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Antimicrobial Resistance in Streptococcus pneumoniae: Implications for Patients With Community-Acquired Pneumonia

      Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. During the past decade, the prevalence of penicillin resistance in S pneumoniae has increased dramatically, with resistance rates approaching 45% in some areas of the United States. Streptococcus pneumoniae has also acquired resistance to other commonly used antimicrobials, including cephalosporins, macrolides, and trimethoprim-sulfamethoxazole. While vancomycin and the newer quinolones are currently highly active against most strains of S pneumoniae, reduced susceptibilities to these agents have been identified in some strains. Prior use of antimicrobial agents is the major risk factor for colonization and infection with antibiotic-resistant strains. p-Lactam antibiotics remain the treatment of choice for infections caused by susceptible S pneumoniae. The optimum therapy for penicillin-resistant strains remains unclear. Appropriate empirical therapy for patients with community-acquired pneumonia depends in part on the community-specific resistance patterns of S pneumoniae to various antibiotics. In this article, we provide an overview of the development of S pneumoniae resistance to commonly used antibiotics and discuss the implications of the development of resistance on treatment decisions.
      CAP (community-acquired pneumonia), CDC (Centers for Disease Control and Prevention), MIC (minimum inhibitory concentration), PBP (penicillin-binding protein), TMP-SMX (trimethoprim-sulfamethoxazole)
      Community-acquired pneumonia (CAP) leads to considerable morbidity and mortality. Medical expenditures attributable to CAP amount to almost $10 billion annually in the United States, with inpatient costs accounting for more than 90% of total costs.
      • Lave JR
      • Lin CL
      • Fine MJ
      • Hughes-Cromwick P
      The cost of treating patients with community-acquired pneumonia.
      Streptococcus pneumoniae (pneumococcus) is the leading identified pathogen in patients with CAP.
      • Marston BJ
      • Plouffe JF
      • File Jr, TM
      • et al.
      Community-Based Pneumonia Incidence Study Group. Incidence of community-acquired pneumonia requiring hospitalization: results of a population-based active surveillance study in Ohio.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      Even in those patients with CAP in whom an organism is not identified by routine diagnostic testing, S pneumoniae is likely to be the causative agent.' Streptococcus pneumoniae is implicated in nearly 500,000 cases of CAP annually in the United States,
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      with annual expenditures for the treatment of pneumococcal infections exceeding $4 billion.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      Case-fatality rates for bacteremia or pneumonia caused by S pneumoniae are also substantial, ranging from 9% to 30%.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Hibbs JR
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      Prevalence of human immunodeficiency virus infection, mortality rate, and serogroup distribution among patients with pneumococcal bacteremia at Denver General Hospital, 1984-1994.
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      • Cars O
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      • Saikku P
      • Jean C
      • Scandinavian Sparfloxacin Study Group
      Oral empiric treatment of community-acquired pneumonia: a multicenter, double-blind, randomized study comparing sparfloxacin with roxilhromycin.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      For more than 4 decades, penicillin G was the mainstay of therapy for pneumococcal infection. However, the prevalence of penicillin-resistant pneumococci, first reported in the 1960s, has escalated at an alarming rate within the past decade.
      • Chenoweth C
      • Lynch III, JP
      Antimicrobial resistance: implications for managing respiratory failure.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Gold HS
      • Moellering Jr, RC
      Antimicrobial-drug resistance.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      By 1997, about one third of pneumococci were resistant to penicillin.” Unfortunately, penicillin-resistant strains are also often resistant to non—β-lactam antibiotics, including macrolides, clindamycin, tetracyclines, chloramphenicol, and trimethoprim-sulfamethoxazole (TMP-SMX).
      • Chenoweth C
      • Lynch III, JP
      Antimicrobial resistance: implications for managing respiratory failure.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      Development of antimicrobial resistance to specific classes of antimicrobials reflects patterns of antibiotic use.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
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      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      The vast majority of S pneumoniae strains (both penicillin-sensitive and penicillin-resistant) are susceptible to carbapenems, rifarnpin, and the newer fluoroquinolones.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Blondeau JM
      A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new “respiratory quino-lones,”.
      • Casellas JM
      • Gilardoni M
      • Tome G
      • et al.
      Comparative in-vitro activity of levofloxacin against isolates of bacteria from adult patients with community-acquired lower respiratory tract infections.
      • Thomson KS
      • Chartrand SA
      • Sanders CC
      • Block L, S
      In-vitro activity of levofloxacin against Streptococcus pneumoniae with various levels of penicillin resistance.
      More than 90% of strains are susceptible to carbapenems.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      Although the newer fluoroquinolones also have activity against more than 99% of isolates, reports of decreased susceptibility of pneumococci to fluoroquinolones are emerging.
      • Chen DK
      • McGeer A
      • de Azavedo JC
      • Low DE
      • Canadian Bacterial Surveillance Network
      Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada.
      All strains of pneumococci remain susceptible to vancomycin; however, the development of tolerance to vancomycin in some strains of S pneumoniae suggests vancomycin resistance may soon emerge.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Novak R
      • Henriques B
      • Charpentier E
      • Normark S
      • Tuomanen E
      Emergence of vancomycin tolerance in Streptococcus pneumoniae.
      • McCullers JA
      • English BK
      • Novak R
      Isolation and characterization of vancomycin-tolerant Streptococcus pneumoniae from the cerebrospinal fluid of a patient who developed recrudescent meningitis.
      When treatment decisions must be made for an individual patient with CAP, the physician is usually unaware of the exact pathogen causing the infection and, thus, is unaware also of the precise antimicrobial susceptibilities. 2,4,22,23 Therefore, most treatment of CAP is given on an empirical basis, often based on clinical practice guide lines.
      • Rhew DC
      • Riedinger MS
      • Sandhu M
      • Bowers C
      • Greengold N
      • Weingarten SR
      A prospective, multicenler study of a pneumonia practice guideline.
      • Bartlett JG
      • Breiman RF
      • Mandell LA
      • File Jr, TM
      • Infectious Diseases Society of America
      Community-acquired pneumonia in adults: guidelines for management.
      • Niederman MS
      • Bass Jr, JB
      • Campbell GD
      • et al.
      American Thoracic Society, Medical Section of the American Lung Association. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy.
      When choosing an antibiotic for the treatment of CAP, physicians must be aware of the current patterns of antibiotic susceptibility in their community, as well as the patient's risk factors for carriage of resistant pneumococci.

      PENICILLIN RESISTANCE TO S PNEUMONIAE

      Pneumococcal susceptibilities to penicillin are defined in terms of the minimum inhibitory concentration (MIC) of penicillin. Streptococcus pneumoniae is susceptible to penicillin if the MIC is 0.06 ug/ml, or lower, has intermediate resistance if the MIC is 0.1 to 1.0 ug/ml., and is resistant if the MIC is 2 ug/ml, or higher.
      • Chenoweth C
      • Lynch III, JP
      Antimicrobial resistance: implications for managing respiratory failure.
      • Gold HS
      • Moellering Jr, RC
      Antimicrobial-drug resistance.
      • Barry AL
      Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in North America.
      Penicillin resistance is caused by mutations in chromosomal genes, which lead to alterations in penicillin-binding proteins (PBPS).
      • Chenoweth C
      • Lynch III, JP
      Antimicrobial resistance: implications for managing respiratory failure.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Gold HS
      • Moellering Jr, RC
      Antimicrobial-drug resistance.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      Alteration of PBPs decreases binding to penicillin and other β-lactam antibiotics, including β-lactamase inhibitor combinations and cephalosporins.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      Resistance has occurred primarily through a stepwise process, with successive genetic mutations resulting in increasing resistance.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      • Chambers HF
      Penicillin-binding protein-mediated resistance in pneumococci and staphylococci.
      In addition, some evidence suggests that S pneumoniae gained penicillin resistance genes through transformation with penicillin-resistant viridans streptococci.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      • Chambers HF
      Penicillin-binding protein-mediated resistance in pneumococci and staphylococci.
      Finally, clonal dissemination of resistant strains of pneumococci has occurred in the United States and worldwide. Currently in the United States, most strains of penicillin-resistant S pneumoniae are represented by relatively few clonal groups.
      • Doern GV
      • Brueggemann AB
      • Huynh H
      • Wingert E
      Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997-98.
      This suggests that the US strains arose from a few imported strains of penicillin-resistant pneumococci circulating in other countries.
      • Doern GV
      • Brueggemann AB
      • Huynh H
      • Wingert E
      Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997-98.
      Rates of resistance to non—β-lactam antimicrobials are also higher in penicillin-resistant strains.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      • Appelbaum PC
      Antimicrobial resistance in Streptococcus pneumoniae: an overview.
      Resistance to non—β-lactam antibiotics may be acquired through transformation of DNA from other streptococcus species (eg, viridans group streptococci), transposons, or diverse spontaneous mutations due to selection pressure.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      • Appelbaum PC
      Antimicrobial resistance in Streptococcus pneumoniae: an overview.
      Antimicrobial resistance correlates with specific serotypes in the pneumococci. More than 80% of resistant isolates are classified into 6 serotypes (6A, 6B, 9V, 14, 19F, 23F).
      • Chenoweth C
      • Lynch III, JP
      Antimicrobial resistance: implications for managing respiratory failure.
      • Gold HS
      • Moellering Jr, RC
      Antimicrobial-drug resistance.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Docrn GV
      • Brueggemann AB
      • Blocker M
      • et al.
      Clonal relationships among high-level penicillin-resistant Streptococcus pneumoniae in the United States.
      All these serotypes are associated with infections in humans and are represented by the currently available pneumococcal vaccine. Serotypes
      • Lave JR
      • Lin CL
      • Fine MJ
      • Hughes-Cromwick P
      The cost of treating patients with community-acquired pneumonia.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Ruiz-Gonzalez A
      • Falguera M
      • Nogues A
      • Rubio-Caballero M
      Is Streptococcus pneumoniae the leading cause of pneumonia of unknown etiology? a microbiologie study of lung aspirates in consecutive patients with community-acquired pneumonia.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Ortqvist A
      • Valtonen M
      • Cars O
      • Wahl M
      • Saikku P
      • Jean C
      • Scandinavian Sparfloxacin Study Group
      Oral empiric treatment of community-acquired pneumonia: a multicenter, double-blind, randomized study comparing sparfloxacin with roxilhromycin.
      • Gold HS
      • Moellering Jr, RC
      Antimicrobial-drug resistance.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      and 18 rarely carry antibiotic-resistant genes.
      • Chenoweth C
      • Lynch III, JP
      Antimicrobial resistance: implications for managing respiratory failure.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Gold HS
      • Moellering Jr, RC
      Antimicrobial-drug resistance.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Pallares R
      • Gudiol F
      • Liñares J
      • et al.
      Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.

      Prevalence and Epidemiology

      The prevalence of penicillin resistance among

      The prevalence of penicillin resistance among pneumococci varies widely. Penicillin-resistant pneumococci arose from a few clones in a few geographic locations (eg, South Africa, Australia) in the late 1960s and then spread throughout the world.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      • Pallares R
      • Gudiol F
      • Liñares J
      • et al.
      Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.
      However, multiple genetic mutations that confer resistance have emerged independently in Switzerland and other selected countries.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      The rate of penicillin resistance is very high in some areas (eg, Spain, Israel, South Africa), ranging from 25% to 86%.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      In contrast, penicillin-resistant strains remain uncommon (<5%) in Sweden, Finland, Canada, and some other geographic areas.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      • Chambers HF
      Penicillin-binding protein-mediated resistance in pneumococci and staphylococci.
      • Doern GV
      • Brueggemann AB
      • Huynh H
      • Wingert E
      Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997-98.
      • Appelbaum PC
      Antimicrobial resistance in Streptococcus pneumoniae: an overview.
      • Docrn GV
      • Brueggemann AB
      • Blocker M
      • et al.
      Clonal relationships among high-level penicillin-resistant Streptococcus pneumoniae in the United States.
      • Pallares R
      • Gudiol F
      • Liñares J
      • et al.
      Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.
      • Ortqvist A
      Pneumococcal disease in Sweden: experiences and current situation.
      In the United States, the prevalence of penicillin resistance is highly variable.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Centers for Disease Control and Prevention
      Geographic variation in penicillin resistance in Streptococcus pneumoniae-selected sites. United States, 1997.
      In 1997, a survey by the Centers for Disease Control and Prevention (CDC) found that 25% of 3237 isolates from patients with invasive pneumococcal disease were not susceptible to penicillin.
      • Centers for Disease Control and Prevention
      Geographic variation in penicillin resistance in Streptococcus pneumoniae-selected sites. United States, 1997.
      However, the proportion varied widely between geographic areas; Maryland had the lowest rate of strains not susceptible to penicillin (15.3%) and Tennessee had the highest rate (38.3%).
      • Centers for Disease Control and Prevention
      Geographic variation in penicillin resistance in Streptococcus pneumoniae-selected sites. United States, 1997.
      The prevalence of resistance to penicillin in the United States has increased steadily over the past decade.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      A nationwide surveillance program sponsored by the CDC detected high-grade resistance to penicillin in only 0.02% of pneumococci isolated from 1979 to 1987.
      • Spika JS
      • Facklam RR
      • Plikaytis BD
      • Oxtoby MJ
      • Pneumococcal Surveillance Working Group
      Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987.
      By 1988, 0.2% of strains were highly resistant.
      • Jorgensen JH
      • Doern GV
      • Maher LA
      • Howell AW
      • Redding JS
      Antimicrobial resistance among respiratory isolates of Haemophlius influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States.
      After 1989, however, resistance increased substantially, as outlined in Table 1. This dramatic rise in penicillin resistance during the past decade is indeed worrisome and requires that clinicians at least consider initially prescribing antimicrobial agents effective against resistant strains of S pneumoniae routinely for empirical initial treatment of severely ill patients with CAP. Once the causative organism is identified and susceptibilities are known, antibiotics could be changed based on this information and the clinical response.
      Table 1Evolution of Penicillin Resistance in Streptococcus pneumonias in the United States
      Pc-I = intermediate resistance to penicillin; Pc-R = high resistance to penicillin.
      SourceStudy yearsNo. of isolatesPel or Pc-R S pneumoniae isolates (%)Pc-R S pneumoniae isolates (%)
      Spikaetal,
      • Spika JS
      • Facklam RR
      • Plikaytis BD
      • Oxtoby MJ
      • Pneumococcal Surveillance Working Group
      Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987.
      1991
      1979-8754595.0<0.01
      Jorgensen et al,
      • Jorgensen JH
      • Doern GV
      • Maher LA
      • Howell AW
      • Redding JS
      Antimicrobial resistance among respiratory isolates of Haemophlius influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States.
      1990
      1987-894874 I0.2
      Breiman et al,
      • Breiman RF
      • Butler JC
      • Tenover FC
      • Elliott JA
      • Facklam RR
      Emergence of drug-resistant pneumococcal infections in the United States.
      1994
      1991-925446.61 3
      Barry etal,
      • Barry AL
      • Pfaller MA
      • Fuchs PC
      • Packer RR
      In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from US medical centers in 1992 and 1993.
      1994
      1992-9379922.27.3
      Butler et al,
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      1996
      1993-9474014.03.2
      Doern et al,
      • Doern GV
      • Brueggemann A
      • Holley Jr, HP
      • Rauch AM
      Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
      1996
      1994-95152423.69.5
      Thornsberry et al,
      • Thornsberry C
      • Ogilvie FT
      • Holley Jr, HP
      • Sahm DF
      In vitro activity of grepafloxacin and 25 other antimicrobial agents against Streptococcus pneumoniae: correlation with penicillin resistance.
      1998
      1996-97919034.014.0
      Doemetal,
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      1998
      199784543.816.0
      * Pc-I = intermediate resistance to penicillin; Pc-R = high resistance to penicillin.

      Risk Factors

      Endemic foci and person-to-person transmission of clones of penicillin-resistant strains have been documented within daycare centers, hospitals, nursing homes, homeless shelters, and correctional facilities.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Pallares R
      • Gudiol F
      • Liñares J
      • et al.
      Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.
      • Nuorti JP
      • Butler JC
      • Crutcher JM
      • et al.
      An outbreak of multidrug-resistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents.
      • Hoefnagels-Schuermans A
      • Van Eldere J
      • Van Lierde S
      • Verbist L
      • Verhaegen J
      • Peetermans WE
      Increase in penicillin resistance rates in Belgium due to clonal spread of a penicillin-resistant 23F Streptococcus pneumoniae strain.
      Prior antibiotic use is the dominant risk factor associated with antimicrobial-resistant pneumococci.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      Risk factors for colonization with resistant pneumococci include prior antibiotic use, age younger than 6 years, and attendance in daycare centers.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Nuorti JP
      • Butler JC
      • Crutcher JM
      • et al.
      An outbreak of multidrug-resistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents.
      • Hoefnagels-Schuermans A
      • Van Eldere J
      • Van Lierde S
      • Verbist L
      • Verhaegen J
      • Peetermans WE
      Increase in penicillin resistance rates in Belgium due to clonal spread of a penicillin-resistant 23F Streptococcus pneumoniae strain.
      • Decks SL
      • Palacio R
      • Ruvinsky R
      • et al.
      Streptococcus pneumoniae Working Group Risk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae.
      • Syrogiannopoulos GA
      • Grivea IN
      • Beratis NG
      • et al.
      Resistance patterns of Streptococcus pneumoniae from carriers attending daycare centers in southwestern Greece.
      Risk factors for penicillin
      resistance among invasive pneumococcal infections include prior β-lactam use, residence in nursing homes or recent hospitalization, and underlying immunosuppressive disease.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Nuorti JP
      • Butler JC
      • Crutcher JM
      • et al.
      An outbreak of multidrug-resistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents.
      • Bedos JP
      • Chevret S
      • Chastang C
      • Geslin P
      • Régnier B
      Epidemiological features of and risk factors for infection by Streptococcus pneumoniae strains with diminished susceptibility to penicillin: findings of a French survey.
      • Nava JM
      • Bella F
      • Garau J
      • et al.
      Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae: a population-based study.

      OTHER DRUG RESISTANCE IN S PNEUMONIAE

      Cephalosporins

      Resistance to other β-lactam antibiotics increases in parallel with penicillin resistance.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      Resistance to cephalosporins arises via alterations of PBPs 2x, 2b, and la, which result in reduced affinity for cephalosporins
      • McDougal LK
      • Rasheed JK
      • Biddle JW
      • Tenover FC
      Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States.
      Among penicillin-resistant isolates, the activity of firstand second-generation cephalosporins is often POOr, but third-generation cephalosporins (cefotaxime and ceftriaxone) usually retain adequate activity.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Pallares R
      • Gudiol F
      • Liñares J
      • et al.
      Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.
      In some areas, however, up to 40% of S pneumoniae are resistant to cefotaxime and ceftriaxone.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Syrogiannopoulos GA
      • Grivea IN
      • Beratis NG
      • et al.
      Resistance patterns of Streptococcus pneumoniae from carriers attending daycare centers in southwestern Greece.
      A 1994 CDC survey found that, overall, 4.1% of S pneumoniae had intermediate resistance and 0.4% had high resistance to cefotaxime.
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      In Atlanta, Ga, however, 4% of isolates from invasive pneumococcal infections in 1994 were highly resistant to cefotaxime.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      Cefotaxime-resistantstrains will likely increase in the future because of the high utilization of β-lactam antibiotics.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • McDougal LK
      • Rasheed JK
      • Biddle JW
      • Tenover FC
      Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States.

      Carbapenems

      Most S pneumoniae, including penicillin-resistant strains, remain susceptible to the carbapenems.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Jones RN
      • Pfaller MA
      Bacterial resistance: a worldwide problem.
      Meropenem appears to have in vitro activity against penicillin-resistant strains of pneumococci 1 to 2 dilutions higher than imipenem.
      • Kaplan SL
      • Mason Jr, EO
      Management of infections due to antibiotic-resistant Streptococcus pneumoniae.
      In a recent survey of 971 S pneumoniae strains, 85.9% were inhibited by meropenem at concentrations of 0.12 ug/ml, or lower; all were inhibited at 4 μg/mL or lower.
      • Jones RN
      • Pfaller MA
      Bacterial resistance: a worldwide problem.
      Therefore, the carbapenems may play a more important role in the treatment of patients with CAP in whom penicillin-resistant pneumococcus is suspected.

      Macrolides and Clindamycin

      Erythromycin resistance (defined as an MIC >1 µg/ml.) has increased in frequency worldwide, but prevalence rates are highly variable (0%_49%).
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
      • Bernaldo de Quiros JC
      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      • Syrogiannopoulos GA
      • Grivea IN
      • