Immunotherapy Of Specific Bacterial Infections

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Staphylococcus aureus

There have been a number of attempts to develop type-specific antibodies for use in the treatment of staphyloccal infections (1-4). Most of them have focused on the development of vaccines to induce immunity against staphylococci (1,2) or the use of nonvirulent staphylococci to colonize individuals and prevent colonization by virulent staphylococci (3,4). None of these strategies has been shown to be effective to date, although it should be possible eventually to develop a vaccine against staphylococcal antigens that could induce protective immunity against invasive disease. One such antigen would be the toxic shock syndrome toxin (TSST).

Pooled immunoglobulins have been used in the treatment of staphylococcal-associated toxic shock syndrome (5,6). This appears to be a successful strategy in some cases, but no controlled clinical trials have been conducted to evaluate its potential fully, and no TSST-specific, hyperimmune, sera have been developed to further evaluate their potential efficacy in reducing the morbidity and mortality of this disease.

Because staphylococci, especially S. aureus, have become increasingly resistant to antibiotics currently in use, emphasis should be placed on the development of both active vaccines and hyperimmune sera directed against specific antigens to prevent and treat invasive disease.

Streptococci

Prior to the advent of antimicrobials, antisera were developed to combat pneumo-coccal infections, especially pneumonia (7). The use of these preparations became standard practice and did lead to a significant reduction in the mortality of the disease. As effective antibiotics were developed, the use of antipneumococcal sera was abandoned. Now that strains of pneumococci have become resistant to p-lactams, it may become necessary to reconsider the use of antisera as adjunctive, if not primary, therapy of serious pneumococcal infections. It should not be difficult to prepare hyperimmune sera from individuals immunized with polyvalent preparations of pneumococcal polysac-charides who have high titers against the prevalent serotypes of pneumococci.

No antisera directed against the polysaccharides or proteins of any of the hemolytic streptococci have been developed to date. In studies of the use of various intravenous immunoglobulin (IVIG) preparations in the prevention and treatment of sepsis in low-birth-weight and other neonates, there appeared to be a small, but significant effect on decreasing the mortality rate associated with sepsis (8,9). Group B streptococci are an important cause of neonatal sepsis, but these studies did not specifically address these organisms, and it is as yet unclear whether the use of standard IVIG preparations would prevent or augment the treatment of serious group B streptococcal infections. Group B streptococci can also cause serious disease in adults, especially those with underlying diabetes, cirrhosis, and malignancy, but these infections have not posed a threat in terms of antibiotic resistance, and it would seem unlikely that hyperimmune antisera to group B streptococcal antigens would significantly facilitate the resolution of the disease, compared with the use of antibiotics alone. It would seem important, however, to develop vaccines against specific group B streptococcal antigens for use in susceptible adults, if not in neonates.

Group A streptococcal infections remain an important cause of morbidity and mortality in most human populations. Attempts to develop vaccines that induce protective immunity have faltered because of potential cross-reactions with normal human tissues (10). Nonetheless, these attempts should continue, as should the development of specific, hyperimmune sera, to augment the treatment of serious infections such as necro-tizing fasciitis, septicemia, and complicated cellulitis. Streptococcal toxins, especially TSST, appear to be important virulence factors in the pathogenesis of systemic infection (11), and the early use of IVIG, similar to that in staphylococcal infections, appears to ameliorate the effects of TSST-associated streptococcal infections (12). Ideally, controlled clinical studies should be conducted to prove that this approach would work. In this regard, hyperimmune sera directed against TSST should be developed for use in such studies, and for use in selected clinical situations.

Other Gram-Positive Organisms

The use of specific hyperimmune globulins in the treatment of diseases associated with toxins produced by corynebacteria and clostridia is now well established (13-15). Diphtheria antitoxin, when administered early in the disease, appears to prevent a number of complications associated with diphtheria (13). Similarly, the use of tetanus and botulinum antitoxins is critical to the recovery of patients with tetanus and botulism (14,15). One anecdotal study suggested that the use of IVIG facilitated the resolution of Clostridium difficile enterocolitis (16).

Gram-Negative Cocci and Coccobacilli

Hemophilus influenzae is an important cause of invasive disease, especially meningitis, in infants and young children. An effective vaccine directed against a major outer membrane protein, as well as a vaccine directed against the specific polysaccharide, has now been in routine use (17). Currently available antibiotics are still very effective against disease caused by H. influenzae in children and adults; thus, it would not appear necessary to try to develop hyperimmune antisera for adjunctive use in the treatment of serious infections caused by this organism.

Neisserial infections, especially those caused by Neisseria meningitidis and Neisseria gonorrhea, remain worldwide problems. Vaccines have been developed for Groups A and C meningococci, and work is proceeding on developing a vaccine for group B as well (18,19). Work is also proceeding on the development of a gonococcal-specific vaccine (20). As for the potential use of hyperimmune IVIG preparations directed against meningococci or gonococci, there would not seem to be any compelling need for the development of such sera.

Gram-Negative Bacilli

Much attention has been paid to the prevention and treatment of infections caused by enteric Gram-negative bacilli and Pseudomonas aeruginosa. Infections caused by these organisms have been of increasing importance as pathogens, especially in hospitals, causing significant morbidity and mortality (21). As more immunosuppressive treatments are used to control malignancies and other disorders, the incidence of secondary infections caused by Gram-negative bacilli increases. The ability of these organisms to become resistant to antibiotics over relatively short periods also presents a compelling argument for the development of effective prophylactic and therapeutic strategies to combat the frequently life-threatening infections associated with them. It would appear at times that significant progress has been made in this area, only to find evidence to the contrary. Nonetheless, the bulk of the evidence supports the idea that successful immunization against these organisms is possible and that immunotherapy of infection in progress is also possible.

Braude et al. (22) and McCabe (23) made the initial observations that the core gly-colipids of the endotoxin molecule, common to all Enterobacteriaceae, could be used to prevent infection from both homologous and heterologous enteric bacteria and that antisera directed against this endotoxin core could both prevent and treat infections caused by different enteric bacteria. Clinical trials initially using human antiserum to the core of the endotoxin molecule of a mutant E. coli, and subsequently a monoclonal antibody preparation (HA-1A) against the same J5 mutant, showed that both mortality and morbidity (i.e., shock) could be prevented in patients with documented Gramnegative bacteremia (24,25). A number of other clinical trials also showed therapeutic or prophylactic benefit of immunoglobulin preparations (26-28), although other trials did not show any benefit of core-endotoxin hyperimmune globulin over that of standard IVIG preparations (29,30). Because overall mortality of patients was not reduced in control patients in the HA-1A trial, implying an adverse effect of the antibody preparation in patients with Gram-positive bacteremia or with no defined etiology, because two other trials failed to show a beneficial effect against Gram-negative sepsis, and because of a number of other issues, including the use of subanalyses, and the potential costs of this therapy, the HA-1A preparation did not receive U.S. Food and Drug Administration approval for use in patients with suspected Gram-negative sepsis. The various issues, however, remain unresolved, as argued by Cross et al (31), and it is hoped that this approach will be re-examined and refined, not abandoned.

Another series of trials directed against infections caused by Klebsiella species and Pseudomonas aeruginosa ended without definitive conclusions. In these trials, patients in intensive care units in Department of Veterans Affairs hospitals in the United States were given hyperimmune sera derived from immunized human volunteers to determine whether these preparations were more effective than an albumin placebo in preventing infection, mortality, and morbidity caused by these important pathogens. In the first trial, it appeared that Klebsiella infections were being prevented and modified, but because there was no effect against Pseudomonas infections, that trial was stopped by the Data Monitoring Board (DMB) and a new trial begun using greater concentrations of hyperimmune sera (32). The second trial was never completed, however, because of the many adverse effects (e.g., hypotension, fever) of the hyperimmune IVIG preparation and because the DMB was not convinced that the trial would yield significant differences when and if sufficient patient enrollment could be achieved. Subsequent analyses suggested that the hyperimmune preparation had a therapeutic effect on patients who were already infected at the time of patient entry into the study, but the numbers did not achieve statistical significance. No subsequent studies were considered by the manufacturer or by the Department of Veterans Affairs, leaving the possibility of therapeutic and/or prophylactic benefit unresolved.

Miscellaneous Observations

Limited, anecdotal, studies in various other settings have suggested some therapeutic and prophylactic benefit of standard IVIG preparations. These include sepsis following cardiac surgery in high-risk patients (33), patients with cerebrospinal fluid shunt infections (34), and patients with multiple myeloma (35). No effect was found in preventing infections in pediatric head trauma patients (36). One report suggested that early treatment with IVIG prevented polyneuropathy following multiple organ failure and Gramnegative sepsis (37). Another report suggested that IVIG facilitated the recovery of lymphocytic meningoradiculitis associated with Lyme disease (38). Experimentally, the use of human IVIG protected rabbits from diarrhea and death associated with E. coli shiga-like toxin (39).

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