Resistant Pneumococcus


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Resistant Pneumococcus

  1. 1. Impact of Antimicrobial Resistance on the Treatment of Invasive Pneumococcal Infections Paulo Rocha, MD, Carlos Baleeiro, MD, and Allan R. Tunkel, MD, PhD Address others. Penicillin G became widely available to the civilian Department of Medicine, MCP Hahnemann University, 3300 Henry population in 1945; by 1952, it had saved an estimated 1.5 Avenue, Philadelphia, PA 19129, USA. million lives [2]; mortality associated with bacteremic pneu- Email: mococcal disease dropped from 80% in untreated patients to Current Infectious Disease Reports 2000, 2:399–408 17% in those treated with penicillin [3]. Current Science Inc. ISSN 1523–3847 Copyright © 2000 by Current Science Inc. Over the past two decades, however, the Pneumococcus has become resistant to penicillin, as well as to other anti- microbial agents; this problem has achieved epidemic pro- Infectious diseases, such as pneumococcal pneumonia, portions in certain parts of the world and has clearly which were almost invariably lethal in the pre-antibiotic changed the way invasive pneumococcal infections are era, caused radically less mortality with the advent of anti- being treated [3,4]. The National Committee for Clinical microbial chemotherapy. However, the use, misuse, and Laboratory Standards (NCCLS) has set up definitions for abuse of these agents have led to the emergence of anti- strains of penicillin-nonsusceptible Streptococcus pneumo- microbial resistance. In the past, pneumococci were all niae (PNSP), with minimal inhibitory concentration exquisitely sensitive to penicillin G. By the late 1960s, (MIC) breakpoints that define intermediate (Pen-I) and penicillin-nonsusceptible Streptococcus pneumoniae high-level resistance (Pen-R). The NCCLS also gives defini- (PNSP) was being described. Since then, this problem tions for strains that have reduced susceptibility to the has achieved epidemic proportions in many areas of the cephalosporins (Table 1) [5]. world, including the United States. Many experts no longer This article reviews the salient epidemiologic features consider penicillin an acceptable therapy for patients of PNSP infection, the mechanisms of resistance, and how suspected of having invasive pneumococcal disease, antimicrobial resistance is affecting the way clinicians especially if the central nervous system (CNS) is involved. currently manage invasive pneumococcal infections, and Recommendations for therapy are based on theoretical discusses key aspects of reducing the frequency of disease concerns, in vitro susceptibility testing, animal data, and caused by this microorganism. a few, scattered reports of penicillin failure in patients with invasive disease. Epidemiology The phenomenon of drug resistance among pneumococci is Introduction not a new one. In 1943, pneumococcal isolates resistant to Streptococcus pneumoniae is a ubiquitous pathogen, being sulfonamides were reported [6] and, in that same year, peni- responsible for the majority of cases of community- cillin-resistant pneumococci were recovered from acquired bacterial upper respiratory tract infections, and laboratory mice treated with low doses of penicillin [1•]. The producing acute, life-threatening illnesses, such as pneu- first clinical isolate of PNSP (penicillin MIC = 0.6 µg/ml) was monia, bacteremia, and meningitis. It is estimated that the reported from Australia in 1967, from a patient with hypo- Pneumococcus is responsible for approximately 3000 cases gammaglobulinemia and bronchiectasis [1•]. In 1969, a of meningitis, 50,000 cases of bacteremia, 500,000 cases of PNSP was isolated from the throat of a healthy 3-year-old pneumonia, and more than 7 million cases of otitis media boy in a small village in New Guinea; the isolate had a each year in the United States [1•]. penicillin MIC of 0.5 µg/ml, but was susceptible to other The one characteristic of the Pneumococcus that always antimicrobial agents [7••]. By 1974, the prevalence of PNSP comforted clinicians in the past was its exquisite in vitro in Australia and New Guinea approached 12% [1•]. susceptibility to a wide variety of antimicrobial agents, The first highly penicillin-resistant pneumococcal including the penicillins, sulfonamides, tetracyclines, cepha- strains (with MICs of 4 to 8 µg/ml) were described in 1977 losporins, chloramphenicol, and the macrolides, among from South Africa; in 1978, multidrug–resistant pneumo-
  2. 2. 400 Sepsis Table 1. Definitions of pneumococcal resistance susceptibility to penicillin was 21.2% (6.4% Pen-R). In agree- ment with the data from the United States, there was marked Penicillin Cephalosporins geographic variation in the incidence of PNSP, varying from Interpretation µ MIC (µg/ml) µ MIC (µg/ml) 22.5% to 34.6% in the western provinces to no more than Susceptible < 0.1 ≤ 0.5 5% in the eastern provinces; fluoroquinolone resistance was Intermediate 0.1–1.0 1 low (no more than 0.3%) in this survey. Resistant ≥2 ≥2 This is in contrast to the results of a large, multicenter study in which 7551 isolates, obtained from hospitals and Data from National Committee for Clinical Laboratory Standards [5]. offices of all Canadian provinces in 1988 and from 1993 to 1998, were analyzed. The overall incidence of PNSP was cocci were identified [1•]. Since then, the frequency of 9.1%, but only 37% of the 7551 isolates were from the PNSP has been increasing throughout the world. PNSP was respiratory tract. Of importance is the increase in fluoro- first described in the United States in the 1980s, but it was quinolone resistance from 0% in 1993 to 1.7% during the an uncommon phenomenon (< 5% of strains) and high- 1997 to 1998 period (P = 0.01), especially among penicil- level resistance was extremely rare [7••]. By the 1990s, lin-resistant S. pneumoniae. Multivariate analysis revealed however, there was a marked increase in frequency of these old age, pneumococcal isolation from the respiratory tract, resistant strains [7••,8]. occurrence