key: cord-010570-ytv7dwr0
authors: Casadevall, Arturo; Scharff, Matthew D.
title: Return to the Past: The Case for Antibody-Based Therapies in Infectious Diseases
date: 1995-07-17
journal: Clin Infect Dis
DOI: 10.1093/clinids/21.1.150
sha: 
doc_id: 10570
cord_uid: ytv7dwr0

In the preantibiotic era, passive antibody administration (serum therapy) was useful for the treatment of many infectious diseases. The introduction of antimicrobial chemotherapy in the 1940s led to the rapid abandonment of many forms of passive antibody therapy. Chemotherapy was more effective and less toxic than antibody therapy. In this last decade of the 20th century the efficacy of antimicrobial chemotherapy is diminishing because of the rapidly escalating number of immunocompromised individuals, the emergence of new pathogens, the reemergence of old pathogens, and widespread development of resistance to antimicrobial drugs. This diminishment in the effectiveness of chemotherapy has been paralleled by advances in monoclonal antibody technology that have made feasible the generation of human antibodies. This combination of factors makes passive antibody therapy an option worthy of serious consideration. We propose that for every pathogen there exists an antibody that will modify the infection to the benefit of the host. Such antibodies are potential antimicrobial agents. Antibody-based therapies have significant advantages and disadvantages relative to standard chemotherapy. The reintroduction of antibody-based therapy would require major changes in the practices of infectious disease specialists.

The antibiotic era is about 60 years old. As we approach the 21st century, the progress made in controlling infections is threatened by the growing numbers of immunosuppressed individuals; the emergence of new pathogens; the reemergence of old pathogens; and the widespread resistance of organisms to antimicrobial drugs. Each development poses its own set of challenges; in combination, these developments are already undermining the efficacy of antimicrobial chemotherapy. There is a worldwide epidemic of immunosuppression due to malnutrition, AIDS, medical therapies for cancer and autoimmune diseases, and organ transplantation. Immunosuppressed hosts provide ecological niches for low-virulence microorganisms [1] . In addition, antimicrobial drugs are less effective and sometimes are unable to eradicate infection in individuals with impaired immunity. Classical pathogens such as Mycobacterium tuberculosis and Treponema pallidum have reemerged and are difficult to treat in immunosuppressed individuals [2, 3] . The increasing frequency of drug-resistant organisms is an equally alarming development, and resistance may be developing faster than new antibiotics can be introduced [4] . For example, in one New York City hospital, the percentage of vancomycinsusceptible Enterococcus faecium decreased from 86% to 26% in 2 years [5] . The problem of resistance is not limited to bacteria; there are numerous reports of fluconazole-resistant Candida albicans [6] .

We briefly review the use of antibody-based therapy in the early 20th century and make the case for reintroducing passive antibody administration for the treatment ofinfectious diseases. Advances in monoclonal antibody (mAb) technology provide new opportunities for developing antibody-based therapies. In the case of pathogens for which antimicrobial chemotherapy already exists, antibody-based therapies could be used with existing chemotherapy to improve outcome and possibly reduce the development of resistance. In the case of pathogens for which no effective chemotherapy exists, antibody-based therapies could be used for primary therapy. Given the diminishing efficacy of existing antimicrobials because of widespread resistance and the difficulties of treating infections in immunosuppressed individuals, the reintroduction of antibody-based therapies is an option that should be given serious consideration. This reintroduction would require major changes in the practice of infectious disease medicine.

The administration of immune serum (usually animal) for the treatment of infections was called serum therapy and was introduced in the 1890s for the treatment of diphtheria. By the 1930s, serum therapy was widely used for the treatment of Table 1 . Infectious diseases that were treated with antibody-based therapies in the preantibiotic era.

bacterial and viral infections (table 1) . For example, in the late 1930s, 86% of patients with type I pneumococcal pneumonia admitted to Boston City Hospital were treated with type-specific serum [36] . From 1927 to 1932 at Bellevue Hospital (New York), > 3,000 patients with erysipelas were treated with serum [37] (figure 1). The efficacy of serum therapy varied with the type or severity of infection. Several large controlled studies revealed that type-specific serum reduced the mortality ofpneumococcal pneumonia [7] .

Serum therapy also appears to have significantly reduced mortality due to meningococcal meningitis in some epidemics [7, 38] . Serum therapy reduced mortality due to Haemophilus irif/uenzae meningitis, but the effect was small [8] [9] [10] . Serum therapy for erysipelas reduced mortality in comparison to historical controls [37, 39] . Serum therapy reduced mortality in diphtheria, and antibody therapy continues to be used today to treat this disease [40] . The efficacy of serum therapy for whooping cough, anthrax, dysentery (Shigella dysenteriae), and gas gangrene was uncertain. Human convalescent serum was effective for prophylaxis ofmeasles, which had a mortality rate of 6%-7% in some populations [29] [30] [31] . The effectiveness of serum in the pre-paralytic stage of poliomyelitis was uncertain [31, 32] . No consistently effective sera were developed against many pathogens, including Staphylococcus [41] , Mycobacterium, and Salmonella species [42] .

