Pneumococcal disease: a symposium in honor of Robert Austrian, MD—a summary

Pneumococcal Disease: A Symposium in Honor of Robert Austrian, MD—A Summary Charles V. Sanders, MD

The Pneumococcus ’97 symposium, convened under the direction of Dr. Stephan L. Kamholz, brought together a preeminent faculty to discuss the current state of our knowledge about Streptococcus pneumoniae and to honor Dr. Robert Austrian, one of the pioneers in the research into what was once one of the primary killers of humankind. My task here is to summarize these diverse presentations and the articles that evolved from them for publication in this supplement to The American Journal of Medicine. Am J Med. 1999;107(1A):86S–90S. © 1999 by Excerpta Medica, Inc.

From the Department of Medicine, Louisiana State University School of Medicine, New Orleans, Louisiana, USA. Requests for reprints should be addressed to Charles V. Sanders, MD, Department of Medicine, LSU School of Medicine, 1542 Tulane Avenue, New Orleans, Louisiana 70112-2822. 86S © 1999 by Excerpta Medica, Inc. All rights reserved.

ROBERT AUSTRIAN The supplement begins with a brief history of some of the principal contributions to our current knowledge of the pneumococcus, presented by the honoree, Dr. Robert Austrian. He noted that the earliest known case of pneumonia may be that seen in a mummy dating from 1250 – 1000 BC, and certainly pneumonia and pleurisy were known to Hippocrates. As Dr. Jørgen Henrichsen also notes, the pneumococcus was isolated simultaneously in 1880 by Dr. George Miller Sternberg in the United States and by Louis Pasteur in France. It was then identified by the Gram technique in 1882 and established as the principal bacterial cause of lobar pneumonia in humans in 1886. In the context of this symposium, it is interesting that, as Dr. Austrian notes, many of the next steps in our knowledge of the pneumococcus originated with researchers based in the northeast United States, many of them based here in Brooklyn, New York. In fact, the Hoagland Laboratory was established in Brooklyn in 1888, with George Miller Sternberg as the first director. Subsequent leaders included George Benjamin White, whom Oswald T. Avery joined in 1913. It was Avery who, in his long tenure at various institutions, was involved with the introduction of serotherapy for pneumococcal pneumonia, identification of the pathogenic role of the pneumococcal capsule and its polysaccharide nature, the birth of quantitative immunology, and identification of the pneumococcal transforming principle as DNA. This last discovery revolutionized modern biology. An enduring monument to Avery’s work is the monograph The Biology of Pneumococcus1 that White, Avery’s first mentor, published in 1938. Along with identification of the pneumococcus, research on the attendant disease took place. An analysis of 1,000 cases of pneumonia at Massachusetts General Hospital between 1821 and 1889 reported a fatality rate of 25%. However, in the years since then, therapy for pneumococcal pneumonia has improved greatly in the general population: a review by Heffron2 reported that serum therapy reduced the fatality rate to 20 –25%; sulfonamides reduced this to 12–15%; and penicillin, chloramphenicol, and chlortetracycline reduced the rates to 5– 8%—all before recognition of antibiotic resistance and the need for newer treatment modalities. With the introduction of new and ever more efficacious therapies, the medical profession began to think 0002-9343/99/$20.00 PII S0002-9343(99)00110-2

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that the disease was cured, and the result was a precipitous decline in pneumococcal serotyping. However, although reported death rates at 3 weeks with penicillin were dramatically reduced in the early 1950s, for those destined to die within 5 days treatment, whether intended as curative or simply as symptom management, made no difference. Today, there has been an explosion of identified strains of pneumococci, with varying degrees of resistance against almost every component of the pharmaceutical armamentarium. Against the background of this introduction, the remainder of this symposium discusses the bacterium, the disease, and its treatment.

CHARLES V. SANDERS The article by Dr. Stephanie N. Taylor and the present author, Dr. Charles V. Sanders, recalls that the unusual manifestations of invasive pneumococcal disease occurred frequently in the preantibiotic era but declined as antibiotics became available. Now, with the onset of the human immunodeficiency virus (HIV) epidemic and the emergence of antibiotic-resistant pneumococci, these unusual manifestations seem to be with us again. In one of its more severe forms, invasive pneumococcal disease appears as the clinical triad of pneumococcal pneumonia, meningitis, and endocarditis—a syndrome that bears Dr. Austrian’s name. We also report our review of cases of unusual invasive pneumococcal disease published from 1966 to 1997, which revealed 95 different types of unusual pneumococcal infections representing 2,064 cases. Examples of these infections included a wide range of diseases such as pancreatic abscess, aortitis, gingival lesions, phlegmonous gastritis, inguinal adenitis, testicular abscess, tubo-ovarian abscess, and necrotizing fasciitis. The major underlying conditions—such as alcoholism, HIV infection, splenectomy, connective tissue disease, corticosteroid use, diabetes mellitus, and intravenous drug use—remain common risk factors for invasive pneumococcal infections. Especially in light of the increasing problem of antibiotic resistance, it has become vitally important to diagnose and treat unusual manifestations of pneumococcal infection promptly and to attempt to prevent these infections by administering pneumococcal vaccine to highrisk populations.

