presently registered. A major reason for the difficulty in finding useful antiviral agents is that viral replication is strictly dependent on host cell processes. Antiviral agents must be highly selective because they must stop viral replication without causing toxicity or affecting cell metabolism in uninfected cells. The AIDS epidemic has boosted the scientific interest in the development of new antiviral agents, and modern molecular techniques are now used to develop new agents. In recent years several potent new drugs have been developed and accepted for the treatment of viral infections: aciclovir against herpes viruses (O'Brien & Campoli-Richards 1989), ganciclovir (Faulds & Heel 1990) and foscarnet (Chrisp & Clissold 1991) for infection caused by cytomegalovirus (CMV) and recently zidovudine (AZT) against the human immunodeficiency virus (HIV) (Langtry & Campoli-Richards 1989; Mitsuyo et al. 1985). Increasing knowledge of the viral replication process in host cells should lead to better identification of molecules that can be used as targets in antiviral therapy and useful new agents will undoubtedly be discovered in the near future (De Clerq 1989; Smith et al. 1987). The increasing use of antiviral drugs has been associated with the emergence of resistant strains and clinical problems associated with this resistance. There have been reports of aciclovir-resistant herpes simplex virus [HSV] (Erlich et al. 1989), ganciclovir-resistant CMV (Erice et al. 1989) and zidovudine-resistant HIV in patients receiving this drug longer than 6 months (Lader et al. 1989). The clinical implications of these findings need further study. Antiviral chemotherapy also includes combin-
2. Immunotherapy Infected patients fell generally into 2 groups: the majority who respond readily to treatment and the minority (with whom we are more concerned) who do not. The latter group require intensification of therapy and while antimicrobial drugs remain the cornerstone of treatment, other approaches should be used to minimise the deleterious effects of bacterial products on the physiological functions of the host and to supplement or stimulate host defences. As a complement to the long accepted strategies of developing more potent, safer, and more broadly directed antimicrobial agents, considerable efforts have been made to enhance or restore human immune responses to pathogenic and opportunistic microorganisms, and other forms of treatment, such as immunotherapy, have been explored. Protectiv~ antibodies obtained by active or passive immunisation are needed to augment host defences. Active immunisation by means of vaccines is and will be used as a prophylactic rather than therapeutic measure because of the prolonged time (10 to 20 days) needed for an optimal immune response. Moreover, active immunisation in compromised patients may fail because intensely immunosuppressed subjects may not develop a substantial humoral antibody response (Young 1988). Some bacterial vaccines have been employed to immunise donors as a source for immunoglobulin therapy (Ziegler et al. 1982). 2.1 Passive Immunotherapy in GramNegative Infections Passive immunotherapy offers the option of rapid and safe administration of antibodies directed against whole microorganisms and/or their
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toxic products, such as lipopolysaccharides (LPS) from Gram-negative bacteria. In recent years 2 major technological advances in the preparation of antibody-containing solutions have re-established the viability of immunotherapy in the treatment of infections: the rendering of human -y-globulin safe for intravenous infusion and the development of monoclonal antibodies. Bacteraemic infections and septic shock remain a major, if not the principal, infectious disease problem. Septic shock is a life-threatening complication of infection that can be triggered by a variety of microorganisms (Parillo et al. 1990). Although the precise incidence of those infections is still unknown, a current estimate of the annual incidence in the US is 400000 cases of sepsis, 200000 of septic shock and 100 000 deaths from this disease (Mortality, Morbidity and Weekly Reports, USA 1990). Gram-negative bacteraemia occurs in about 30% of patients with septicaemia (Ziegler et al. 1982) with a mortality rate of 20 to 60% (Bone et al. 1987; Kreger et al. 1980; Veterans Administration Systemic Sepsis Cooperation Study Group 1987). In patients developing Gram-negative septic shock mortality rates are as high as 50 to 80% (Bone et al. 1987; Calandra et al. 1988; Ziegler et al. 1982). Most of our present knowledge on the pathogenic mechanism in septic shock is derived from experimental and clinical data obtained in animals or in humans infected with Gram-negative bacteria. Control of these infections often is very difficult and the relative ineffectiveness of antibiotics can be partially explained by the debilitating effect of the underlying disease in these patients (Pizzo & Young 1984) and by the fact that antibiotic therapy can initially increase the circulating load of free endotoxin by killing or lysing the infecting bacteria (Shenep et al. 1985, 1988). Because endotoxin, a LPS in the membrane of Gram-negative bacteria, has been proposed as the initiating mediator of all types of septic shock (Morrison & Ryan 1987), immunotherapy against LPS, particularly serotherapy, has been investigated.
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2.2 Polyclonal Antibodies against LPS Naturally occurring antibodies to endotoxin have a protective effect (Mattsby-Baltzer & Alving 1984; Schellekens et al. 1988) and were associated with increased survival in Gram-negative septic shock in humans (Lachman et al. 1984). Antibodies to the core lipid A obtained by immunisation of volunteers with E. coli J5 mutants of E. coli 0 III B4 lacking the O-specific side chain but possessing lipid A were shown to be cross-protective against Gram-negative infections (Baumgartner et al. 1985; Ziegler et al. 1982). In contrast to the protective effect of J5 antiserum, a purified intravenous immunoglobulin G preparation obtained from J 5 antiserum was not superior to standard immunoglobulin in reducing mortality or in reversing Gram-negative septic shock (Calandra et al. 1988). Protection of immune serum in the Ziegler and Baumgartner studies may have been partially due to IgM antibodies directed against lipid A which are absent from the IgG preparation or to some nonspecific component of host defence. Use of antiserum, however, clearly has limitations. One of the most important drawbacks in the use of plasma-derived polyclonal antibodies is the necessity to administer unneeded antibody protein along with active antibodies, so that a rather large amount of antibody protein must be administered to achieve therapeutic effects. Monoclonal antibodies may circumvent this dilemma. 2.3 Monoclonal Antibodies against LPS
Monoclonal antibodies are traditionally produced by fusing sensitised murine B-Iymphocytes with myeloma cells, resulting in a 'hybridoma' cell line (Golfre & Milstein 1981). These hybridomas provide a continuous scource of monoclonal antibodies and clones could be selected by serological and functional screening for those producing the most desirable antibody products. The use of monoclonal antibodies should enhance therapeutic efficiency because less protein is needed than with polyclonal antibodies. Recently many monoclonal
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antibodies have been developed that recognise various epitopes of the core region of endotoxin (De Jongh-Leuvenink et al. 1990; Greenman et al. 1991; Pollack et al. 1989; Teng et al. 1985; Young et al. 1989; Ziegler et al. 1991). Two of those monoclonal antibodies, one murine (designated as E5) [Greenman et al. 1991] and one human (HAI A) [Plosker & Goa 1992; Ziegler et al. 1991], both of the IgM class, have been reported to specifically bind to the lipid A of endotoxin and to be protective. Both antibodies have been tested in the treatment of patients with Gram-negative bacterial infections and were given in addition to standard antibiotic therapy and supportive care. In a clinical study 486 patients with suspected Gram-negative bacterial infection were randomly assigned to receive intravenously either murine E5 antibodies or placebo (Greenman et al. 1991). In the group of 316 patients with Gram-negative infection as a whole no decrease of mortality was observed. There was a significant decrease of mortality in a subgroup of patients with Gram-negative sepsis, but only if those patients did not have refractory shock at study entry (n = 137, p = 0.03), whereas patients with shock were not protected. Because E5 was shown to be effective only in a subgroup of patients without shock, a second multicentre trial has been initiated to verify this protection and the results are not yet known. Recently the results of treatment of patients with Gram-negative bacteraemia and septic shock with HA-IA human IgM monoclonal antibodies against lipid A were published (Ziegler et al. 1991). 543 patients with sepsis and a presumed diagnosis of Gram-negative infection were assigned to receive either a single dose of HA-IA or placebo (human albumin). Mortality was not improved overall, but enhanced survival was observed in patients with Gram-negative bacteraemia (n = 200, p = 0.014) and in patients with Gram-negative bacteraemia and septic shock (n = 101, p = 0.017). In patients without Gram-negative bacteraemia there was no significant difference in mortality between the study groups. The therapeutic effect of HA-I A in this trial was specific for patients with sepsis and Gram-negative bacteraemia (patients with endotoxin in the
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bloodstream). The authors suggest that monoclonal antibodies block the toxic effects of circulating endotoxin, including induction and release of the mediator of shock and tissue damage. Because sepsis requires prompt treatment before blood cultures are known, the authors advocate empirical immunotherapy with HA-IA in all patients with suspected Gram-negative infection who present with sepsis. However, before monoclonal antibodies are used as standard therapy in a great number of patients, it must be shown that the beneficial effect was really due to monoclonal antibodies directed against lipid A rather than other mechanisms (controls with an IgM antibody or polyclonal anti-J 5 antiserum were not used in Ziegler study; human albumin was administered in the placebo group). Immunotherapy with E5 and HA-IA promises to be a new tool in the treatment of patients with Gram-negative infections. However, the group of patients that may benefit the most remains to be defined more clearly (Bone 1991). Therefore, further experimental and clinical studies are warranted. 2.4 Passive Immunisation with Anticytokine Antibodies Producing antibodies which provide broad crossprotection against mUltiple LPS is problematic and results oflaboratory and clinical studies, using anticore glycolipid immunotherapy have been variable and sometimes contradictory (Baumgartner et al. 1985; Calandra et al. 1988; Ziegler et al. 1982). Another approach to the treatment of infection is the use of antibodies that recognise tumour necrosis factor (TNF). There is increasing evidence that TNF-a is a principal mediator in the cascade of pathophysiological events that follow Gram-negative septicaemia (Beutler & Cerami 1987, 1988). Antibodies directed against TNF might provide protection against many of the injurious effects of endotoxin during Gram-negative sepsis (Beutler et al. 1985; Tracey et al. 1987). Clinical studies have demonstrated that TNF levels are elevated in some septic states, such as meningococcaemia (Girardin et al. 1988; Waage et al. 1987), and human trials
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with the controlled administration of LPS have demonstrated that serum levels of TNF rise rapidly in response to LPS administration (Hesse et al. 1988; Michie et al. 1988). Anti-TNF antibody protected rodents from the lethal doses of LPS (Beutler et al. 1985) and a baboon shock model demonstrated protective efficacy of an anti-TNF monoclonal antibody after intravenous challenge with a large inoculum of E. coli (Tracey et al. 1987). Opal et al. (1990) have shown that monoclonal antibodies against TNF-a protected neutropenic rats from lethal infection with Pseudomonas aeruginosa (53% survival rate) and that the combination of monoclonal antibodies with ciprofloxacin treatment improved survival further (100% survival rate). Infusion of anti-TNF-a antibodies into patients with severe septic shock improved mean arterial pressure without causing significant side effects (Exley et al. 1990). Anticytokine antibody therapy might be particularly useful in combination with antimicrobials in the light of evidence that antimicrobial treatment frequently increases endotoxic levels in septic animals and humans (Shenep et al. 1985, 1988). Further studies in humans are warranted to determine whether anticytokine immunotherapy is a useful adjunct to standard antimicrobial agents in the treatment of patients with Gram-negative sepsis. However, anticytokine antibody therapy must be used with caution in future human trials, because it may mitigate against some of TNF's potential beneficial effects during clinical infection (Urbaschek & Urbaschek 1987). Further studies are needed to determine whether using anti-TNF monoclonal antibodies in combination with other anticytokine or anti-LPS antibody treatments has added benefits. Monoclonal antibodies also have drawbacks, however. For example, murine monoclonal antibodies obviously contain foreign protein and can sensitise human recipients. Human monoclonal antibodies with in vitro and in vivo activity against infectious agents, have been developed and these may circumvent the problems with murine protein. Epstein-Barr viral transformation of human B-Iymphocytes is commonly used in the produc-
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tion of human monoclonal antibodies and the presence of Epstein-Barr virus genome in these preparations must be considered (Masuho 1988). Recent development of chimeric antibodies, produced by cell lines transfected with immunoglobulin genome from both murine and human sources may alleviate some of these difficulties (Morrison et al. 1984; Riechmann et al. 1988). Because of th~ great diversity of antigens on the outer surface ofoocteria it will be necessary to either prepare a large number of monoclonals that correspond to a large number of the antigenic epitopes or - better but more difficult - look for a common antigen and produce monoclonals that will be effective against a whole group of microbes, e.g. Gram-negative bacteria. A broad range of monoclonals specific for viral infections, for which there are few therapeutic agents, would be of great benefit. Production of human monoclonal antibodies is difficult. They must be shown to have in vitro and in vivo activity and to be safe for use in humans, and no cross-reaction should occur with normal human tissues. The possibility of contamination by viruses, mycoplasma, bacteria, etc. and risks of carcinogenicity should be ruled out. Taking into account all these problems, we should consider the development of monoclonal antibodies only when it is proven that polyclonal serum is effective in the experimental and clinical setting. 2.5 Immunomodifiers in Infectious Diseases Improved understanding of microbial pathogenesis and the cellular immune response has given rise to an improved understanding of the inflammatory response and new pharmaceutical products. Recombinant DNA technology has given us the ability to use interferons, interleukins and colony stimulating factors therapeutically. Administering interferon-"Y (IFN"Y) enhances the production of reactive oxygen metabolites and the killing of intracellular bacterial and protozoal pathogens in vivo or in vitro (Murray 1988). IFN"Y has been shown to be effective in the prevention of infection
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in patients with chronic granulomatous disease (International Chronic Granulomatous Disease Cooperative Study Group 1991; Todd & Goa 1992). Moreover, interferons have recently been shown to be a potentially important adjuct to conventional therapy for systemic Leishmaniasis (Badaro et al. 1990) and leprosy (Nathan et al. 1986). Interferons have shown a favourable effect on hepatitis markers in chronic hepatitis B patients (Lok et al. 1988); however, only 15% of the patients had sustained clearance of HBeAg 12 months after the end of the therapy. In hepatitis C an initial response to low dose, long term IFN-y has also been observed (Hoofnagle et al. 1986), but the disease may return after stopping therapy. Many combinations of interferon with antiviral agents act synergistically in vitro: e.g. interferon combined with aciclovir against varicella zoster virus (Baba et al. 1984) and against CMV (Rasmussen et al. 1984); other combinations have shown similar effects. Potential benefits of combination therapy also include reduced toxicity due to lowering of individual drug dosing schedules, and reduced chances of the emergence of resistant clinical isolates. The biological properties and in vitro as well as experimental in vivo results of granulocyte colonystimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), suggest 2 potential therapeutic objectives, raising the circulatory cell count by stimulating haematopoiesis after chemotherapy-induced granulocytopenia and improving the function of neutrophils and macrophages (Grant & Heel 1992; Ruef & Coleman 1990), thereby reducing infection rates (Reed et al. 1987; Vadhan-Raj et al. 1987; Weiser et al. 1987). G-CSF is a therapeutic option in patients with neutropenia. It was shown to reduce the occurrence of infections in individuals with congenital or cyclic neutropenia (Bonilla et al. 1989). Both G-CSF and GM-CSF have been shown to reduce mortality after an otherwise lethal dose of whole body irradiation, a situation in which many patients die from secondary infections (Talmadge et al. 1989).
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3. Conclusion Any single therapy is probably of limited use and the most beneficial approach to infectious disease may be a combination of therapies. For example, in the treatment of septicaemia in the immunocompromised host much better results are achieved with a combination of antimicrobial drugs with antiendotoxin serum than with either treatment alone. The use of potent antibiotics, an improved delivery system and activating cytokines results in more rapid killing of intracellular pathogens such as mycobacteria, than any of these approaches alone (Bermudez & Young 1988). In the future, potent combinations of immune modulators, antibiotics and antibodies may well provide the broadest possible approach to the persisting therapeutic challenges offered by infections complicating altered host states by underlying disease, immunosuppression and/or invasive procedures. However, there is still a long way to go, and well planned clinical studies are needed to definitively determine which approach will be the best for each category of patients.
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in the immunosuppressed host: looking at both sides of the coin. American Journal of Medicine 76: 101-107, 1984 Plosker GL, Goa KL. HA-IA (Human monoclonal antibody against endotoxin): a novel pharmacological approach for the treatment of Gram-negative bacteraemia and septic shock. Drugs 43: in press, 1992 Polin RA. Monoclonal antibodies against microorganisms. European Journal of Clinical Microbiology 4: 1-9, 1985 Pollack M, Chia JKS, Koles NL, Miller M, Guelde G. Specificity and cross-reacting of monoclonal antibodies reactive with the core and lipid A region of bacterial lipopolysaccharide. Journal of Infectious Diseases 159: 168-188, 1989 Rasmussen L, Chen PT, Mullenax JG, Merigan TC. Inhibition of cytomegalovirus replication by 9-(l,3-hydroxy-2-propoxymethyl)guanine alone and in combination with human interferons. Antimicrobial Agents and Chemotherapy 26: 441-445, 1984 Reed EC. Bowden RA, Dandliker PS, Lilleby KE, Meyers JD, et al. Treatment of cytomegalovirus pneumonia with ganciciovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Annals of Internal Medicine 109: 783-788, 1988 Reed SG, Nathan CF, Pihl DL, Rodricks P, Shanebeck K, et al. Recombinant granulocyte/-macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzei and release of hydrogen peroxide. Journal of Experimental Medicine 166: 1734-1746, 1987 Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature 332: 323-327, 1988 Ruef F, Coleman DL. Granulocyte-macrophage colony stimulating factor: pleiotropic cytokine with potential clinical usefulness. Reviews of Infectious Diseases 12: 42-62, 1990 Sabra R, Branch RA. Amphotericin B nephrotoxicity. Drug Safety 5: 94-108, 1990 Schellekens J, Benne CA, De Zeeuw GR, Rozenberg-Arska M, Verhoef J. Naturally occurring IgG and IgM antibodies to gramnegative bacteria and lipopolysaccharides in human sera. Serodiagnosis and Immunotherapy in Infectious Diseases 2: 433444, 1988 Shenep JL, Barton RP, Mogan KA. Role of antibiotic class in the rate ofliberation of endotoxin during therapy for experimental gram-negative bacterial sepsis. Journal of Infectious Diseases 151: 1012-1018, 1985 Shenep JL, Flynn PM, Barrett FF, Stidham GL, Westen kirchner DF. Serial quantitation of endotoxin and bacteremia during therapy for gram-negative bacterial sepsis. Journal of Infectious Diseases 157: 565-568, 1988 Smith DH, Byrn RA, Masters SA, Gregory T, Groopman JE, et al. Blocking of HIV -I infectivity by a soluble, secreted form of the CD4 antigen. Science 238: 1704-1707, 1987 Talmadge JE, Tribble H, Pennington R, Bowersox 0, Schneider MA, et al. Protective, restorative, and therapeutic properties of recombinant colony-stimulating factors. Blood 73: 2093-2103, 1989 Teng NNH, Kaplan HS, Hebert JM, Moore C. Douglas H, et al.
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Protection against gram-negative bacteremia and endotoxin with human monoclonal IgM antibodies. Proceedings of the National Academy of Science of the USA 82: 1790-1794, 1985 Todd PA, Goa KL. Interferon Gamma-Ib: a review of its pharmacology and therapeutic potential in chronic granulomatous disease. Drugs 43: in press, 1992 Tracey KJ, Fong Y, Hesse DG, Manoque KR, Lee AT, et al. Anticachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 330: 662-664, 1987 Urbaschek R, Urbaschek B. Tumor necrosis factor and interleukin-I as mediators of endotoxin-induced beneficial effects. Reviews of Infectious Diseases 9 (Suppl.): S607-S615, 1987 Vadhan-Raj S, Keating M, LeMaistre A, Hittelman WN, McCredie K, et al. Effects of recombinant human granulocytemacrophage colony-stimulating factor in patients with myelodysplastic syndromes. New England Journal of Medicine 317: 1545-1552, 1987 Veterans Administration Systemic Sepsis Cooperation Study Group. Effect of high dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. New England Journal of Medicine 317: 659-665, 1987 Waage A, Halstensen A, Espevik T. Association between tumor necrosis factor serum and total outcome in patients with meningococcal disease. Lancet I: 355-357, 1987 Weiser WY, Van Niel A, Clark SC, David JR, Remold HG. Recombinant human granulocyte/macrophage colony stimulating factor activates intracellular killing of Leishmania donovani by human monocyte derived macrophages. Journal of Experimental Medicine 166: 1436-1446, 1987 Woodford N, Johnson AP, George RC. Detection of glycopeptide resistance in clinical isolates of Gram-positive bacteria. Journal of Antimicrobial Chemotherapy 28: 483-490, 1991 Young LS. Management of infections in leukemia and lymphoma. In Rubin RH & Young LS (Eds) Clinical approach to infection in the compromised host, pp. 467-502, New York, Plenum Press, 1988 Young LS, Gascon R, Alam S, Bermudez LE. Monoclonan antibodies for treatment of gram-negative infections. Reviews of Infectious Diseases II (Suppl. 7): SI564-SI571", 1989 Ziegler EJ, McCutchan JA, Fierer J, Glauser MP, Sadoff JC, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. New England Journal of Medicine 307: 1225-1230, 1982 Ziegler EJ, Fisher Jr CJ, Spring CL, Straube RC, Sadoff JC, et al. Treatment of gram-negative bacteremia and septic shock with HA-IA human monoclonal antibody against endotoxin: a randomized, double-blind placebo controlled trial. New England Journal of Medicine 324: 429-436, 1991
Correspondence and reprints: Dr M. Rotenberg-Arska. Department of Clinical Microbiology and Laboratory of Infectious Diseases University Hospital Utrecht, HP G 04.515, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
Drugs 43 (5): 629-636, 1992 00 12-6667/92/0005-0629/$04.00/0 © Adis International Limited. All rights reserved. DRUl140
Infectious Disease Therapy in the 1990s Where are we Heading?
M. Rozenberg-Arska and M.R. Visser Department of Clinical Microbiology and Laboratory of Infectious Diseases, University Hospital Utrecht, Utrecht, The Netherlands
Although effective antimicrobial agents have been in use for more than 50 years, patients still die from infection. Remarkable progress has been made in the prevention and treatment of infectious diseases and in the development of more potent, safer and more broadly active antimicrobial agents. Considerable efforts have also been made to enhance or restore human immune responses against pathogenic and opportunistic microorganisms. Why, then, do antimicrobial drugs fail in some patients with severe infections and how should we treat such infections in the future? Antimicrobial treatment may fail for several reasons: antibiotics may be administered too late; the infecting microorganism(s) may be resistant to the agent used; despite adequate antimicrobial therapy leading to efficient killing of microorganisms, released microbial products may cause damage to essential physiological mechanisms; or the patient's immune defences may be inadequate to provide the support that antimicrobial therapy requires. With regard to the first point, it is important to establish a specific microbial diagnosis and initiate the appropriate antimicrobial therapy as rapidly as possible. New techniques, such as probes and polymerase chain reaction for detection of microbial RNA or DNA, may be able to detect pathogens in the early stage of disease and small amounts of infectious particles (Polin 1985).
1. Antimicrobial Therapy Because microorganisms are developing resistance to the available antimicrobials there is still a need for new and more active drugs (Neu 1991). 1.1 Antibacterial Agents At present, there are probably sufficient effective drugs against bacteria, especially those of a Gram-negative nature. However, some microorganisms in patients with chronic, progessive diseases requiring prolonged therapy (e.g. patients with cystic fibrosis) may cause therapeutic problems in future because of increasing resistance to all available agents. Problems with Gram-positive bacteria may arise because of the development of resistance to vancomycin (Woodford et al. 1991). 1.2 Antifungal Agents Potent and efficacious drugs are needed in the treatment of fungal infections. The therapy of choice in severe systemic fungal infections, especially in neutropenic patients, remains amphotericin B. However, failures are still numerous, as are relapses (Meunier 1988). Moreover, administration of this drug has been associated with major adverse effects and toxicity (Sabra & Branch 1990). To increase the therapeutic index of amphotericin B and diminish the toxicity, new modes of admin-
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istration of this agent have been used, such as encapsulation in liposomes (Meunier 1989). This new form of drug administration will probably be applied to other drugs in order to avoid toxicity and to allow the use of much higher doses.
ation therapy with other antiviral drugs or with biological agents such as interferon and 'Y-g1obulin for augmentation of the treatment and possibly for the prevention of the emergence of resistant strains (Baba et al. 1984; Hoofnagle et al. 1986; Lok et al. 1988; Rasmussen et al. 1984; Reed et al. 1988).
1.3 Antiviral Agents In comparison with the wealth of antibacterial agents available only a few specifically antiviral drugs are presently registered. A major reason for the difficulty in finding useful antiviral agents is that viral replication is strictly dependent on host cell processes. Antiviral agents must be highly selective because they must stop viral replication without causing toxicity or affecting cell metabolism in uninfected cells. The AIDS epidemic has boosted the scientific interest in the development of new antiviral agents, and modern molecular techniques are now used to develop new agents. In recent years several potent new drugs have been developed and accepted for the treatment of viral infections: aciclovir against herpes viruses (O'Brien & Campoli-Richards 1989), ganciclovir (Faulds & Heel 1990) and foscarnet (Chrisp & Clissold 1991) for infection caused by cytomegalovirus (CMV) and recently zidovudine (AZT) against the human immunodeficiency virus (HIV) (Langtry & Campoli-Richards 1989; Mitsuyo et al. 1985). Increasing knowledge of the viral replication process in host cells should lead to better identification of molecules that can be used as targets in antiviral therapy and useful new agents will undoubtedly be discovered in the near future (De Clerq 1989; Smith et al. 1987). The increasing use of antiviral drugs has been associated with the emergence of resistant strains and clinical problems associated with this resistance. There have been reports of aciclovir-resistant herpes simplex virus [HSV] (Erlich et al. 1989), ganciclovir-resistant CMV (Erice et al. 1989) and zidovudine-resistant HIV in patients receiving this drug longer than 6 months (Lader et al. 1989). The clinical implications of these findings need further study. Antiviral chemotherapy also includes combin-
2. Immunotherapy Infected patients fell generally into 2 groups: the majority who respond readily to treatment and the minority (with whom we are more concerned) who do not. The latter group require intensification of therapy and while antimicrobial drugs remain the cornerstone of treatment, other approaches should be used to minimise the deleterious effects of bacterial products on the physiological functions of the host and to supplement or stimulate host defences. As a complement to the long accepted strategies of developing more potent, safer, and more broadly directed antimicrobial agents, considerable efforts have been made to enhance or restore human immune responses to pathogenic and opportunistic microorganisms, and other forms of treatment, such as immunotherapy, have been explored. Protectiv~ antibodies obtained by active or passive immunisation are needed to augment host defences. Active immunisation by means of vaccines is and will be used as a prophylactic rather than therapeutic measure because of the prolonged time (10 to 20 days) needed for an optimal immune response. Moreover, active immunisation in compromised patients may fail because intensely immunosuppressed subjects may not develop a substantial humoral antibody response (Young 1988). Some bacterial vaccines have been employed to immunise donors as a source for immunoglobulin therapy (Ziegler et al. 1982). 2.1 Passive Immunotherapy in GramNegative Infections Passive immunotherapy offers the option of rapid and safe administration of antibodies directed against whole microorganisms and/or their
Infectious Disease Therapy in the 1990s
toxic products, such as lipopolysaccharides (LPS) from Gram-negative bacteria. In recent years 2 major technological advances in the preparation of antibody-containing solutions have re-established the viability of immunotherapy in the treatment of infections: the rendering of human -y-globulin safe for intravenous infusion and the development of monoclonal antibodies. Bacteraemic infections and septic shock remain a major, if not the principal, infectious disease problem. Septic shock is a life-threatening complication of infection that can be triggered by a variety of microorganisms (Parillo et al. 1990). Although the precise incidence of those infections is still unknown, a current estimate of the annual incidence in the US is 400000 cases of sepsis, 200000 of septic shock and 100 000 deaths from this disease (Mortality, Morbidity and Weekly Reports, USA 1990). Gram-negative bacteraemia occurs in about 30% of patients with septicaemia (Ziegler et al. 1982) with a mortality rate of 20 to 60% (Bone et al. 1987; Kreger et al. 1980; Veterans Administration Systemic Sepsis Cooperation Study Group 1987). In patients developing Gram-negative septic shock mortality rates are as high as 50 to 80% (Bone et al. 1987; Calandra et al. 1988; Ziegler et al. 1982). Most of our present knowledge on the pathogenic mechanism in septic shock is derived from experimental and clinical data obtained in animals or in humans infected with Gram-negative bacteria. Control of these infections often is very difficult and the relative ineffectiveness of antibiotics can be partially explained by the debilitating effect of the underlying disease in these patients (Pizzo & Young 1984) and by the fact that antibiotic therapy can initially increase the circulating load of free endotoxin by killing or lysing the infecting bacteria (Shenep et al. 1985, 1988). Because endotoxin, a LPS in the membrane of Gram-negative bacteria, has been proposed as the initiating mediator of all types of septic shock (Morrison & Ryan 1987), immunotherapy against LPS, particularly serotherapy, has been investigated.
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2.2 Polyclonal Antibodies against LPS Naturally occurring antibodies to endotoxin have a protective effect (Mattsby-Baltzer & Alving 1984; Schellekens et al. 1988) and were associated with increased survival in Gram-negative septic shock in humans (Lachman et al. 1984). Antibodies to the core lipid A obtained by immunisation of volunteers with E. coli J5 mutants of E. coli 0 III B4 lacking the O-specific side chain but possessing lipid A were shown to be cross-protective against Gram-negative infections (Baumgartner et al. 1985; Ziegler et al. 1982). In contrast to the protective effect of J5 antiserum, a purified intravenous immunoglobulin G preparation obtained from J 5 antiserum was not superior to standard immunoglobulin in reducing mortality or in reversing Gram-negative septic shock (Calandra et al. 1988). Protection of immune serum in the Ziegler and Baumgartner studies may have been partially due to IgM antibodies directed against lipid A which are absent from the IgG preparation or to some nonspecific component of host defence. Use of antiserum, however, clearly has limitations. One of the most important drawbacks in the use of plasma-derived polyclonal antibodies is the necessity to administer unneeded antibody protein along with active antibodies, so that a rather large amount of antibody protein must be administered to achieve therapeutic effects. Monoclonal antibodies may circumvent this dilemma. 2.3 Monoclonal Antibodies against LPS
Monoclonal antibodies are traditionally produced by fusing sensitised murine B-Iymphocytes with myeloma cells, resulting in a 'hybridoma' cell line (Golfre & Milstein 1981). These hybridomas provide a continuous scource of monoclonal antibodies and clones could be selected by serological and functional screening for those producing the most desirable antibody products. The use of monoclonal antibodies should enhance therapeutic efficiency because less protein is needed than with polyclonal antibodies. Recently many monoclonal
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antibodies have been developed that recognise various epitopes of the core region of endotoxin (De Jongh-Leuvenink et al. 1990; Greenman et al. 1991; Pollack et al. 1989; Teng et al. 1985; Young et al. 1989; Ziegler et al. 1991). Two of those monoclonal antibodies, one murine (designated as E5) [Greenman et al. 1991] and one human (HAI A) [Plosker & Goa 1992; Ziegler et al. 1991], both of the IgM class, have been reported to specifically bind to the lipid A of endotoxin and to be protective. Both antibodies have been tested in the treatment of patients with Gram-negative bacterial infections and were given in addition to standard antibiotic therapy and supportive care. In a clinical study 486 patients with suspected Gram-negative bacterial infection were randomly assigned to receive intravenously either murine E5 antibodies or placebo (Greenman et al. 1991). In the group of 316 patients with Gram-negative infection as a whole no decrease of mortality was observed. There was a significant decrease of mortality in a subgroup of patients with Gram-negative sepsis, but only if those patients did not have refractory shock at study entry (n = 137, p = 0.03), whereas patients with shock were not protected. Because E5 was shown to be effective only in a subgroup of patients without shock, a second multicentre trial has been initiated to verify this protection and the results are not yet known. Recently the results of treatment of patients with Gram-negative bacteraemia and septic shock with HA-IA human IgM monoclonal antibodies against lipid A were published (Ziegler et al. 1991). 543 patients with sepsis and a presumed diagnosis of Gram-negative infection were assigned to receive either a single dose of HA-IA or placebo (human albumin). Mortality was not improved overall, but enhanced survival was observed in patients with Gram-negative bacteraemia (n = 200, p = 0.014) and in patients with Gram-negative bacteraemia and septic shock (n = 101, p = 0.017). In patients without Gram-negative bacteraemia there was no significant difference in mortality between the study groups. The therapeutic effect of HA-I A in this trial was specific for patients with sepsis and Gram-negative bacteraemia (patients with endotoxin in the
Drugs 43 (5) 1992
bloodstream). The authors suggest that monoclonal antibodies block the toxic effects of circulating endotoxin, including induction and release of the mediator of shock and tissue damage. Because sepsis requires prompt treatment before blood cultures are known, the authors advocate empirical immunotherapy with HA-IA in all patients with suspected Gram-negative infection who present with sepsis. However, before monoclonal antibodies are used as standard therapy in a great number of patients, it must be shown that the beneficial effect was really due to monoclonal antibodies directed against lipid A rather than other mechanisms (controls with an IgM antibody or polyclonal anti-J 5 antiserum were not used in Ziegler study; human albumin was administered in the placebo group). Immunotherapy with E5 and HA-IA promises to be a new tool in the treatment of patients with Gram-negative infections. However, the group of patients that may benefit the most remains to be defined more clearly (Bone 1991). Therefore, further experimental and clinical studies are warranted. 2.4 Passive Immunisation with Anticytokine Antibodies Producing antibodies which provide broad crossprotection against mUltiple LPS is problematic and results oflaboratory and clinical studies, using anticore glycolipid immunotherapy have been variable and sometimes contradictory (Baumgartner et al. 1985; Calandra et al. 1988; Ziegler et al. 1982). Another approach to the treatment of infection is the use of antibodies that recognise tumour necrosis factor (TNF). There is increasing evidence that TNF-a is a principal mediator in the cascade of pathophysiological events that follow Gram-negative septicaemia (Beutler & Cerami 1987, 1988). Antibodies directed against TNF might provide protection against many of the injurious effects of endotoxin during Gram-negative sepsis (Beutler et al. 1985; Tracey et al. 1987). Clinical studies have demonstrated that TNF levels are elevated in some septic states, such as meningococcaemia (Girardin et al. 1988; Waage et al. 1987), and human trials
Infectious Disease Therapy in the 1990s