in Ontario, and strains isolated during the later A recent (1997–1998) survey, involving 163 US institu- years of surveillance to be independent risk factors for fluo- tions in 43 states, revealed that 35% of the 4152 respiratory roquinolone resistance. Serotyping and pulse-field gel tract isolates of S. pneumoniae were not susceptible to peni- electrophoresis revealed no clustering of fluoroquinolone- cillin and 13% of strains were highly resistant to penicillin resistant pneumococci. The number of fluoroquinolone [9]. In this study, as well as in many others [1•,10•,11], prescriptions in Canada increased from 0.8 per 100 penicillin resistance was a marker for resistance to other persons in 1988 to 5.5 per 100 persons in 1997, with use -lactam and non– -lactam antibiotics, with the notable highest among the elderly and in Ontario, which may also exceptions of the fluoroquinolones and vancomycin. have accounted for the increased frequency of fluoroqui- A number of studies have now demonstrated that the nolone resistance in pneumococci [15••]. incidence of resistant strains varies according to the site of The problem of PNSP also extends well beyond North isolation, with the highest incidence of PNSP from respir- America. In Spain, in the late 1980s, the prevalence of Pen-I atory tract isolates. A case-control study at San Francisco and Pen-R strains was as high as 16% to 30%, and 11% to General Hospital (SFGH) revealed that the absence of bac- 20%, respectively [3]. The US/Spanish 23F serotype of teremia (ie, isolation of S. pneumoniae from the respiratory S. pneumoniae is currently recognized as an international tract only) is an independent predictor of penicillin non- epidemic clone, usually resistant to penicillin, tetracyclines, susceptibility [12]. These findings are supported by chlo ramp henicol, macrolides and trimethoprim- another study [13]. sulfamethoxazole. A 1991–1998 study from Barcelona In contrast, a survey from the Centers for Disease revealed that fluoroquinolone resistance was also on the rise Control and Prevention (CDC), performed in seven differ- in Spain [16]. Of 2822 pneumococcal isolates, 57 (2.0%) ent US regions in 1997, revealed that 25% of the 3237 were resistant to ciprofloxacin, representing an increase in pneumococcal strains isolated from sterile body sites were resistance from 0.9% for the 1991–1992 period to 3.0% in not susceptible to penicillin and that 13.6% were Pen-R 1997–1998. There was a statistically significant correlation [14]. The population in the SFGH study consisted of adults between penicillin resistance and resistance to ciprofloxacin; older than 18 years, whereas 30% of the population in the in accordance with the recent Canadian study, most fluoro- CDC survey were younger than 18 years, which may have quinolone-resistant strains (88.7%) were isolated from the accounted for these differences. Geographic variation in sputum from older patients and correlated with an increase the incidence of penicillin resistance has also been in fluoroquinolone use. There was no evidence of a clonal reported. In Tennessee, as much as 38.8% of the isolates origin of the ciprofloxacin-resistant strains. were not susceptible to penicillin, whereas the overall The situation in Latin America is also alarming. In a incidence in Maryland was only 15.3%. The same 1993–1996 survey involving six Latin American countries, the phenomenon was also observed among different hospitals incidence of penicillin-nonsusceptible strains ranged from within the same region; in Connecticut, the incidence of 15.6% to 48.2% [17]. A more recent investigation PNSP ranged from 0% to 39.1%. documented an increase in PNSP in Latin America to 55.7%, Similar trends toward increasing pneumococcal with the majority of isolates from the respiratory tract [17]. resistance to penicillin have been observed in other countries The problem of PNSP is even greater in some Asian in North America. A 1994–1995 survey involving 39 countries. The Asian Network for Surveillance of Resistant Canadian laboratories revealed an overall PNSP prevalence Pathogens (ANSORP) performed an in vitro analysis of of 11.7% (3.3% Pen-R) [11]; in a subsequent survey from 996 S. pneumoniae isolates from 14 centers in 11 Asian October 1997 to November 1998, the overall non- countries between 1996 and 1997 [10•]. The overall rate of
  3. 3. Impact of Antimicrobial Resistance on the Treatment of Invasive Pneumococcal Infections • Rocha et al. 401 Table 2. Risk factors for antimicrobial-resistant factors for infection caused by PNSP in Spain revealed that pneumococcal infections noninvasive disease (along with prior -lactam use, alcoholism, age younger than 5 years and older than 65 Recent antimicrobial therapy (especially β-lactam agents) years) conferred a significantly increased risk [13]. Day-care center attendance Another study conducted at SFGH from August 1994 Hospitalization White race through December 1996 demonstrated that 21% of HIV infection respiratory isolates, versus only 6.4% of blood isolates, Noninvasive disease were PNSP; all five CSF isolates were Pen-S [12]. When Age < 18 months or > 65 years adult inpatients with a positive culture for PNSP (cases) Alcoholism were matched against adult inpatients with a positive Data from Campbell and Silberman [1•], Ball [3], Jacobs [8], culture for Pen-S pneumococci and no evidence of PNSP Winston et al. [12], Clavo-Sanchez et al. [13], and Tunkel (controls), it was shown that cases were significantly less and Scheld [43••]. likely to have bacteremia (15.4% vs 39.4%; P < 0.001) and pneumonia (50.8% vs 68.9%; P = 0.006). In fact, in a multiple logistic regression analysis, the absence of bacter- penicillin nonsusceptibility was 41%, with the overwhelm- emia (along with recent hospital admission) was an inde- ing majority (66.8%) of isolates coming from the respira- pendent predictor of infection with PNSP. The authors tory tract, followed by blood (23.4%) and cerebrospinal concluded that PNSP might be less virulent or less invasive fluid (CSF; 