Human immune response to immunization with a structurally defined polypeptide fragment of streptococcal M protein.

We tested the ability of pepsin-extracted, highly purified M protein to induce type-specific immunity in experimental animals and humans. M protein was prepared from limited peptic digests of whole group A type 24 streptococci and was purified to chemical homogeneity as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, quantitative amino acid analysis, and Edman degradation. For vaccination, the lyophilized M24 protein preparation (pep M24) was precipitated in aluminum hydroxide. When injected into laboratory animals, alum-precipitated pep M24 produced type-specific protective antibodies and was free of non-type-specific immunoreactivity. In man, skin tests with 1-microgram doses of pep M24 were negative in all 37 adults tested. 12 adult human volunteers received two-four subcutaneous injections of 100-200 micrograms of alum-precipitated pep M24 at intervals of at least 2 wk. The immune response to pep M24 was measured by a variety of assays designed to detect (a) type-specific humoral antibodies (opsonophagocytic, long chain, and mouse protection tests); (b) total humoral antibodies (complement fixation and enzyme-linked immunosorbent assay); (c) cellular immunity (skin tests); and (d) heart cross-reactive antibodies (immunofluorescence). Type-specific opsonic antibodies developed in 10 of the 12 vaccinees, and positive delayed-type skin tests developed in 11. Immune sera from two of the vaccinees were effective in mouse-protection tests against challenge with M24 but not M6 streptococci. None of the volunteers developed heart-reactive antibodies or antibodies to non-type-specific M protein antigens. Alum-precipitated pep M24 was well-tolerated in man, and no serious local or systemic reactions were observed. Thus, pep M24 induces type-specific, protective antibodies in doses that are well-tolerated in man.

Fulminant pneumococcal infections in 'normal' asplenic hosts.

Five asplenic persons with no other detectable underlying disease had over-whelming pneumococcemia. Four of the patients had undergoing splenectomy for trauma, and the fifth had asplenia as an isolated congenital abnormality. Including the cases presented here, there are now at least 26 reported instances of fatal or life-threatening pneumococcal infections in otherwise-normal asplenic patients. Thus, splenectomy per se is associated with an increased risk of over-whelming pneumococcemia. Although the magnitude of the risk is low, mortality associated with these infections is high. Analysis of the clinical data strongly suggests that undiagnosed febrile episodes in asplenic persons should be treated promptly with antibiotics while awaiting culture results. This strategy should be adopted regardless of the age of the patient or his general state of health. The observation that a limited number of pneumococcal serotypes, particularly type XII, appear to predominate in these cases suggests that pneumococcal vaccine might be highly efficacious in preventing overwhelming post-splenectomy pneumococcal infections in otherwise-normal hosts.

Coagulase-negative staphylococcal endocarditis. Occurrence in patients with mitral valve prolapse.

Although coagulase-negative staphylococci (CoNS) are frequent etiologic agents in prosthetic valve endocarditis, they rarely infect native heart valves. We report three cases of CoNS endocarditis in patients with mitral valve prolapse (MVP). Review of other reports of MVP-associated endocarditis and of the limited experience with CoNS infection of native heart valves suggests that our experience is not unique. Coagulase-negative staphylococcal endocarditis superimposed on MVP may be difficult to recognize and to treat. The cardiac dysfunction can be quite subtle, the clinical course indolent, the blood culture results difficult to interpret, and the response to antimicrobial agents suboptimal.

Molecular basis of group A streptococcal virulence.

The group A streptococcus (GAS) (Streptococcus pyogenes) is among the most common and versatile of human pathogens. It is responsible for a wide spectrum of human diseases, ranging from trivial to lethal. The advent of modern techniques of molecular biology has taught much about the organism's virulence, and the genomes of several GAS types have now been deciphered. Surface structures of GAS including a family of M proteins, the hyaluronic acid capsule, and fibronectin-binding proteins, allow the organism to adhere to, colonise, and invade human skin and mucus membranes under varying environmental conditions. M protein binds to complement control factors and other host proteins to prevent activation of the alternate complement pathway and thus evade phagocytosis and killing by polymorphonuclear leucocytes. Extracellular toxins, including superantigenic streptococcal pyrogenic exotoxins, contribute to tissue invasion and initiate the cytokine storm felt responsible for illnesses such as necrotising fasciitis and the highly lethal streptococcal toxic shock syndrome. Progress has been made in understanding the molecular epidemiology of acute rheumatic fever but less is understood about its basic pathogenesis. The improved understanding of GAS genetic regulation, structure, and function has opened exciting possibilities for developing safe and effective GAS vaccines. Studies directed towards achieving this long-sought goal are being aggressively pursued.

Cutaneous infections: microbiologic and epidemiologic considerations.

The normal bacterial flora of the skin represents an important host defense mechanism against invasion by potentially pathogenic organisms. This flora is primarily composed of aerobic diphtheroids (Corynebacterium species), anaerobic diphtheroids (Propriono-bacterium acnes), and coagulase-negative staphylococci. Gram-negative bacilli may be present in limited numbers in intertriginous areas. Localized cutaneous infections occur in ostensibly normal hosts, often after trivial trauma, examples being streptococcal or staphylococcal impetigo, staphylococcal furunculosis, or more unusual infections due to agents such as Mycobacterium marinum. When the skin is injured more extensively by trauma, burns, ischemia with ulceration, or iatrogenic manipulations, or when host immunologic defenses are suppressed, more severe infections are likely to supervene, and the threat of systemic dissemination of infecting microorganisms increases. Cutaneous infection in immunosuppressed hosts may involve the same pyogenic bacteria that affect normal subjects or it may involve a variety of opportunistic invaders, including herpes viruses, gram-negative bacilli, mycobacteria, and deep or superficial mycoses. The skin may also be affected by infections whose primary site lies elsewhere in the body. Cutaneous manifestations may be secondary to hematogenous seeding of the causative agent or to the effects of toxins or immune complexes. Certain microbial agents may initiate a wide variety of cutaneous lesions, depending on route of infection and the status of the host. Thus, cutaneous lesions attributable to Pseudomonas aeruginosa range from "green nail syndrome" and self-limited folliculitis to ecthyma gangrenosum. Similarly, group A streptococci may produce pyoderma, cellulitis, lymphangitis, erysipelas, or scarlet fever. We recently described a syndrome of recurrent cellulitis in the saphenous vein donor extremities of patients who have undergone coronary artery bypass grafts. Most patients have associated tinea pedis. The pathophysiologic aspects of this syndrome are probably multifactorial, involving compromise of lymphatic or venous drainage, bacterial infection, elaboration of bacterial toxins, and hypersensitivity to bacterial or fungal products, or both. Coagulase-negative staphylococci are exhibiting a more prominent pathogenic potential than heretofore. When they infect immunosuppressed hosts or patients with indwelling intravascular catheters or cardiac prostheses, coagulase-negative staphylococci may cause life-threatening disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Non-group A beta-hemolytic streptococcal cellulitis. Association with venous and lymphatic compromise.

Cellulitis occurring in the limbs of patients who have previously undergone saphenous venectomy and coronary bypass surgery has been the subject of several recent reports. Although isolation of pathogenic microorganisms from these lesions has been uncommon, this report describes three patients who had undergone venectomy previously and in whom non-group A beta-hemolytic streptococci were recovered either during acute episodes of cellulitis or during quiescent intervals. There are to date only four other reported cases of post-venectomy cellulitis from which beta-hemolytic streptococci were isolated: one was non-group A and the others were not serologically characterized. Moreover, studies in patients without bypass who have experienced cellulitis in extremities with compromised venous and/or lymphatic circulation have also yielded a substantial number of non-group A streptococci. The data thus far implicate non-group A beta-hemolytic streptococci as a major cause of cellulitis, especially in the setting of circulatory compromise.