with the controlled administration of LPS have demonstrated that serum levels of TNF rise rapidly in response to LPS administration (Hesse et al. 1988; Michie et al. 1988). Anti-TNF antibody protected rodents from the lethal doses of LPS (Beutler et al. 1985) and a baboon shock model demonstrated protective efficacy of an anti-TNF monoclonal antibody after intravenous challenge with a large inoculum of E. coli (Tracey et al. 1987). Opal et al. (1990) have shown that monoclonal antibodies against TNF-a protected neutropenic rats from lethal infection with Pseudomonas aeruginosa (53% survival rate) and that the combination of monoclonal antibodies with ciprofloxacin treatment improved survival further (100% survival rate). Infusion of anti-TNF-a antibodies into patients with severe septic shock improved mean arterial pressure without causing significant side effects (Exley et al. 1990). Anticytokine antibody therapy might be particularly useful in combination with antimicrobials in the light of evidence that antimicrobial treatment frequently increases endotoxic levels in septic animals and humans (Shenep et al. 1985, 1988). Further studies in humans are warranted to determine whether anticytokine immunotherapy is a useful adjunct to standard antimicrobial agents in the treatment of patients with Gram-negative sepsis. However, anticytokine antibody therapy must be used with caution in future human trials, because it may mitigate against some of TNF's potential beneficial effects during clinical infection (Urbaschek & Urbaschek 1987). Further studies are needed to determine whether using anti-TNF monoclonal antibodies in combination with other anticytokine or anti-LPS antibody treatments has added benefits. Monoclonal antibodies also have drawbacks, however. For example, murine monoclonal antibodies obviously contain foreign protein and can sensitise human recipients. Human monoclonal antibodies with in vitro and in vivo activity against infectious agents, have been developed and these may circumvent the problems with murine protein. Epstein-Barr viral transformation of human B-Iymphocytes is commonly used in the produc-
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tion of human monoclonal antibodies and the presence of Epstein-Barr virus genome in these preparations must be considered (Masuho 1988). Recent development of chimeric antibodies, produced by cell lines transfected with immunoglobulin genome from both murine and human sources may alleviate some of these difficulties (Morrison et al. 1984; Riechmann et al. 1988). Because of th~ great diversity of antigens on the outer surface ofoocteria it will be necessary to either prepare a large number of monoclonals that correspond to a large number of the antigenic epitopes or - better but more difficult - look for a common antigen and produce monoclonals that will be effective against a whole group of microbes, e.g. Gram-negative bacteria. A broad range of monoclonals specific for viral infections, for which there are few therapeutic agents, would be of great benefit. Production of human monoclonal antibodies is difficult. They must be shown to have in vitro and in vivo activity and to be safe for use in humans, and no cross-reaction should occur with normal human tissues. The possibility of contamination by viruses, mycoplasma, bacteria, etc. and risks of carcinogenicity should be ruled out. Taking into account all these problems, we should consider the development of monoclonal antibodies only when it is proven that polyclonal serum is effective in the experimental and clinical setting. 2.5 Immunomodifiers in Infectious Diseases Improved understanding of microbial pathogenesis and the cellular immune response has given rise to an improved understanding of the inflammatory response and new pharmaceutical products. Recombinant DNA technology has given us the ability to use interferons, interleukins and colony stimulating factors therapeutically. Administering interferon-"Y (IFN"Y) enhances the production of reactive oxygen metabolites and the killing of intracellular bacterial and protozoal pathogens in vivo or in vitro (Murray 1988). IFN"Y has been shown to be effective in the prevention of infection
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in patients with chronic granulomatous disease (International Chronic Granulomatous Disease Cooperative Study Group 1991; Todd & Goa 1992). Moreover, interferons have recently been shown to be a potentially important adjuct to conventional therapy for systemic Leishmaniasis (Badaro et al. 1990) and leprosy (Nathan et al. 1986). Interferons have shown a favourable effect on hepatitis markers in chronic hepatitis B patients (Lok et al. 1988); however, only 15% of the patients had sustained clearance of HBeAg 12 months after the end of the therapy. In hepatitis C an initial response to low dose, long term IFN-y has also been observed (Hoofnagle et al. 1986), but the disease may return after stopping therapy. Many combinations of interferon with antiviral agents act synergistically in vitro: e.g. interferon combined with aciclovir against varicella zoster virus (Baba et al. 1984) and against CMV (Rasmussen et al. 1984); other combinations have shown similar effects. Potential benefits of combination therapy also include reduced toxicity due to lowering of individual drug dosing schedules, and reduced chances of the emergence of resistant clinical isolates. The biological properties and in vitro as well as experimental in vivo results of granulocyte colonystimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), suggest 2 potential therapeutic objectives, raising the circulatory cell count by stimulating haematopoiesis after chemotherapy-induced granulocytopenia and improving the function of neutrophils and macrophages (Grant & Heel 1992; Ruef & Coleman 1990), thereby reducing infection rates (Reed et al. 1987; Vadhan-Raj et al. 1987; Weiser et al. 1987). G-CSF is a therapeutic option in patients with neutropenia. It was shown to reduce the occurrence of infections in individuals with congenital or cyclic neutropenia (Bonilla et al. 1989). Both G-CSF and GM-CSF have been shown to reduce mortality after an otherwise lethal dose of whole body irradiation, a situation in which many patients die from secondary infections (Talmadge et al. 1989).
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3. Conclusion Any single therapy is probably of limited use and the most beneficial approach to infectious disease may be a combination of therapies. For example, in the treatment of septicaemia in the immunocompromised host much better results are achieved with a combination of antimicrobial drugs with antiendotoxin serum than with either treatment alone. The use of potent antibiotics, an improved delivery system and activating cytokines results in more rapid killing of intracellular pathogens such as mycobacteria, than any of these approaches alone (Bermudez & Young 1988). In the future, potent combinations of immune modulators, antibiotics and antibodies may well provide the broadest possible approach to the persisting therapeutic challenges offered by infections complicating altered host states by underlying disease, immunosuppression and/or invasive procedures. However, there is still a long way to go, and well planned clinical studies are needed to definitively determine which approach will be the best for each category of patients.
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Correspondence and reprints: Dr M. Rotenberg-Arska. Department of Clinical Microbiology and Laboratory of Infectious Diseases University Hospital Utrecht, HP G 04.515, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