16.7%). Pulse-field gel electrophoresis and than susceptible strains. polymerase chain reaction (PCR) fingerprinting of penicil- lin-binding protein (PBP) genes of resistant strains were consistent with a clonal origin of Asian resistant strains Mechanisms of Resistance (23F epidemic clone). Pneumococci develop resistance to -lactams by undergo- There was significant geographic variation in the preva- ing changes at the site of action, in the penicillin-binding lence of penicillin-nonsusceptible organisms in Asia, with proteins (PBPs). Tomasz [7••] has published an elegant the highest rates seen in Korea (79.7%), followed by Japan model to study the acquisition of penicillin resistance in (65.3%) and Vietnam (60.8%). In contrast, a lower preva- S. pneumoniae. The premise is that pneumococci in a lence of PNSP was seen in China (9.8%), Malaysia (9.0%) physiologic state called “competence” are able to integrate and India (3.8%). In another study in India, only four of free DNA molecules from their environment into their 303 strains tested (1.3%) had intermediate susceptibility chromosomes. In this model, a susceptible Pneumococcus to penicillin; there were no Pen-R strains [18•]. In South incorporates, from nonpneumococcal bacteria, DNA that Africa, rates of penicillin nonsusceptibility among carries PBP genes of reduced penicillin-affinity, giving gives pneumococci range from 40% to 70% [8]. rise to clonal pneumococci with low-level penicillin Many studies have examined risk factors for the acqui- resistance. Under the right selective pressures, proliferation sition of PNSP (Table 2). The majority of studies identified via cell division occurs, with pneumococci of each genera- previous -lactam therapy or antimicrobial prophylaxis as tion undergoing further recombination, and each recombi- among the most important predictors of the presence of nation increasing the level of resistance of the pathogen. PNSP [3]. The risk for selection is greater in the presence of This model is supported by genetic and epidemiologic low antimicrobial concentrations, when agents with poor studies. In fact, in most areas of the world, the appearance in vitro activity are used, or following prolonged courses of of pneumococci with low levels of penicillin resistance was therapy [19]. The use of -lactam agents in the therapy of documented before highly resistant strains were identified. community-acquired upper respiratory tract infections, One of the few exceptions to this rule is Iceland, where most notably otitis media in children, plays a major role in multidrug-resistant and highly resistant strains preceded the selection of PNSP [3]. Non– -lactam antimicrobial the appearance of strains with low-level resistance. agents are also capable of selecting for PNSP [19]. The However, the sudden increase in pneumococcal resistance prophylactic use of trimethoprim-sulfamethoxazole in in Iceland was likely a result of the importation of a patients infected with human immunodeficiency virus Spanish epidemic clone, rather than a stepwise increase in may explain the increased incidence of infection by PNSP resistance in response to local selective pressures. in this patient population. Trimethoprim-sulfamethox- Not all -lactams bind to the same PBPs, and the azole use was also implicated in the emergence of PNSP in affinity with which they bind to the different PBPs may also Brazilian communities [20]. differ. Therefore, some -lactam agents may still retain some Attendance at pediatric day care centers, hospitaliza- activity against pneumococci, despite high levels of penicillin tion, and younger age (most notably < 18 months) are also resistance. Penicillin resistance is a marker for resistance to well documented markers for acquisition of PNSP [1•,3,8]; other antimicrobial agents. The incidence of erythromycin- HIV infection was identified as a risk factor in some studies resistant pneumococci in the United States is approximately but not in others [13]. A multivariate analysis of risk 19% [1•]. Pneumococci may become resistant to macrolide
  4. 4. 402 Sepsis antibiotics by undergoing a ribosomal modification or by The optimal treatment for pneumococcal pneumonia developing an active drug efflux apparatus. remains unclear. There have been few prospective studies Specific acquired genetic mutations are responsible for looking at the impact of penicillin resistance on the outcome these distinct phenotypes; the ermAM gene encodes the of pneumococcal pneumonia. In one study of 108 children ribosome-modifying enzyme that promotes high-level with nonmeningeal pneumococcal infections, 78 of whom resistance to macrolides, lincosamides and streptogramin had pneumonia, the clinical success of antimicrobial therapy B (MLSB-type resistance pattern). A different determinant, was the same against PNSP and Pen-S strains [25]. However, the mefE gene, encodes for the efflux system and confers only one isolate was highly resistant to penicillin. low-level resistance to macrolides (M-type resistance In a 10-year study of 504 adults with severe culture- pattern). There seems to be a wide geographic variation in proven pneumococcal pneumonia, the crude unadjusted the macrolide resistance pattern, with the MLSB-type pre- mortality was 38% for PNSP, versus 24% for Pen-S organisms dominating in some areas and the M-type in others [21]. (P = 0.001) [26]. However, after adjustment for predictors of In one 5-year study done in Siena, Italy, the frequency of severity, there was no difference in overall mortality. Further- erythromycin resistance increased from 7.1% in 1993 to more, 29% of isolates were PNSP but only 13% were Pen-R; 32.8% in 1997; the overwhelming majority (94%) of all isolates had MICs to penicillin of ≤ 4 µg/ml, and only 6% resistant strains exhibited an MLSB-type resistance pattern. of the isolates were resistant to cephalosporins. Similar out- The remaining pneumococci with an M-type resistance comes were demonstrated in another review of 499 clinical pattern carried a mefA determinant (as verified by molecular pneumococcal isolates; however, only 5 of 499 isolates had analysis), demonstrating that mefE is not the only acquired MICs to penicillin ≥ 4 µg/ml [27]. determinant behind this pattern of resistance [21]. Resistance Another study of 75 patients with pneumococcal pneumo- has also been noted for other antimicrobial agents used to nia found no increase in mortality related to decreased penicil- treat invasive pneumococcal infections. Mutations in the lin susceptibility, although the MICs of the isolates were not rpoB gene adversely affect the affinity of rifampin for the reported [28]; similar results were found in another report [12]. subunit of the pneumococcal DNA-dependent RNA A recent study of 192 patients with bacteremic pneu- polymerase, leading to high-level resistance [22]. mococcal pneumonia found increased mortality and an Mutations in parC and gyrA genes are implicated in increased rate of suppurative complications in patients bacterial resistance to the fluoroquinolones [23]. These infected with PNSP strains [29]; the patients with genes encode the bacterial type-II topoisomerases, top- infections caused by PNSP had higher severity scores, and oisomerase IV, and DNA gyrase, the sites of action of this the adjusted mortality difference was not statistically class of antimicrobials. significant. Furthermore, only eight patients (4%) had Depending upon the type of bacteria, the primary infections caused by Pen-R strains. target of fluoroquinolone action will be the DNA gyrase or It sh ou ld be n oted th at all of the stud ies just topoisomerase IV. With fluoroquinolone-resistant mentioned were retrospective, and patients were treated pneumococci, the results of genetic and enzymatic with a variety of antimicrobial agents, making it difficult to analyses point toward topoisomerase IV as the primary propose definitive recommendations for the optimal target for the majority of fluoroquinolones. Sitafloxacin is therapy against pneumococcal pneumonia caused by an exception, because it has identical activity against both PNSP. No prospective study has addressed treatment enzymes. This may explain why sitafloxacin remains active outcome of patients with highly resistant pneumococcal in vitro, even against highly fluoroquinolone-resistant isolates (MICs to penicillin ≥ 8 µg/ml). pneumococcal strains. Mutations of parC alone lead to Despite penicillin’s proven clinical efficacy, there is no low-level fluoroquinolone resistance, whereas the develop- consensus about its optimal use in the treatment of pneu- ment of high-level fluoroquinolone resistance requires mococcal pneumonia. The use of penicillin G for the treat- mutations in both topoisomerase IV (parC) and DNA ment of pneumonia has also been limited by the gyrase (gyrA) [6,23]. difficulty of establishing an early etiologic diagnosis for community-acquired pneumonia [30•,31•]. Different investigators have made specific recommendations about Therapy the therapy of pneumococcal pneumonia [30•,31•,32]. Pneumonia Friedland and McCracken [33] suggest using a third-gener- Pneumonia remains a significant cause of morbidity and ation cephalosporin for sepsis or pneumonia caused by mortality worldwide, and the Pneumococcus is the leading pneumococci with high-level penicillin resistance; they cause of bacterial pneumonia, accounting for 500,000 cases also recommended vancomycin or imipenem for the treat- of pneumonia and 55,000 cases of bacteremia annually in ment of patients in whom PNSP infection is suspected. the United States [1•]. In a recent meta-analysis, the Pneumo- Mandell [34] recommends adding vancomycin for com- coccus accounted for 65% of the cases of community- munity-acquired pneumonia when Pen-R pneumococcal acquired pneumonia and 66% of the deaths among 7057 strains are suspected. Bryant and Salmon [35] suggest cases in which an etiologic agent was identified [24•]. using a third-generation cephalosporin for Pen-I strains
  5. 5. Impact of Antimicrobial Resistance on the Treatment of Invasive Pneumococcal Infections • Rocha et al. 403 and vancomycin for Pen-R strains (MIC > 4 µg/ml) in the one in the treatment of pneumococcal meningitis caused by treatment of pneumococcal empyema. However, clinical Pen-S strains, although its role in the treatment of PNSP data supporting these recommendations are lacking. meningitis remains largely undefined [41]. In the absence of clinical data, in geographic areas In the 1990s, multiple cases of treatment failure of the where Pen-R pneumococcal strains are present, or for third-generation cephalosporins against pneumococcal patients with severe life-threatening disease with one or meningitis were reported from France, Spain and United more risk factors for infection with a Pen-R strain, a sec- States. Patients showed no clinical improvement and ond-generation or third-generation cephalosporin or one repeat CSF cultures were positive after more than 24 hours of the newer fluoroquinolones (eg, levofloxacin, grepaflox- of antimicrobial therapy. In most instances, the pneumo- acin, gatifloxacin, moxifloxacin) is recommended as first- coccal isolates demonstrated MICs of ≥ 2.0 µg/ml associ- line empiric therapy, pending results of susceptibility ated with the use of these agents. A 1995 French study testing [36–38]. The carbapenems (imipenem and revealed a 16.4% incidence of CSF pneumococcal isolates meropenem) and vancomycin are efficacious in the with ceftriaxone/cefotaxime MICs of ≥ 0.5 µg/ml [44]. treatment of pneumococcal pneumonia, but should be Most experts agree that if the pneumococcal MIC to the reserved for severe cases caused by highly resistant organ- third-generation cephalosporins is ≤ 1.0 µg/ml, these isms and cases in which the expected clinical response is agents can still be safely used in the treatment of pneumo- not otherwise achieved. There are no clinical data to coccal meningitis [3,43••] Other experts recommend support the empiric use of either the carbapenems or continuing vancomycin for the duration of therapy if the vancomycin as empiric therapy for community-acquired MIC is ≥ 0.5 µg/ml [40]. Viladrich et al. [41] reported pneumococcal pneumonia. treating seven episodes (six patients) of pneumococcal meningitis caused by isolates with decreased susceptibility Meningitis to cefotaxime (MIC = 1.0 µg/ml in five episodes and MIC = The treatment of pneumococcal meningitis has been 2.0 µg/ml in two episodes). Treatment consisted of cefo- significantly influenced by the growing problem of anti- taxime, 300 mg/kg/day, with a maximum daily dose of 24 microbial resistance. What constitutes the ideal treatment grams. All patients readily improved. remains a matter of debate but, unlike the situation with A recent experimental study using the rabbit meningitis pneumonia, there seems to be no controversy among model confirmed that high doses of ceftriaxone were experts that the use of penicillin is no longer acceptable as efficacious in meningitis caused by cephalosporin-resistant empiric therapy for patients suspected of having pneumo- pneumococcal strains (MIC = 2.0 µg/ml), although the co- coccal meningitis [3,39–41]. administration of dexamethasone significantly increased Early reports documented clinical failure in the major- therapeutic failure (from 0% to 28%) [45]. This contrasts ity of patients with PNSP meningitis who were treated with with the data on pneumococcal meningitis caused by penicillin [41]. The achievable CSF concentrations of peni- susceptible strains, in which dexamethasone use does not cillin seem to be the limiting factor. CSF concentrations of appear to impair the therapeutic r esponse to the -lactam antibiotics at least 10-fold above the minimal cephalosporins [43••]. bactericidal concentration (MBC) of the organism are Vancomycin has also been evaluated for use against needed to achieve a bactericidal effect [42]. Serum concen- PNSP meningitis [46,47]. In one study, vancomycin was trations as high as 20 µg/ml can be achieved with high- used to treat 11 adults with meningitis caused by Pen-I dose intravenous penicillin G (24 million units per day), pneumococcal strains [43••]. Treatment failure was leading to initial CSF concentrations of approximately 1 observed in four patients; in two of the failures, CSF vanco- µg/ml. This is adequate for meningitis caused by Pen-S mycin concentrations were undetectable at 48 hours and in pneumococcal strains, but unreliable against Pen-I strains a third patient, symptoms recurred by the eighth day of and not efficacious against Pen-R strains. Since failure to treatment. The concomitant use of dexamethasone in this sterilize the CSF in the first 24 hours of infection has been study might have played a role in the high treatment failure associated with poor outcome in bacterial meningitis rates. The CSF penetration of vancomycin ranges from cases, the clinician must initiate the most effective therapy 8.4% to 18%, based on experimental meningitis and as soon as possible [43••]. clinical ventriculitis studies [47]. In non-inflamed Based on concerns about the use of penicillin in the meninges, however, vancomycin penetration into the CSF therapy of pneumococcal meningitis, other antimicrobial becomes erratic and requires very high serum concentra- agents have been studied. The third-generation cephalospor- tions. By limiting the inflammatory process in the ins (either cefotaxime or ceftriaxone) achieve CSF concentra- meninges, dexamethasone significantly impairs vancomy- tions sufficient to treat most pneumococcal strains with cin penetration into the CSF, a phenomenon that is much intermediate susceptibility to penicillin [3]. Ceftriaxone and more marked in adults than in children. cefotaxime are used more frequently than ceftizoxime Rifampin has good in vitro activity against most strains because the latter is less active, in vitro, against PNSP [43••]. of PNSP. Its lipophilic properties provide good penetration Cefepime has equivalent efficacy to cefotaxime and ceftriax- into the CSF, even with the co-administration of dexam-
  6. 6. 404 Sepsis ethasone or in the presence of non-inflamed meninges. In ceftriaxone-vancomycin combination [44]. Nevertheless, a mo use model of pneumococcal meningitis that the paucity of data regarding the efficacy of meropenem in compared rifampin and ceftriaxone therapy outcomes, by the treatment of meningitis caused by penicillin and ceph- day six of therapy there were 11 deaths (26%) in the alosporin-resistant pneumococci precludes its routine rifampin group and 21 deaths (49%) in the ceftriaxone recommendation in clinical practice. group [48]. The rapid development of resistance, however, The newer fluoroquinolones (eg, levofloxacin, gatiflox- prohibits the use of rifampin as monotherapy against acin, moxifloxacin) are highly active, in vitro, against pneumococcal meningitis. In the rabbit model of penicil- penicillin and cephalosporin-resistant pneumococcal lin-resistant pneumococcal meningitis, the combination strains, and have recently attained a pivotal role in the of rifampin and a third-generation cephalosporin was management of infections caused by these organisms. synergistic [43••]. An in vitro study using amoxicillin- Their lipophilic properties and low protein binding favors resistant (MICs > 4.0 µg/ml) pneumococcal strains yielded CSF penetration, making them excellent candidates for use contrasting evidence. In this study, adding rifampin to a in bacterial meningitis [50–52]. therapy of a third-generation cephalosporin decreased the Trovafloxacin demonstrated bactericidal activity killing of ceftriaxone-susceptible strains by 10 fold. comparable to vancomycin in an experimental rabbit Antagonism also resulted when rifampin was added to model of highly penicillin-resistant pneumococcal meropenem against ceftriaxone-susceptible and intermedi- meningitis, and the combination of trovafloxacin and ate strains [49]. vancomycin was synergistic [53]. An in vitro study showed Controlled clinical trials evaluating the role of rifampin similar killing activities for β-lactam (amoxicillin, in the