Underlying cardiac lesions in adults with infective endocarditis. The changing spectrum.

The spectrum of recognized cardiac lesions underlying infective endocarditis has been changing as a result of the decline in incidence of rheumatic heart disease, the recognition of the entity of mitral valve prolapse, and the improvement in cardiac diagnostic techniques. Sixty-three cases of native valve endocarditis diagnosed in Memphis hospitals between 1980 and 1984 were reviewed. All diagnoses of underlying cardiac lesions were confirmed by two-dimensional echocardiography, cardiac catheterization, and/or histopathologic examination of valve tissues. Major categories of underlying lesions were as follows: mitral valve prolapse, 29 percent; no underlying disease, 27 percent; degenerative lesions of the aortic or mitral valve, 21 percent; congenital heart disease, 13 percent; rheumatic heart disease, 6 percent. Thus, mitral valve prolapse and, in the elderly, degenerative lesions have displaced rheumatic and congenital heart diseases as the major conditions underlying endocarditis. Redundancy of the mitral valve leaflets was noted in 17 of 18 patients in whom endocarditis was superimposed upon mitral valve prolapse. The risk of infective endocarditis appears to be substantially increased in the subset of patients with mitral valve prolapse who exhibit valvular redundancy.

Molecular aspects of bacterial colonization.

Bacteria have developed a wide variety of molecular mechanisms that permit firm adherence to a biologic surface. This review summarizes basic principles involved in this process, as exemplified by adherence of the group A streptococcus to oral epithelium, staphylococci to indwelling prostheses, and Escherichia coli to uroepithelium and enterocytes.

Nosocomial infections in HIV-infected patients: preliminary results from a multicenter surveillance system (1989-1995).

OBJECTIVE: To describe the characteristics of and trends in nosocomial infection among human immunodeficiency virus (HIV)-infected patients. DESIGN: Multicenter prospective cohort study. SETTING/PATIENTS: HIV-infected patients were enrolled at time of first inpatient admission at five Veterans' Administration Medical Centers (VAMCs). RESULTS: As of March 1995, 2,541 patients with 6,625 inpatient admissions had been monitored in the five VAMCs. A total of 530 nosocomial infections were detected using standard Centers for Disease Control and Prevention definitions. Overall distribution by infection site was 31% for primary bloodstream infections (BSIs), 28% for urinary tract infections, 15% for pneumonia, and 26% for all other sites. Of BSIs, 63% were central line-associated bloodstream infections (CLABs). The rate of CLABs per 1,000 central line days was 6.5 (range, 2.3-8.3) for all patients from participating hospitals, similar to the median CLAB rate of 6.0 for patients in medical intensive-care units (ICUs) of National Nosocomial Infections Surveillance (NNIS) System hospitals from January 1990 through September 1994. For ICU-specific CLABs, the rate from hospitals reporting at least one ICU CLAB was 12.7 (range, 12.1-13.1), comparable to the 90th percentile of NNIS hospital medical ICUs (13.1). Staphylococcus aureus, associated with 35% of BSIs, was the most common nosocomial BSI pathogen. Our data demonstrated the following: 13 (10%) of 134 patients with CD4 counts > or = 200 cells/mm3 had a CLAB, compared with 61 (6%) of 1,011 patients with CD4 counts < 200 cells/mm3, P = .08; the per-day risk of CLABs did not change with increased duration of catheterization (P = .4); and the per-day risk of a temporary (ie, short-term) CLAB was greater than that of a permanent CLAB (P < .001). CONCLUSIONS: The data suggest that HIV-infected patients were at higher risk of acquiring a BSI than were patients in the NNIS population; patients with CD4 counts > or = 200 cell/mm3 and temporary central lines were at increased risk for BSI, perhaps reflecting widespread prophylaxis with trimethoprim-sulfamethoxazole among patients with CD4 counts < 200 cells/mm3, and, in contrast to most studies, S aureus, not coagulase-negative Staphylococcus, was the most common BSI pathogen.

Antimicrobial prophylaxis of infection.

Antimicrobial agents are used to prevent infections in a variety of clinical circumstances. In certain instances, the precise indications for prophylaxis remain controversial, and the preferred regimens undergo alterations based upon evolving clinical experience, changing patterns of microbial susceptibility, and innovations in medical and surgical practice. This article outlines the general principles underlying the use of antimicrobial prophylaxis and presents recommendations for the use of such prophylaxis in three areas: (1) surgery involving contaminated, clean-contaminated, and clean procedures; (2) prevention of infections due to specific pathogens, including Neisseria meningitidis, Hemophilus influenzae, Streptococcus pneumoniae, and Streptococcus pyogenes; and (3) prevention of infective endocarditis.

Hepatobiliary abnormalities associated with postanginal sepsis. Common manifestations of an uncommon disease.

We describe eight patients with postanginal sepsis, a rare, potentially life-threatening complication of oropharyngeal infection. Six of the patients manifested jaundice, hepatomegaly, and liver function abnormalities, and in several this led to an erroneous suspicion of primary hepatobiliary disease. All eight patients survived the infection, although many suffered local or disseminated septic complications and required prolonged hospitalization. The pathophysiologic mechanisms responsible for hepatotoxicity in patients with postanginal sepsis are not understood. Physicians must be cognizant, however, of the frequent occurrence of jaundice in septicemic anaerobic processes, and this finding should not obscure the existence of postanginal parapharyngeal and jugular venous infection.

Clinical and laboratory evaluation of cefoperazone.

Cefoperazone, a third-generation cephalosporin derivative, has been reported to have excellent antibacterial activity against a wide range of gram-positive and gram-negative pathogens, including Pseudomonas aeruginosa. We treated 54 patients with a variety of clinical infections with cefoperazone and determined the susceptibilities of their 90 bacterial isolates. An additional 25 aerobic isolates obtained from patients treated with cefamandole in a comparison study were also tested for susceptibility to cefoperazone. Thus a total of 115 isolates were studied in vitro. One hundred nine (95%) of 115 bacterial isolates, including gram-positive and gram-negative aerobes and anaerobes, were susceptible to less than or equal to 32 microgram/ml. Only four isolates (three Escherichia coli and one Serratia marcescens) were highly resistant (minimal inhibitory concentration greater than or equal to 128 microgram/ml). We were able to assess clinical outcome of cefoperazone therapy in 53 patients; favorable responses (cure of improvement) were found in 48 (91%). P. aeruginosa was a major pathogen in three patients treated with cefoperazone; all three showed a favorable response. Side effects of cefoperazone therapy were noted in seven (13%) patients, and laboratory abnormalities were observed in 11 (20%) patients; all of these were mild and readily reversible. Cefoperazone thus appears to be safe, well tolerated, and suitable for use in a variety of human infections.

Infections associated with prosthetic devices: clinical considerations.

The successful development of synthetic materials and introduction of artificial devices into nearly all body systems has been shadowed by the adaptation of microorganisms to the opportunities these devices afford for eluding defenses and invading the host. Clinicians are faced with the task of recognizing the manifestations of device-associated infection, predicting the likely pathogens involved, knowing the appropriate diagnostic methods, and initiating appropriate therapy. Infections associated with prosthetic heart valves are particularly challenging to successfully treat; surgical replacement may be necessary. Infection associated with an artificial joint usually requires removal of the device in addition to appropriate antibiotics. Intravascular associated infections are the leading cause of nosocomial bacteremias and, because of their intravascular location, these infections are often life catheter threatening if not promptly diagnosed and treated. Even contact lenses, external to epithelial surfaces, may give rise to serious sight-threatening infections. Although artificial devices play a paramount role in medicine today, infection is an ever present potential with which clinicians must be familiar.