The historical use of serum therapy provides lessons for the effective use and development of antibody-based therapies. Accurate microbiological diagnosis was essential for successful treatment, and serum therapy was most effective when used for prophylaxis or for therapy early in the course of infection. NOTE. This is not a complete list. [7] [7] [8] [9] [10] Nevertheless, it was possible to treat established bacterial infections such as meningococcal meningitis and pneumococcal pneumonia if antibody was administered shortly after symptoms began [7] . Antibodies functioned as direct antibacterial agents (e.g., pneumococcal antisera) or antitoxins (e.g., diphtherial antisera). Nonphysiological and nontherapeutic animal models of infection allowed investigators to successfully identify clinically useful antibody reagents [7] . A considerable amount of basic immunologic and microbiological research was required to develop each serum, and many fundamental discoveries were made in the search for better sera. (The contributions of pneumococcal research to basic science are discussed in [43] .)

Sulfonamides were introduced in 1935 and rapidly became the standard therapy for many infections [44] . Because antimicrobial chemotherapy had significant advantages over serum therapy, the latter was largely abandoned. Systemic administration of animal sera caused fevers, chills, and allergic reactions [23, 45] ; "serum sickness," a self-limited syndrome characterized by rash, proteinuria, and arthralgias, occurred in 10%-50% of patients because of immune complex disease. In addition, strain typing was necessary for choosing pneumococcal antisera; there was significant lot-to-lot variation in serum efficacy [46] ; and dosing was based on clinical experience. Inadequate dosage, delays in treatment, errors in typing, mixed infections, and complicated infections (e.g., empyema) could result in failure of serum therapy [47] . Serum was expensive because of the costs of animal husbandry, antibody purification, refrigeration, and reliance on mouse protection tests for standardization.

Chemotherapy was less toxic and more effective than serum therapy. Treatment with type-specific serum reduced the mortality of pneumococcal pneumonia from 30%-40% to 10%-20% [7] , whereas the mortality rate among patients treated with sulfonamide was 7% [48] . Serum therapy reduced the mortality rate of erysipelas from 10% to 7% [37] , whereas the mortality rate for patients treated with sulfonamides was 1%-2% [49] . For meningococcal meningitis, the efficacy of serum depended on the epidemic. In the mid-1930s, Waghelstein [50] reported that the mortality rate for patients with meningococcal meningitis who were treated at Sydenham Hospital (Baltimore, MD) with sulfonamide was 15.3% and for those treated with serum it was 27%. In controlled trials, the superiority of chemotherapy over serum therapy was lessevident. For example, the mortality among patients with meningococcal meningitis who were treated early with adequate serum therapy was 16.7% vs. 11.6% for sulfanilamide therapy [50] . The mortality among patients with pneumococcal pneumonia treated with antimicrobial drugs or serum was 11% and 16.7%, respectively, but there was no difference in the mortality rates among younger ..

Literature sent on request.

is used at Bellevue Hospital. It is supplied in packages of one therapeutic dose of approximately ten cubic centimeters. The data cited were published in [37] .

patients, and younger patients who received serum recovered faster than those who received antimicrobials [51] .

In the early days of the antibiotic era there was interest in using combination therapies with antibiotics and serum. Sulfonamides and serum had a synergistic or additive effect against Streptococcus pneumoniae [52] [53] [54] [55] , streptococci [56] , and meningococci [57] . The finding that sulfonamides made pneumococci more susceptible to antibody-mediated phagocytosis supported the idea of combination therapy [58] . It was similarly recognized that sulfonamides, unlike antibody, did not neutralize bacterial toxins or modify the course of disease caused by diphtheria or tetanus toxins [59] . Combination therapy was recommended for scarlet fever [60] , pneumococcal pneumonia [44, 54, 61] , whooping cough [20] and meningitis due to pneumococcus [8, 62] , meningococcus [8, 50, 63, 64] , or H. influenzae [8] . However, the side effects of serum made the potential benefits of combination therapy marginal [50] .

In summary, serum therapy was abandoned because of toxicity, difficulty in administration, narrow specificity, lot-to-lot variation, and expense. Chemotherapy was less toxic and easier to use, lots were more consistent, and it was more effective in eradicating infection. In addition, there was no need for strain typing with chemotherapy. However, it is ironic that the broad antimicrobial activity of these drugs used for chemotherapy might have contributed to widespread resistance, and today susceptibility testing is essential to the selection of appropriate antimicrobial drugs.

Although antibodies are no longer used directly as antibacterial drugs, they continue to be used in infectious diseases (for recent reviews see [65] [66] [67] ). The majority of antibody preparations are now human. Antibody administration reduces infection in individuals with immunodeficiencies [65] [66] [67] [68] and is effective for postexposure prophylaxis against measles, hepatitis A and B, rabies, and varicella viruses. Specific antibody is used for the treatment of botulism [22] , diphtheria [40] , tetanus [22] , snake bites [69] , and spider stings [70] . Passive antibody administration has been used for prophylaxis and/or therapy of several viral infections, including cytomegalovirus (CMV) [71, 72] , rotavirus [73] , Lassa virus [74] , varicella [75] , enterovirus [76, 77] , and parvovirus B19 infections [78] . In recent years, there has been renewed interest in the use of antibody preparations to prevent infection in high-risk groups. Intravenous administration of polyclonal antibody has been reported to reduce the number of infections in patients with AIDS [79] [80] [81] , patients in surgical intensive care units [82] , organ transplant recipients [83] , and neonates [84, 85] (for critical reviews and commentary on this practice see [86] [87] [88] [89] ).

Antibody therapy is used for a variety of illnesses that may or may not be infectious, including autoimmune thrombocytopenia, Kawasaki disease, and autoimmune neuromuscular diseases [65, 66] . Passive antibody administration is used for prevention of Rh-hemolytic disease [90] . Equine lymphocyte antiserum [91] and murine mAbs to lymphocytes are used to prevent organ rejection [92] . Digitalis-binding antibodies are useful for the treatment of digoxin toxicity [93] . Thus, antibody therapy is still widely used in medicine, but its role in the treatment of infections is limited largely to viral and toxin neutralization and replacement therapy in patients with immunoglobulin deficiencies.

In reconsidering the antibody option it is clear that heterologous antibody (i.e., serum therapy) is a poor choice because of toxicity. Human immune sera have fewer side effects, but there are concerns about availability, potency, and consistency. A major disadvantage of all immune sera is that specific antibodies make up a small minority of the antibody present. There is significant variation in pathogen-specific opsonic activity of commercially available immunoglobulin preparations [94] .

There is also concern about the potential of human sera to transmit infectious agents [95] .

The discovery of hybridoma technology in 1975 [96] and recent advances in mAb technology, including the generation of humanized antibodies [97] , make mAb-based therapies a more attractive therapeutic option. In contrast to polyclonal sera, mAbs are homogeneous and reproducible reagents that can be generated in large amounts. Generation of mAbs from mice and rats is still easier and more efficient than production of human mAbs. However, several technologies are available for the humanization of murine mAbs and generation of human mAbs [97] . Mouse-human chimeric antibodies can be constructed by linking the genes expressing the mouse variable region to human constant region genes [97] . The result is a molecule that is mostly human and has a longer half-life than the murine precursor [98] . As an alternative, the antigen binding regions of murine mAbs can be grafted into human antibody frameworks by molecular techniques [97] , resulting in molecules that are almost completely human in origin. Other strategies to generate human antibodies are the transformation of human B cells, the generation ofrecombinant antibody libraries from human B cells, and the use of transgenic mice that have the human immunoglobulin locus.

Recent Setbacks for mAb-Based Therapies: Historical Perspective Clinical trials of antiendotoxin mAbs for gram-negative sepsis have produced inconclusive results [99, 100] . When the difficulties encountered in developing antiendotoxin mAb strategies are considered in the context of the development of serum therapy, they do not seem unusual or unexpected. For example, passive protection with pneumococcal antisera was demonstrated in 1891 by the Klemperers [101] , but 30-40 years elapsed before serum therapy for pneumococcal pneumonia was widely accepted. For pneumococcal antiserum therapy to be consistently successful, several developments were necessary. These included the appreciation of antigenic variation in pneumococci [102] , the need for type-specific sera [103] , the development of rapid in vitro assays to establish antigenic type (i.e., capsular swelling and agglutination reactions) [104] , the development of methods to standardize potency (mouse protection test) [46] , and improved purification techniques that would reduce the toxicity of serum. For meningococcal antisera the situation was reversed; Flexner's serum significantly reduced mortality in early epidemics of meningitis [38] but was subsequently less effective, possibly as a result of antigenic changes in Neisseria meningitidis [7] . Research into better meningococcal antisera was then hampered by the lack of useful animal models, loss of strain virulence in vitro, and poor understanding of the antigenic diversity of N meningitidis [105, 106] . A lesson from the preantibiotic era is that a considerable amount of basic research on the immunology and pathogenesis of each infection is usually necessary before antibody therapy can be developed that will be successful in clinical practice.

Spectrum ofactivity. Antibodies can modify bacterial, fungal, parasitic, and viral infections and are a class of biological agents with broad antimicrobial activity against diverse pathogens. Antibody-based therapies are usually pathogen-specific and have the theoretical advantage that they should not affect the normal flora of the patient or select for resistance in nontargeted microbes. Nevertheless, narrow specificity is a disadvantage because mixed infections may not be treated by a single antibody preparation. Pneumonia due to S. pneumoniae with more than one serotype was recognized as a reason for the failure of type-specific serum therapy [107] . One solution is to use cocktails of mAbs active against common antigenic types. Cocktails may be designed to include mAbs to multiple serotypes and mAbs with multiple isotypes to enhance antibody effector function. Pathogen-specific drugs (such as mAbs) are less attractive to the pharmaceutical industry because the narrow specificity reduces the potential market for the drug. However, the increasing incidence of resistant organisms resulting from the use of broad-spectrum antibiotic regimens could make pathogen-specific drugs attractive to drug companies. Precedents for the development of pathogen-specific drugs already exist in the area of antiviral drug research.

Mechanisms ofaction. Antibodies mediate protection by a variety of mechanisms. Direct antibody mechanisms of action include inhibition of attachment, agglutination (and immobili-cm 1995;21 (July) zation), viral neutralization, toxin neutralization, antibodydirected cellular cytotoxicity, complement activation, and opsonization [108] . Antibody therapy has the potential to enhance immune function in immunosuppressed hosts. However, since the mechanism of action of many antibodies involves promoting microbial clearance through nonspecific cellular immunity, antibody-based therapies may be less effective in individuals with defective macrophage, neutrophil, and natural killer cell function. In this regard, it is encouraging that antibodies are effective against Pseudomonas aeruginosa in neutropenic mice [109] and that they can reduce the number of infections in pediatric patients with AIDS [79] .

Antibodies are usually considered to be "protective" effector molecules of the immune system. However, not all antibody responses to pathogens are protective and some may be deleterious to the host. For example, some viral-specific antibodies are capable of enhancing infection [110] . Thus, antibody molecules being considered for clinical development will require extensive testing in vitro and in vivo. Studies of the mechanisms of antibody action are important for understanding the mode of protection and for designing clinical trials.

Pharmacokinetics. The pharmacokinetics of human IgG suggests several useful characteristics for its role as an antiinfective agent. These include a long half-life (~20 days [111]), good tissue penetration [112] , and, depending on the isotype, the ability to either cross the placenta to provide antibody protection to fetuses and newborns [113] or to be excluded from the placenta if fetal toxicity is a concern. Heterologous mAbs (i.e., murine mAbs) have shorter half-lives in humans, but chimeric and humanized mAbs have longer half-lives than their murine precursors. mAbs with a longer half-life can, in principle, be engineered by altering the regions of the constant domain that regulate clearance.

A disadvantage of antibody-based therapies is the need for systemic administration. Oral administration is unlikely to be effective, with the possible exception of therapy for enteric pathogens [73, 114] . The blood-brain barrier is a potential obstacle for antibody therapy for infections of the brain. However, in infections of the brain in which there is inflammation, there is increased antibody penetration, and intravenous administration of antibodies appears to have been successfully used for therapy of meningococcal meningitis [115] . Antibodybased therapies can also be administered directly into the subarachnoid space, as has been done for the treatment ofmeningococcal and H. influenzae meningitis [8, 38] . Enhanced penetration of the brain can be achieved by modifying the charge of the molecule [116] or by linking it to carrier proteins that cross the blood-brain barrier [117] . Antibody therapy for brain infections may be feasible if the blood-brain barrier is leaky, if antibody is administered directly into the subarachnoid space, or if antibodies with greater brain penetration are used. Additional research into the pharmacokinetics of antibodies in infection is likely to be required for optimal use of antibody-based therapies. Studies of antibody binding to tumors have revealed complex pharmacokinetics [112] . There may be problems with antibody penetration into abscesses as have been found with tumors.

Toxicity. Immunoglobulins are generally safe drugs [67] . Nevertheless, serious side effects have been reported with highdose (0.5-2 g/kg) antibody therapy, including rare cases of renal failure [118] , aseptic meningitis [119] , and thromboembolic events [120, 121] . High-dose immunoglobulin therapy is unlikely to be required in antiinfective mAb therapy. In the past, serum therapy was effective against various pathogens despite the fact that immune sera contained only small amounts of specific antibody. mAbs have significantly higher specific activity than polyclonal preparations. For example, 0.7 mg of two anti-tetanus toxin human mAbs provides the same activity as 100-170 mg of immune globulin [122] . Thus, the toxicities described for high-dose immunoglobulin therapy may not be relevant in antiinfective therapies with mAbs.

Until fully human mAbs are available, rodent, mousehuman chimeric, or humanized mAbs are therapeutic options. For over a decade, murine mAbs directed against T cells have been used to prevent organ graft rejection in humans [92] . A murine IgM to endotoxin (E5) was tested in 247 patients with sepsis and appeared to be a safe treatment [123] . Although administration of murine mAbs is generally well tolerated in humans, allergic reactions occur in 1%-2% of patients [123] and most patients develop antibody responses to the murine mAbs that may interfere with their therapeutic function [43, 124] . Experience with human-mouse chimeric antibodies and humanized mAbs is accumulating rapidly as clinical trials with several compounds progress. A chimeric anti-CD4 mAb for the treatment of rheumatoid arthritis has been well tolerated [125] , but approximately half the patients had infusion-related side effects (headaches, nausea, fever, and chills), which were diminished by slowing the infusion rate [125] . Mouse-human chimeric and humanized mAbs are less immunogenic than their murine precursors [98, 126] , but antiidiotypic responses occur after repeated treatments [127] . Overall, the experience with chimeric and humanized mAbs suggests that they are relatively safe compounds [98, [125] [126] [127] [128] .

Antigenic variation and antibody resistance. The efficacy of antibody-based therapies may be diminished by antigenic changes in the pathogen. This could be minimized by antigenic surveillance systems, as is presently done for influenza virus. Antibody-resistant mutants can be generated in the laboratory [129] , and it is likely that the same can occur in patients. Mechanisms of antibody resistance include mutations that change the antigenic site and protease production. Antibody use may select for antigenically distinct variants. Evidence for the horizontal transfer of IgA protease genes exists in Neisseria gonorrhoeae and it is conceivable that widespread antibody use would result in selection of protease-producing strains for many pathogens [130] . Thus, large-scale use of antibody-based therapies may result in rapid emergence of antibody resistance in a manner analogous to that of antibiotic resistance. However, one advantage of antibody-based therapies is the versatility of antibody compounds. For example, emergence of an antibodyresistant strain could be countered by a new antibody directed toward the mutated epitope or another antigenic target. Emergence of protease-producing strains could be countered by designing antibodies without protease cleavage sites (although these may then be recognized as foreign and be immunogenic) or by addition of antiprotease mAbs. Selection of antibodyresistant organisms could be minimized by using cocktails of mAbs directed at multiple antigenic targets or by using a combination of antibodies and antimicrobials.

Cost. Cost effectiveness is a significant concern that is likely to be a major obstacle for the development of passive antibody therapies. Antibody prophylaxis for CMV infections can cost $4,000 to $9,000 per patient [71] . The cost effectiveness of antibody therapy for prevention of infection in leukemic patients has been questioned [88, 131] . However, in selected populations such as premature infants, antibody therapy may be cost effective [85] . Furthermore, the cost of a drug when first introduced may not reflect its long-term costs given the potential for improvements in technology and production. mAbs are presently made in tissue culture, so the cost of production is high. mAbs can be made in bacteria or yeast, and less costly means of production might be developed [97] . In the past, serum therapy was used despite its high cost because it was believed to be effective. New antibody-based therapies are likely to be used if they prove to be effective.

For pathogens such as S. pneumoniae, N. meningitidis, and H infiuenzae, there is a large body of experimental and clinical evidence to support the development of passive antibody therapy. However, for many pathogens, antibody immunity has not been proven to be important. For example, Cryptococcus neoformans is a fungus for which the importance of antibody immunity is uncertain. However, administration of preformed antibodies can modify the course of cryptococcal infection in various animal models [132] [133] [134] [135] [136] , and the combination of antibody and amphotericin B is a more effective treatment than the use of either agent alone [137] [138] [139] . Studies with mAbs have shown that there are protective, nonprotective, and deleterious antibodies to the C. neoformans capsule polysaccharide [136] . Heavy chain isotype [136, 140] and epitope specificity [141] are important determinants of protective efficacy. The existence of protective and nonprotective antibodies against C. neoformans, a fungus for which antibody immunity mayor may not be important, provides a paradigm that may be applicable to other pathogens.

We propose the hypothesis that for every pathogen there exists an antibody that will modify the course of infection to the benefit of the host; such antibodies are candidates for development as antimicrobial drugs. Our proposal includes the use of antibodies for intracellular pathogens; for example, anti-bodies may exist that could prevent cell entry of intracellular bacteria and/or shift the intracellular location of such bacteria by promoting internalization through Fe receptors. An mAb that inhibits intracellular Toxoplasma gondii infection has recently been described [142] . In addition, antibodies have been described that can neutralize viruses intracellularly [143] or penetrate the nuclear membrane [144] .

Our proposal is not limited to those pathogens for which antibody immunity has been demonstrated to be protective. Conclusions on the importance of antibody immunity are usually based on observations made with polyclonal sera (i.e., passive protection or correlation of immunity with the presence of antibody). Since polyclonal sera might contain protective antibodies, nonprotective antibodies, and disease-enhancing antibodies, the existence of protective antibodies cannot be ruled out on the basis of absence of protection in experiments involving passive transfer of polyclonal sera or immunizations.

Conversely, experiments that demonstrate that polyclonal sera can mediate protection indicate the existence of protective antibodies. For pathogens for which polyclonal antibody has shown no protection, the question of whether useful antibodies exist must be reevaluated with mAbs since the presence of nonprotective or deleterious antibodies in polyclonal sera could create confounding variables. A corollary of our proposal is that antibody-based therapies may be developed against pathogens for which antibody immunity is not considered to be important.

Infections that are difficult to treat and that can be modified by antibody immunity provide a logical starting point for the development of antibody-based therapies. Antibodies have historically been more effective in prophylaxis than in therapy. Antibody-based therapies have traditionally been most effective in infections where viral and toxin neutralization modifies the course of the disease. However, most of the historical experience was gained with polyclonal preparations of uncertain composition and mayor may not be applicable to mAb preparations with high activity.

Opportunistic infections. Infections with low-virulence organisms in immunosuppressed individuals are often difficult to treat and are sometimes incurable. Since the problem is deficient immunity, antibody therapy is an attractive option because antibodies can enhance immune function. Table 2 lists examples of opportunistic pathogens for which antibody can modify the course of infection.

Antibiotic resistance. Drug-resistant organisms are targets for development of antibody-based therapies. The spread of penicillin-resistant S.pneumoniae, methicillin-resistant Staphylococcus aureus, and multiply-drug-resistant E. faecium has limited the useful antibiotic arsenal against these pathogens [4, 6, 153] . For pneumococcus, antibody therapy has been shown to be useful [7] . Antibody may be useful against staphylococcal infection [154, 155] . For E.faecium, the role of antibody immu-ern 1995;21 (July) Table 2 . Opportunistic pathogens for which experimental data suggest a potential role for antibody-based therapies. nity is uncertain, but some patients make opsonic antibodies, which might be protective [156] . Significant work has already been done in the development of pseudomonal antibodies for resistant gram-negative organisms (table 2). The addition of antibody-based therapies to chemotherapy may slow the development of resistance and improve outcome.

Toxin neutralization. The ability to neutralize toxins is a unique characteristic ofantibody-based therapies. Antitoxin antibodies are useful for the treatment of diphtheria, tetanus, botulism, snake bites, and black widow bites (see above). Recent attempts to develop antibody therapy for gram-negative sepsis have focused on mAbs to neutralize endotoxin [123, 157, 158] and cytokines [159] . Pseudomonas aeruginosa sepsis, combination therapy with mAbs to endotoxin and tumor necrosis factor was superior to therapy with a single mAb [160] . Examples ofpotential targets for antibody-based therapy include the toxins and proteases associated with toxic shock syndromes [161, 162] . Combination therapy with antibodies to exotoxins could improve outcome, but cocktails of mAbs may be necessary because of toxin heterogeneity [162] . Intravenous immunoglobulin administration has been associated with dramatic clinical improvement in a patient with Streptococcus pyogenes toxic shock syndrome [163] .

Antivirals. Virus neutralization is an established property of antibodies. In the preantibiotic era, serum was used for prophylaxis ofmeasles, chickenpox, mumps, and poliomyelitis. Recently, the potential of antibody therapy against many viruses, including hepatitis B [164] , HIV [165] , respiratory syncytial virus [166] , CMV [150] , and parvovirus [167] , has received considerable attention. Newly identified viral illnesses are targets for antibody drug research.

Combination ofantibody therapy and chemotherapy. Antibody-based therapies are unlikely to be used alone unless they are the only available therapy or are being used for prophylaxis of infection. Combinations of antibody therapy and chemotherapy offer theoretical advantages. Antibodies promote microbial killing directly by a complement-mediated lytic process or indirectly by enhancing nonspecific immune mechanisms. Table 3 lists examples of bacterial, fungal, and viral pathogens for which combination therapy has shown promise. Combination therapy could reduce the amount of either agent required to Table 3 . Pathogens for which the combination of chemotherapy and antibody based therapy has shown some promise.

Pathogen Chemotherapy Antibody [57, 168] Neisseria meningitidis Sulfanilamide Horse immune sera [55] Streptococcus pneumoniae

Rabbit immune sera [8, 9] Haemophilus infiuenzae Sulfonamide Rabbit, horse immune sera [169] Staphylococcus aureus 

Sparftoxacin Human IgG1 mAb [172] P. aeruginosa

Human IgM mAb [173] P. aeruginosa

Murine E5 LPS antibodies [170] P. aeruginosa

Human gamma globulin [172] Escherichia coli

Murine E5 LPS antibodies [174] Shistosoma mansoni Praziquantel Rabbit immune sera [175] Candida albicans Amphotericin B Human gamma globulin [137] Cryptococcus neoformans Amphotericin B Rabbit immune sera [138, 139] C. neoformans Murine IgG1 mAb [176] C. neoformans

Murine IgG1 mAb [177] Lassa virus Ribavirin Monkey immune sera [72, 178] Cytomegalovirus Ganciclovir Murine immune sera [179] Herpes simplex virus Adenine arabinoside Rabbit and human sera [180] Herpes simplex virus Acycloguanosine Human immune globulin NOTE. This is not a complete list.

achieve a therapeutic effect. For example, some antibiotics are quite toxic, and the ability to reduce doses could lessen side effects. In a similar vein, the addition of chemotherapy to antibody therapy could reduce the amount of antibody necessary to achieve a therapeutic effect, which would lessen the cost of therapy.

The availability of broad-spectrum antibiotics has diminished the need for making exact microbiological diagnoses. For example, gram-negative sepsis or presumed fungal infections can be treated with empirical therapy without identifying the pathogen. This situation is in contrast to the practice of infectious diseases in the 1930s when identification of the pathogen (and its serotype) was necessary for choosing the correct antiserum. For antigenically diverse pathogens such as S. pneumoniae, rapid protocols were developed for typing strains. The present practice of infectious diseases is not unlike a gambling strategy where the probability of infection by a given microbe is matched to the likelihood of activity by the available antibiotics. This has resulted in great emphasis on broad-spectrum antibiotic "coverage" and less emphasis on making an exact microbiological diagnosis. Although the relative merits of this practice are beyond the scope of this article, widespread antimicrobial resistance is decreasing the effectiveness of existing antibiotics, and increased caution is warranted when designing broad-spectrum combinations.

A return to antibody therapy would force greater emphasis on precise microbiological diagnosis and would foster the development of more accurate and more rapid diagnostic strategies. The use of antibody-based therapies may also require antigenic screening in the clinical laboratory, a practice not unlike the present one of antimicrobial susceptibility testing. In cost-conscious times these measures may not immediately appear to be attractive. In this regard it is worth remembering that penicillin was unobtainable in 1943 [181] but half a century later it is one of our least-expensive therapies. When one is reconsidering the option of antibody-based therapies, it is important not to underestimate the human capacity for improving technology and the effect of the pressures of a competitive market on long-term costs.

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A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery

Progress in chemotherapy of bacterial and other diseases; with special reference to the prontosils, sulfanilamide and sulfapyridine

The therapy of (horse) serum reactions: general rules in the administration of therapeutic serums

The units of protective antibody in anti-pneumococcus serum and antibody solution

The use of serum, sulfanilamide, and sulfapyridine in the treatment of pneumococcic infections

The results of sulfapyridine therapy in 400 cases of typed pneumococcic pneumonia

Sulfanilamide treatment of erysipelas

Sulfanilamide in the treatment of 106 patients with meningococcic infections

The treatment of pneumococcus pneumonia: a comparison of the results obtained with specific serum and with sulfapyridine

Sulfapyridine and serum therapy in experimental lobar pneumonia of rats

P-aminobenzenesulfonamide and antipneumococcal serum therapy in type I pneumococcal infections of rats

Chemotherapy of pneumococcic pneumonia. Clinical leeture at S1. Louis session

Combined therapy of pneumococcic rat infections with rabbit antipneumococcic serum and sulfapyridine (2-sulfanilyl aminopyridine)

The treatment of bacterial infections with the combination of antibiotics and gamma globulin

Sulphanilamide, serum, and combined drug and serum therapy in experimental meningococcus and pneumococcus infections in mice

The action of prontosil-soluble and sulfanilamide on the phagocytic activity of leukocytes and on the dissociation of streptococci

Failure of sulfanilamide to inactivate preformed hemotoxins, diphtheric toxin, or tetanal toxin

Sulfanilamide and serum in the treatment and prophylaxis of scarlet fever

Specific serotherapy and chemotherapy of the pneumococcus pneumonias

Treatment of pneumococci meningitis: a study of ten cases treated with sulfanilamide alone or in various combinations with antipneumococcic serum and complement, including six recoveries

The treatment of meningococcic meningitis with sulfanilamide: preliminary report

Serum and sulphanilamide in acute meningococcal meningitis: a preliminary survey based on 113 cases

Intravenous usage of gammaglobulin: humoral immunodeficiency, immune thrombocytopenic purpura, and newer indications

Intravenous immunoglobulins as therapeutic agents

Newer uses of intravenous immunoglobulins as antiinfective agents

Prevention of infection in patients with B cell defects: focus on intravenous immunoglobulin

Poisonous snakebite treatment in the United States

Medical toxicologist's notebook: snakebite treatment and international antivenin index

Prophylaxis of primary cytomegalovirus disease in renal transplant recipients: a trial of ganciclovir vs. immunoglobulin

Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants

A randomised trial of oral gammaglobulin in low-birth-weight infants infected with rotavirus

Lassa immune serum

Prevention of varicella in high risk children: a collaborative study

Persistent and fatal central-nervous system echovirus infections in patients with agammaglobulinemia

Chronic ECHO type 5 virus meningoencephalitis in X-linked hypogammaglobulinemia: treatment with immune plasma

Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-l): a treatable cause of anemia in AIDS

Crossover of placebo patients to intravenous immunoglobulin confirms em 1995;21 (July) efficacy for prophylaxis of bacterial infections and reduction of hospitalizations in human immunodeficiency virus-infected children

Does intravenous immune globulin have a role in HIV-infected patients?

The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection

Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infection

A randomized prospective trial of acyclovir and immune globulin prophylaxis in liver transplant recipients receiving OKT3 therapy

Intravenous gammaglobulin therapy for prophylaxis of infection in high-risk neonates

Multicenter Group for the Study of Immune Globulin in Neonates. Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates

Intravenous immunoglobulin use in the neonate: role in prophylaxis and therapy of infection

Use of immunoglobulins in prevention and treatment of infection in critically ill patients: review and critique

New uses for intravenous immune globulin

Immune globulin to prevent nosocomial infections

Rhesus haemolytic disease

The clinical value of antilymphocyte antibodies

Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants

Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases

Opsonic activity of commercially available standard intravenous immunoglobulin preparations

Human immunoglobulins for intravenous use and hepatitis C viral transmission

Continuous cultures of fused cells secreting antibody of predefined specificity

Genetically engineered antibodies: progress and prospects

Mouse/human chimeric monoclonal antibody in man: kinetics and immune response

Anti-endotoxin monoclonal antibodies

Introduction of new technology into critical care practice: a history ofHA-lA human monoclonal antibody against endotoxin

Versuche tiber immunisirung und heilung bei der pneumokokkeninfektion

A biologic classification of pneumococci by means of immunity reactions

Weitere Untersuchungen uber Pneumokokken-Heilsera. Arb a d k

The reliability of sputum typing and its relation to serum therapy

The meningococcus (Neisseria intracellularis)

Serums, antitoxin, and drugs in the treatment of meningococcus meningitis

The management of the pneumonias

Principles and practice of infectious diseases

Therapeutic effects of a human antiflagella monoclonal antibody in a neutropenic murine model of Pseudomonas aeruginosa pneumonia

Immune enhancement of viral infection

Metabolism of immunoglobulins

Immunologic and pharmacologic concepts of monoclonal antibodies

Placental transfer of human IgG subclasses

Treatment of chronic cryptosporidial infection with orally administered human serum immune globulin

Intravenous treatment of meningococcic meningitis with meningococcus antitoxin

Blood-brain barrier transport of cationized immunoglobulin G: enhanced delivery compared to native protein

Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier

Acute renal failure after intravenous immunoglobulin therapy

Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors

High-dose weekly intravenous immunoglobulin to prevent infections in patients undergoing autologous bone marrow transplantation or severe myelosuppressive therapy: a study of the American Bone Marrow Transplant Group

High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events

Immunotherapy with human monoclonal antibodies: fragment A specificity of polyclonal and monoclonal antibodies is crucial for full protection against tetanus toxin

A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis

Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy

Chimeric CD4 monoclonal antibody cM-T412 as a therapeutic approach to rheumatoid arthritis

Human mouse chimeric CD7 monoclonal antibody (SDZCHH380) for the prophylaxis of kidney transplant rejection

Humanised monoclonal antibody therapy for rheumatoid arthritis

Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-lH

Antibody-resistant mutants of Borrelia burgdorferi: in vitro selection and characterization

Mosaic-like organization ofIgA protease genes in Neisseria gonorrhoeae generated by horizontal genetic exchange in vivo

Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia

Passive immunization in murine cryptococcosis

Passive immunization against Cryptococcus neoformans

Protection of mice against experimental cryptococcosis by anti-Cryptococcus neoformans monoclonal antibody

Passive immunization against Cryptococcus neoformans with an isotype-switch family of monoclonal antibodies reactive with cryptococcal polysaccharide

Protective murine monoclonal antibodies to Cryptococcus neoformans

Serum protein enhancement of antibiotic therapy in cryptococcosis

Improved amphotericin B activity by a monoclonal anti-Cryptococcus neoformans antibody: study during murine cryptococco sis and mechanisms of action

Therapeutic efficacy of monoclonal antibodies to Cryptococcus neoformans glueuronoxylomannan alone and in combination with Amphotericin B

Isotype switching from IgG3 to IgG 1 converts a non-protective murine antibody to C. neoformans into a protective antibody

Protective and nonprotective monoclonal antibodies to Cryptococcus neoformans originating from one B cell

Toxoplasma gondii: a monoclonal antibody that inhibits intracellular replication

Intracellular neutralization of virus by immunoglobulin A antibodies

A subgroup of murine monoclonal anti-deoxyribonucleic acid antibodies traverse the cytoplasm and enter the nucleus in a time-and temperature-dependent manner

Passive immunoprophylaxis with specific monoclonal antibody confers partial protection against Pneumocystis carinii pneumonitis in animal models

Anti-Cryptosporidium parvum antibodies inhibit infectivity in vitro and in vivo

Production, characterization, and antibody specificity of a mouse monoclonal antibody reactive with Cryptococcus neoformans capsular polysaccharide

Autoantibody to heat-shock protein 90 can mediate protection against systemic candidosis

Mills 1. Prevention and treatment of experimental herpes simplex virus encephalitis with human immune serum globulin

Human monoclonal antibodies neutralizing cytomegalovirus (CMV) for prophylaxis of CMV disease: report of a phase I trial in bone marrow transplant recipients

Polyclonal and monoclonal antibody therapy for experimental Pseudomonas aeruginosa pneumonia

vitro and in vivo activity of polyclonal and monoclonal human immunoglobulins G, M, and A against Pseudomonas aeruginosa lipopolysaccharide

Confronting drug-resistant pneumococci

Immunoglobulin G enhances C3 degradation on coagulase-negative staphylococci

Passive local immunotherapy of experimental staphylococcal pneumonia with human intravenous immunoglobulin

Roles of antibodies and complement in phagocytic killing of enterococci

Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli

Phase I study of a murine monoclonal anti-lipid A antibody in bacteremic and nonbacteremic patients

Therapy with antibody to tumor necrosis factor in sepsis

The efficacy of combination immunotherapy in experimental Pseudomonas sepsis

Microbiology of toxic shock syndrome: overview

Association of phenotypic and genotypic characteristics of invasive Streptococcus pyogenes isolates with clinical components of streptococcal toxic shock syndrome

Intravenous immunoglobulin therapy for toxic shock syndrome

Human combinatorial antibody libraries to hepatitis B surface antigen

Passive immunization for the prevention and treatment ofHIV infection

Human monoclonal Fab fragments derived from a combinatorial library bind to respiratory syncytial virus F glycoprotein and neutralize infectivity

Efficacy of human immunoglobulin and penicillin G in treatment of experimental group B streptococcal infection

Protection of mice against meningococcus infection by polyvalent antimeningococcic serum

Combined protective action of human gamma globulin and antibiotics when administered simultaneously in experimental staphylococcal infections

Synergism between human gamma globulin and chioroamphenicol in the treatment of experimental bacterial infections

Combined serum and sulphanilamide in the treatment of streptococcal infections in mice

Monoclonal antibodies for treatment of gram-negative infections

Efficacy of anti-endotoxin monoclonal antibody E5 alone or in combination with ciprofloxacin in neutropenic rats with Pseudomonas sepsis

Praziquantelinduced exposure of Schistosoma mansoni alkaline phosphatase: drugantibody synergy which acts preferentially against female worms. Parasite Immuno11994

Effects of immunoglobulin G and low-dose amphotericin B on Candida albicans infections in burned mice

Combination of 5-flucytosine and capsule-binding monoclonal antibody in therapy of Cryptococcus neoformans infection

Enhanced treatment of Lassa fever by immune plasma combined with ribavirin in cynomolgus monkeys

-3-Dihydroxy-2-Propoxymethyl) guanine prevents death but not immunity in murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Combined effects of acycloguanosine and humoral antibodies in experimental encephalitis due to Herpesvirus hominis

Synergistic antiviral effects of adenine arabinoside and humoral antibodies in experimental encephalitis due to Herpesvirus hominis

Unequalled but unobtainable