treatment of meningitis caused by resistant pneumo- cefotaxime, ceftriaxone, cefpirome, meropenem) in combi- coccal strains are lacking. Pending the results of clinical nation with either trovafloxacin or vancomycin, against trials, we do not recommend the routine use of rifampin in ceftriaxone-resistant pneumococcal strains [49]. the empiric treatment of pneumococcal meningitis; the Moxifloxacin was shown to be as effective as ceftriax- clinician should consider using rifampin in combination one in the rabbit model of meningitis caused by a penicil- with vancomycin plus a third-generation cephalosporin lin-susceptible pneumococcal strain [50]; CSF penetration when treating meningitis caused by highly-resistant of moxifloxacin was only slightly reduced by the co- pneumococci and when the expected clinical or bacterio- administration of dexamethasone. Moxifloxacin has also logic response is delayed. shown efficacy in the treatment of penicillin-resistant Chloramphenicol has been extensively used in the pneumococcal meningitis in an experimental rabbit model treatment of bacterial meningitis. It has excellent CSF [51]. A recent in vitro study of 60 CSF isolates of S. pneumo- penetration and in vitro activity against most penicillin- niae revealed moxifloxacin to be active against all the peni- resistant strains of S. pneumoniae. However, one study has cillin-resistant isolates tested. Further, cephalosporin raised significant concerns about its use in patients with resistance did not affect its in vitro activity [54]. meningitis caused by penicillin-resistant isolates [43••]. Gatifloxacin was recently evaluated in the treatment of Despite susceptibility on disk testing, 20 of 25 children experimental cephalosporin-resistant pneumococcal men- treated with chloramphenicol had an unsatisfactory ingitis; it had excellent CSF penetration (46% to 56%) and outcome (ie, death, serious neurologic deficit, poor clinical was as effective as a single agent, compared to the ceftriax- response), probably because of the poor bactericidal one-vancomycin combination [52]. Gemifloxacin was also activity of chloramphenicol against these strains. effective in a rat model of pneumococcal meningitis [55]. New agents are currently being evaluated for their The above studies point to the new fluoroquinolones efficacy in treating pneumococcal meningitis. Meropenem as a very promising group of agents for the treatment of is active, in vitro, against most penicillin-resistant strains of antimicrobial-resistant pneumococcal meningitis. S. pneumoniae, has a mean penetration into inflamed CSF Randomized, well-controlled clinical trials confirming of 8%, and has less propensity to cause seizures than these findings are eagerly awaited. imipenem does [44]. It has been extensively studied in the The effects of antimicrobial resistance on the treatment treatment of bacterial meningitis in children and has of pneumococcal meningitis has not been carefully shown efficacy comparable to that demonstrated by the assessed. In a 1994–1996 study of meningitis caused by third-generation cephalosporins. The Food and Drug PNSP, using cases from Atlanta, Baltimore, and San Anto- Administration has approved meropenem for the treat- nio, the CDC failed to demonstrate an increase in mortal- ment of bacterial meningitis in children three months of ity or duration of hospitalization [41]. In a review of 180 age and older [43••]. episodes of pneumococcal meningitis spanning a three- A recent study compared the in vitro killing activities of year period, with cases from eight children’s hospitals, meropenem and other antibiotics, at clinically achievable there were no bacteriologic failures among the patients CSF concentrations, against Pen-R S. pneumoniae isolates with ceftriaxone-nonsusceptible isolates (7% of the from children with meningitis; no significant difference isolates were intermediately susceptibility and 2.8% were was observed between the activities of meropenem and the fully resistant to ceftriaxone). Further, none of the 14
  7. 7. Impact of Antimicrobial Resistance on the Treatment of Invasive Pneumococcal Infections • Rocha et al. 405 deaths was associated with bacteriologic failure [41]. Of Table 3. Strategies to reduce the frequency of note, only five patients with cephalosporin-nonsusceptible antimicrobial-resistant pneumococcal infections isolates received vancomycin, and two received mero- penem. Further epidemiologic studies on the outcome of Increased surveillance for antimicrobial-resistant infections Rational use of antimicrobial agents patients with meningitis caused by these strains are Pneumococcal vaccination needed, to define their clinical importance. Based on currently available data from in vitro suscep- Data from Butler and Cetron [4], Ortqvist [56], Butler et al. [57], tibility studies, experimental animal models, and clinical Food and Drug Administration [58], Black et al. [59••], and Lieu et al. [60•]. results, the combination of vancomycin and a third-gener- ation cephalosporin (either cefotaxime or ceftriaxone) is until the symptoms abated. Perhaps the most drastic SSIP recommended as empiric therapy for pneumococcal protocol was the removal from day care of children carry- meningitis, pending results of susceptibility testing. In ing PNSP until two negative cultures were obtained. These cases of pneumococcal meningitis caused by Pen-R strains, measures might be responsible for the maintenance of very rifampin should be added if clinical response to the third- low levels of PNSP (3% to 4% of strains) in Sweden. generation cephalosporin-vancomycin combination is inadequate. Intrathecal vancomycin remains an option in Antimicrobials nonresponding patients. A repeat lumbar puncture should The second strategy—and conceivably the most difficult to be performed at 36 to 48 hours after initiation of anti- implement—is the judicious use of antimicrobial agents, microbial therapy if the patient is not responding since misuse provides the major selective pressure for the adequately or if a pneumococcal isolate resistant to the emergence of resistant organisms [4]. third-generation cephalosporins is involved. The newer Antimicrobial agents used in the treatment of commu- fluoroquinolones are very promising alternatives but nity-acquired upper respiratory tract infections play a cannot be recommended until clinical trials results central role in pneumococcal drug resistance; the majority confirm safety and efficacy. of these infections are viral in origin, but physicians are often quick to prescribe antimicrobials. Changing such established behavior would require intense marketing, Prevention targeting not only physicians and health-care personnel The association between the increasing frequency of but also the general population. This has been successfully penicillin resistance and multidrug-resistance among done in Sweden [56]. pneumococci is of great concern. New antimicrobial agents are currently in differing stages of development; it is hoped Vaccination that one or more of these agents will prove to be effective The last and perhaps most important strategy is vaccination in the treatment of invasive pneumococcal infections [4]. The first whole-cell pneumococcal vaccine was devel- [3,41]. However, preventive measures to control the spread oped in 1911 to immunize South African gold miners [57]. of PNSP are also of critical importance (Table 3). Three By the 1940s, controlled trials of bivalent, trivalent and prevention strategies bear consideration: quadrivalent polysaccharide vaccines had provided good evidence for the efficacy of these vaccines [57]. With the Surveillance development and widespread use of penicillin G, interest in The first strategy for prevention involves improved surveil- pneumococcal vaccines was lost; by the 1950s, they had been lance for PNSP [4]. Better surveillance allows for a more withdrawn from the market [57]. In a report of some 2000 comprehensive understanding of the scope of the problem cases of pneumococcal pneumonia treated at Kings County of antimicrobial resistance, which helps clinicians make Hospital between 1952 and 1962, almost 25% of patients rational choices about empiric antimicrobial therapy for with bacteremic pneumococcal pneumonia died, despite presumed pneumococcal infections. adequate antimicrobial therapy. The work of Austrian and All clinical microbiology laboratories should screen for others led to the ultimate licensure of a 14-valent pneumo- PNSP with an oxacillin disk diffusion test and, if penicillin coccal polysaccharide vaccine in the United States, which was nonsusceptibility is suggested (ie, zone diameter less than replaced by a 23-valent vaccine in 1983 [57]. This vaccine 19 mm), perform formal MIC determinations for penicil- includes the vast majority (approximately 85%) of serotypes lin and ceftriaxone or cefotaxime susceptibility. that cause infections in individuals over the age of 65 years In 1995, the South Swedish Intervention Project (SSIP) [4]. Despite its decreased immunogenicity in certain began to trace contacts of all individuals carrying PNSP, as populations, the overall efficacy of the vaccine in preventing they are detected [56]. Under the SSIP protocol, contacts invasive pneumococcal disease among immunocompetent carrying PNSP in the nasopharynx were followed; biweekly adults over age 65 is 75% [4]. However, despite this nasopharyngeal cultures were performed until two efficacy, the 1995 Behavioral Risk Factors Surveillance negative cultures were documented. Any carrier who System reported that only 35% of elderly Americans remem- developed a respiratory infection was advised to stay home bered ever receiving a dose of the vaccine [4].
  8. 8. 406 Sepsis On February 17, 2000, the FDA approved a seven- References and Recommended Reading valent conjugate vaccine for the prevention of invasive Papers of particular interest, published recently, pneumococcal disease in children [58]. A multicenter, have been highlighted as: controlled, double-blind study of 37,868 children was • Of importance •• Of major importance performed to evaluate the efficacy of this vaccine in the prevention of invasive disease caused by pneumococcal 1.• Campbell GD, Silberman R: Drug-resistant Streptococcus serotypes contained in the vaccine. Efficacy was 97.4% pneumoniae. Clin Infect Dis 1998, 26:1188–1195. This paper provides an excellent review of the epidemiology, (95% confidence interval [CI], 82.7% to 99.9%, P < 0.001) diagnosis, risk factors, preventive strategies and therapy of resistant in the fully vaccinated group and 93.9% (95% CI, 79.6% pneumococcal infections. to 98.5%, P < 0.001) in the intention-to-treat analysis 2. Bryan CS: Treatment of pneumococcal pneumonia: the case for penicillin G. Am J Med 1999, 107:63S–68S. group. Overall efficacy was 88.9% (95% CI, 63.8% to 3. Ball P: Therapy for pneumococcal infections at the millen- 97.8%) against invasive pneumococcal disease, regardless nium: doubts and certainties. Am J Med 1999, 107:77S–85S. of serotype [59••]. The vaccine was administered at 2, 4, 6, 4. Butler JC, Cetron MS: Pneumococcal drug resistance: the new and 12 to 15 months of age. If these data are confirmed in “special enemy of old age”. Clin Infect Dis 1999, 28:730–735. 5. National Committee for Clinical Laboratory Standards clinical practice, this vaccine is likely to have a major (NCCLS). Methods for dilution antimicrobial susceptibility impact in the epidemiology of pneumococcal infections tests for bacteria that grow aerobically: approved standard. and, consequently, pneumococcal antimicrobial resistance. Document M7-A4 edn 3. NCCLS. Wayne, PA; 1997. 6. Barry AL: Antimicrobial resistance among clinical isolates In a recent cost-effectiveness analysis of pneumococcal of Streptococcus pneumoniae in North America. conjugate vaccination of healthy infants and young Am J Med 1999, 107:28S–33S. children (a hypothetical US birth cohort of 3.8 million 7.•• Tomasz A: New faces of an old pathogen: emergence and infants), it was estimated that vaccination would prevent spread of multidrug-resistant Streptococcus pneumoniae. Am J Med 1999, 107:55S–62S. more than 12,000 cases of meningitis and bacteremia, and This outstanding paper reviews historical aspects of the global 116 deaths due to pneumococcal infection for each US dissemination of penicillin-resistant strains of S. pneumoniae birth cohort, and has the potential to be cost-effective and the mechanisms of penicillin resistance. 8. Jacobs MR: Drug-resistant Streptococcus pneumoniae: relative to other preventive health strategies [60•]. rational antibiotic choices. Am J Med 1999, 106:19S–25S. 9. Thornsberry C, Hickey ML, Kahn J, et al.: Surveillance of antimicrobial resistance among respiratory tract pathogens in the United States, 1997 to 1998. Drugs Conclusion 1999, 58(Suppl 2):361–363. Penicillin resistance among pneumococci is a growing 10.• Song J, Lee NY, Ichiyama S, et al.: Spread of Streptococcus problem in the US and other parts of the world. In Korea, pneumoniae in Asian Countries: Asian Network for close to 80% of pneumococcal isolates are no longer Surveillance of Resistant Pathogens (ANSORP) Study. Clin Infect Dis 1999, 28:1206–1211. susceptible to penicillin. Penicillin resistance serves as a This important epidemiologic study reveals areas with the highest marker for resistance to other antimicrobial agents. The incidence of PNSP in the world. new fluoroquinolones retain in vitro activity, even against 11. Zhanel GG, Karlowsky JA, Palatnick L, et al.: Prevalence of antimicrobial resistance in respiratory tract isolates of Strep- the highly penicillin-resistant and multidrug-resistant tococcus pneumoniae: results of a Canadian national surveil- pneumococci, but recent reports of increasing resistance lance study. Antimicrob Agents Chemother 1999, 43:2504–2509. among these agents are a cause for concern. 12. Winston LG, Perlman JL, Rose DA, Gerberding JL: Penicillin- nonsusceptible Streptococcus pneumoniae at San Francisco In patients without CNS involvement, high doses of General Hospital. Clin Infect Dis 1999, 29:580–585. penicillin G or expanded-spectrum cephalosporins are 13. Clavo-Sanchez AJ, Giron-Gonzalez JA, Lopez-Prieto D, et al.: usually sufficient to treat infections caused by resistant Multivariate analysis of risk factors for infection due to pneumococcal strains. In meningeal infections, however, penicillin resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study. Clin Infect Dis 1997, the achievable CSF concentration of penicillin prohibits 24:1052–1059. the use of this agent, even against meningitis caused by 14. CDC: Geographic variation in penicillin resistance in Pen-I strains. High doses of the third-generation cepha- Streptococcus pneumoniae—selected sites, United States, 1997. MMWR 1997, 48(30):656–661. losporins are able to overcome the majority of nonsuscep- 15.•• Chen DK, McGeer A, De Azavedo JC, Low DE: Decreased tible pneumococci, but the highly-resistant strains require susceptibility of Streptococcus pneumoniae to fluoroquinolo- the addition of vancomycin for CSF sterilization. nes in Canada. N Engl J Med 1999, 341:233–239. This large multicenter survey alerts clinicians to the increasing Newer antimicrobial agents for therapy of invasive pneu- prevalence of fluoroquinolone resistance among pneumococci in mococcal infections are currently being evaluated in clinical Canada as a result of the increased use of this class of drugs. trials. The key to containing the spread of these organisms is 16. Linares J, De La Campa AG, Pallares R: Fluoroquinolone an organized prevention strategy, involving increased surveil- resistance in Streptococcus pneumoniae [letter]. N Engl J Med 1999, 341:1546–1547. lance of resistant strains, rational use of antimicrobial agents 17. Odland BA, Jones RN, Verhoef J, et al.: Antimicrobial activity of and widespread use of pneumococcal vaccines. The new hep- gatifloxacin (AM-1155, CG5501), and four other quinolones tavalent conjugate vaccine has the potential to radically tested against 2,284 recent clinical strains of Streptococcus pneumoniae from Europe, Latin America, Canada and the change the epidemiology of pneumococcal disease and, United States. The SENTRY Antimicrobial Surveillance consequently, pneumococcal antimicrobial resistance. Group (Americas and Europe). Diag Microbiol Infect Dis 1999, 34:315–320.
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  10. 10. 408 Sepsis 54. Tarasi A, Capone A, Tarasi D, et al.: Comparative in-vitro 59.•• Black S, Shinefield H, Fireman B, et al.: Efficacy, safety and activity of moxifloxacin, penicillin, ceftriaxone and immunogenicity of heptavalent pneumococcal conjugate ciprofloxacin against pneumococci isolated from meningitis. vaccine in children. Pediatr Infect Dis J 2000, 19:187–195. J Antimicrob Chemother 1999, 43:833–835. This large study provides compelling data on the efficacy of the new 55. Lewandowski T, Berry V, Demarsh P, et al.: In-vivo activity of heptavalent conjugate vaccine in preventing invasive pneumococcal gemifloxacin (SB-265805) in an infant rat meningitis model disease in children. with Streptococcus pneumoniae [abstract]. In Proceedings of the 60.• Lieu TA, Ray GT, Black SB, et al.: Projected cost-effectiveness Interscience Conference on Antimicrobial Agents and Chemotherapy. of pneumococcal conjugate vaccination of healthy infants Washington, 1999:82. and young children. JAMA 2000, 283:1460–1468. 56. Ortqvist A: Pneumococcal disease in Sweden: experiences This is the first study to analyze the cost-effectiveness of the and current situation. Am J Med 1999, 107:44S–49S. heptavalent pneumococcal conjugate vaccine, compared with other 57. Butler JC, Shapiro ED, Carlone GM: Pneumococcal vaccines: preventive health interventions. history, current status and future directions. Am J Med 1999, 107:69S-76S. 58. Food and Drug Administration: First pneumococcal vaccine approved for infants and toddlers [press release]. Rockville, MD: U.S. Department of Health and Human Services; February 17, 2000. Available on-line at < NEWS/NEW00716.html>.