ARTHUR L. BARRY Dr. Arthur L. Barry presents a historical overview of the development of pneumococcal antibiotic resistance, with special emphasis on the dramatic increase in the prevalence of penicillin resistance in pneumococci in recent years. Dr. Barry defined antibiotic resistance, based on the

National Committee for Clinical Laboratory Standards guidelines, as susceptible, minimum inhibitory concentration (MIC) ⱕ0.06 ␮g/mL; intermediately resistant, MIC 0.1–1.0 ␮g/mL; and highly resistant, MIC ⱖ2.0 ␮g/ mL. In the United States, only about 75% of all pneumococci are fully susceptible to penicillin, 15% exhibit intermediate resistance, and approximately 10% are highly resistant. Risk factors for penicillin-resistant pneumococcal infection include being hospitalized or living in high-prevalence areas, in nursing homes, or in day-care centers; HIV infection; infection with certain clones of pneumococci (specifically strains 9, 14, and 23); multiple exposures to ␤-lactam antibiotics; and being elderly. It is interesting that resistance rates are extremely high in certain parts of the country but lower or almost unheard of in other regions. Multidrug resistance introduces the need for carefully considered therapeutic strategies. Dr. Barry discusses which drugs are appropriate, focusing chiefly on the United States, with some data from Canada. In looking at the activity of oral cephalosporins against intermediate penicillin-resistant pneumococci, cefuroxime, cefpodoxime axetil, and cefprozil look best. Cefixime is not very active against these intermediate penicillin-resistant pneumococci. Dr. Barry discusses the mechanisms whereby pneumococci develop resistance to erythromycin and notes that the macrolides (erythromycin, clarithromycin, and dirithromycin) and azalide (azithromycin) all show complete cross-resistance to each other. The streptogramin quinupristin/dalfopristin and the ketolide HMR 3647 do not show such cross-resistance and thus may be effective against macrolide-resistant strains of pneumococci. Although some strains of pneumococci are resistant to the older quinolone (ciprofloxacin), most are susceptible to the newer quinolones (levofloxacin, sparfloxacin, grepafloxacin, and trovafloxacin). There is certainly a growing problem with drug-resistant S. pneumoniae and with it a need to find new drugs to combat infections caused by these resistant strains.

MAURICE A. MUFSON In a study we will cite for years to come, Dr. Maurice A. Mufson and colleagues conducted a 20-year longitudinal study for the years 1978 –1997, investigating the epidemiology and clinical significance of community-acquired bacteremic pneumococcal pneumonia in Huntington, West Virginia. They found an overall case-fatality rate of 20%, with most deaths occurring in adults ⬎50 years of age. Case-fatality rates were highest in those ⬎80 years old; however, case-fatality rates fell in each 5-year period, from 30% in 1978 –1982 to 16% in 1993–1997. On the other hand, incidence rates increased severalfold, to 44.5 cases per 100,000 population in children ⬍4 years old, to

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38.5 per 100,000 in adults 70 years old, and to 76.2 cases per 100,000 in adults ⬎80 years old. As in previous studies of community-acquired bacteremic pneumococcal pneumonia, most of the patients who died did so within the first week of hospitalization. Interestingly, during the second 10 years of the study, a capsular change in the pneumococcus appears to have occurred, resulting in the increased prevalence of serotypes 6, 9, 14, 19, and 23; these were frequently penicillin resistant. Until 1996 –1997, only strains with intermediate resistance to penicillin had appeared, but then the highly resistant strains appeared in the community and quickly surfaced in the hospitals. As Dr. Mufson points out, bacteremic pneumococcal pneumonia remains a challenge, and there should be an urgent call for physicians to administer the pneumococcal vaccine to their elderly patients.

¨ RTQVIST ÅKE O ¨ rtqvist discusses current data on the epidemiDr. Åke O ology of pneumococcal disease in Sweden and focuses on pneumonia and invasive disease. The cases of invasive pneumococcal infections in Sweden increased more than threefold from 1988 through 1992, and although the exact incidence of pneumococcal pneumonia in Sweden is not known, he estimates that an annual rate of about 5–10 per 1,000 seems reasonable. Pneumococcal bacteremia has increased from 5 per 100,000 in 1990 to nearly 15 per 100,000 in 1995, whereas the incidence of pneumococcal meningitis remains just over 1 per 100,000. In contrast to a case-fatality rate of 20 – 40% for invasive pneumococcal disease in the United States, a Swedish study of 285 cases for the period 1977–1984 reported a fatality rate of just 7%. However, another Swedish study found an overall fatality rate of 21% in a set of 424 adult patients. A further contrast can be seen in Dr. Mufson’s study in Huntington, West Virginia, comparing alcoholics with nonalcoholics: Whereas the case-fatality rate for alcoholics was similar in both locations, the rate for nonalcoholics with chronic disease in Huntington was about 15 times higher than the rate in Sweden. ¨ rtqvist notes that the antibiotic resistance situaDr. O tion, especially penicillin resistance, is “still generally favorable” in Sweden, possibly because of the formation of national and regional Strategy Groups for Rational Use of Antibiotics and Reduced Antibiotic Resistance. However, he notes that antibiotic use was dropping in Sweden even before these initiatives, with the use of tetracyclines, macrolides, and narrow-spectrum penicillin clearly decreasing, whereas the use of ␤-lactams other than penicillin and quinolones has remained at a stable low level. Dr. ¨ rtqvist reported results of a randomized, placebo-conO trolled, multicenter study of a pneumococcal vaccine in middle-aged and elderly immunocompetent patients hospitalized for community-acquired pneumonia. 88S

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Whereas there appeared to be no statistical difference in new cases of pneumonia in the placebo compared with the vaccinated groups, only 1 patient in the vaccine group (0.1 per 100 person-years) acquired bacteremic pneumococcal pneumonia, compared with 5 in the placebo group (P ⫽ 0.23).

ALEXANDER TOMASZ Dr. Alexander Tomasz discusses the molecular aspects of pneumococci, beginning with a micrograph of the pneumococcus as it has always looked. He then proceeds to detail the way and the extent to which it has managed to acquire antibiotic-resistance properties. As Dr. Tomasz explains, by using polyacrylamide gel electrophoresis, it is possible to track the “footprints” of recombination events. The result is that looking at the gel is like reading a text in English and then suddenly shifting to Hungarian, then back to English, and so forth. The ability to perform this analysis allows us to bring fantastic resolution to epidemiology: it is possible to recognize a bacterium, its genetic background, and its penicillinbinding protein genes. This reveals that the pneumococcus has been modified, not by natural evolution but by recombination events in which a DNA donor was not a pneumococcus. Indeed, acquisition of foreign DNA sequences seems to have occurred in every one of the penicillin-resistant pneumococci observed so far. However, the pneumococcus has other methods for modifying its molecular biology, for example, homologous recombination. What appears to have happened in this case is that a pneumococcus has passed down and altered the penicillin-binding protein gene by homologous recombination with another pneumococcus. However, even this does not exhaust the fantastic ability of the pneumococcus to adapt to its environment, as was appreciated once it became possible actually to “see” the cell surface structures, the “wall,” of the bacterium. As a result, the cell wall is no longer considered an inert sort of exoskeleton of the bacterium, but rather has come to be seen as having built-in ligands, which means that this is a highly interactive surface, both with the host and with the external world of the bacterium. As Dr. Tomasz notes, to our astonishment, it has now been found that the chemistry of the cell-wall structure can change so completely that, by the taxonomy (which is based on the cross-linking mode of peptidoglycans), the various strains of the pneumococcus might not be classified as pneumococci at all—and yet they are. Regarding worldwide distribution of the pneumococcus serotypes, Dr. Tomasz notes that most of the penicillin-resistant pneumococci worldwide are the so-called “pediatric” serotypes (i.e., serotypes 6 –9, 14, 19, and 23). Although the reasons for this distribution are not fully understood, it is certainly useful information to have when creating a vaccine against a bacterium. Clearly, if

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these are the serotypes that predominate, then these are the serotypes to include in a vaccine if the goal is to corner the penicillin-resistant pneumococcus. Finally, when it comes to the question of antibiotic use and resistance patterns, it appears that what is occurring is that antibiotic use is often not selecting for an ab initio emergence of resistance from a stepwise resistance but rather serves as an invitation for the exportation of already existent clones. The moral of the story concerning these “superbugs,” which are being seen all over the world, is that if they have not been seen in your geographic area yet, stay tuned, because they are probably coming your way in the near future.

JØRGEN HENRICHSEN Dr. Jørgen Henrichsen began his presentation at the same historical point as did Dr. Austrian: with the isolation, culture, and description of the pneumococcus in the United States and France, by George Miller Sternberg and Louis Pasteur, respectively—Sternberg by inoculating his own saliva into rabbits and Pasteur by inoculating rabbits with the saliva of a child who had died from rabies. The simultaneous typing of pneumococci led to competing systems of nomenclature, as discussed by Dr. Henrichsen. Over the next 5 decades, researchers in Europe, South Africa, and the United States conducted investigations that led to the introduction of serum therapy. This led, in turn, to development of a rapid typing method, which became very important because serotype-specific therapy dramatically decreased the number of deaths due to pneumococcal pneumonia. Just before the sulfonamides and penicillins were introduced, horse serum was replaced by rabbit sera, which resulted in another reduction in mortality. Dr. Henrichsen also discusses important methods of typing pneumococci—the capsular reaction tests, latexand co-agglutination, and capillary precipitation— using a large variety of sera, as well as the newer typing methods, including the use of DNA probes and DNA sequence– based subtyping.

CHARLES S. BRYAN Dr. Charles S. Bryan begins by noting that although penicillin is widely endorsed for specific treatment of pneumococcal pneumonia, it is rarely used for this purpose, for three reasons: concern about penicillin-resistant S. pneumoniae (PRSP) strains, the difficulty of making an early etiologic diagnosis of pneumonia, and the lack of a clear consensus about the optimum dosage. However, Dr. Bryan notes it is still possible to make a case for using penicillin G to treat pneumococcal pneumonia. The first problem arises from several controversial dosing issues. According to Dr. Bryan, high-dosage penicillin G therapy should result in serum levels suffi-

cient to easily inhibit PRSP strains at the lower limit of MIC values, ⱕ4.0 ␮g/mL. At MIC ⱖ8.0 ␮g/mL, we really do not know what would happen. A second debate concerns whether continuous infusion or intermittent infusion with penicillin is more effective. Continuous infusion appears to be gaining support as an optimal way to administer ␤-lactam antibiotics, but no good controlled studies have looked at intermittent versus continuous penicillin therapy of gram-positive bacterial infections in humans. Continuous infusion is less expensive for patients with normal renal function, because penicillin’s short serum half-life requires frequent dosing to achieve the same clinical results. Concerning dose-related toxicity, available data suggest that setting an upper limit of 20 ␮g/mL for the desired serum level is advisable, and using 24,000,000 U/day as a continuous infusion will generally result in serum levels of 20 ␮g/mL. Of course, one must be careful about the use of probenecid in patients who are receiving penicillin, because it can result in penicillin serum levels that may lead to neurotoxicity. The problem, of course, is that all physicians would use penicillin if there were an easier way to make a diagnosis of pneumococcal pneumonia, but there is no easy way. The American Thoracic Society (ATS) has now bypassed the Gram stain and suggested empiric therapy directed against the most likely pathogens. On the other hand, the Infectious Diseases Society of America guidelines for community-acquired pneumonia in adults, published in the April 1998 issue of Clinical Infectious Diseases, call for resurrection of the sputum Gram stain and other methods to facilitate early and precise diagnosis. As Dr. Bryan points out, a rapid, sensitive, safe, and economical way to diagnose pneumococcal pneumonia would enable investigators to carry out further controlled trials of the various regimens, including high-dose penicillin. In contrast to penicillin, what about vancomycin? Using vancomycin for every patient with presumed pneumococcal disease will simply promote the further spread of vancomycin-resistant enterococci. Dr. Bryan makes the case that penicillin G is still useful for pneumococcal pneumonia, given a specific diagnosis, and that if we could make a specific diagnosis of pneumococcal pneumonia and then use penicillin, we would rely less on the third-generation cephalosporins.

JAY C. BUTLER Dr. Jay C. Butler begins with the observation that the pneumococcus “remains a leading global cause of morbidity and mortality.” In a context that views prevention as at least as important as a cure, he reviews the current polysaccharide vaccines, recommendations for use, and their shortcomings; he also discusses the second-generation vaccines, the conjugate vaccines, and the third-generation protein vaccines, which still await testing in hu-

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mans. This review is important in light of the “Healthy People 2000 Initiative,” which hopes by the year 2000 to achieve a vaccination rate of 60% among those at risk for pneumococcal disease. In this context it should be noted that there presently exists a 23-serovalent vaccine, with proven efficacy. Thus, it is quite disturbing that only 35% of patients ⱖ65 years of age have received the vaccine, because 90% of mortality associated with invasive pneumococcal disease occurs among patients in this age group. However, there are problems associated with pneumococcal vaccines. First, they are not very immunogenic and are even less so in those ⬍2 years of age. However, if the polysaccharide is covalently linked to a protein carrier (and in some cases this has been the outer membrane protein of meningococci), this allows the polysaccharide to be processed as a thymus-dependent antigen, which greatly increases the polysaccharide’s immunogenicity in young children and allows booster responses in all age groups. Other problems remain to be resolved. For example, about 7 serotypes cause approximately 80 – 85% of the invasive disease in children but only about 50% of invasive disease in adults. Nevertheless, Dr. Butler presents a convincing case for using the pneumococcal vaccine.

PETER BALL Dr. Peter Ball’s premise is that management of pneumococcal infections has always posed problems, continues to do so today, and will no doubt continue do to so in the future. Furthermore, bacteremic pneumococcal pneumonia and meningitis still cause excess mortality, and, indeed, with the exception of HIV, the clinical picture of pneumococcal pneumonia may not differ significantly from that of the preantibiotic era. Dr. Ball then points out that penicillin-resistant pneumococci were reported in the 1940s, but by the 1970s the phenomenon had moved out of the laboratory and into the clinic, and, once there, it became a significant global problem in the 1980s and 1990s. In the United States, the prevalence of resistance is currently about 34% of all instances of infection, and of those pneumococci resistant to penicillin, half will be macrolide resistant, and crossresistance within the macrolide group is absolute. To address the problem of the spread of resistant strains globally— by what Dr. Ball calls “bacterial tourism”—we may have to rely on prophylaxis through mass use of inoculation with conjugate vaccines. Dr. Ball then summarizes the current picture regarding therapy, noting that penicillin is still used in Europe, although the ATS guidelines favor alternative ␤-lactams and/or second- and third-generation cephalosporins plus or minus aminoglycosides. He presents substantial evi-

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dence for the continued use of amoxicillin, with or without clavulanate, for non– central nervous system infections in children and adults. The parenteral cephalosporins (i.e., ceftriaxone or cefotaxime) are certainly an improvement over traditional regimens in meningitis but probably not in pneumonia. The presence of penicillin resistance and the failure of third-generation cephalosporins in pediatric meningitis have prompted recommendations for the use of vancomycin and imipenem in pneumococcal meningitis. The problem with imipenem and its use in treating patients with meningitis, of course, is that it is an epileptogenic. Meropenem looks good, but against pneumococci, imipenem may be a bit more active. Several new agents are in various stages of development. The newer fluoroquinolones all have enhanced antipneumococcal activities. New studies with levofloxacin, sparfloxacin, and grepafloxacin, all continue to yield good results for pneumococcal pneumonia. Trovafloxacin, however, although highly effective against pneumococcal disease, has recently been linked to severe hepatotoxicity, and its use is now restricted to life-threatening nosocomial infections. Presumably the general attitude toward fluoroquinolones will change due to the emergence of S. pneumoniae resistant to the older fluoroquinolones and the development of the third-generation fluoroquinolones, which have excellent activity against penicillin-sensitive as well as penicillin-resistant strains. There are also the ketolides–macrolides with activity against penicillin-resistant pneumococci—although there are strains that are resistant to macrolides. Finally, there are the oxazolidinones, which from this vantage point appear to be very exciting new agents.

CONCLUSION In closing, the increasing incidence of antimicrobial resistance, particularly pneumococcal resistance, poses major problems for the microbiologist and the clinician. Emerging resistance also poses problems for the pharmaceutical industry, because of the tremendous expense of bringing new antibiotics to the market. Moreover, we now see that antibiotics are having shorter and shorter effective life spans because of the rapid spread of resistance. The problem is not that we do not have safe drugs but that we need to develop more effective antipneumococcal agents. In the meantime, these resistant pneumococci pose problems for public health officials, and as members of the healthcare profession, we must be ever vigilant and immunize as many patients as we can.

REFERENCES 1. White B. The Biology of Pneumococcus. New York: The Commonwealth Fund, 1938. 2. Heffron R. Pneumonia with Special References to Lobar Pneumonia. New York: The Commonwealth Fund, 1939.

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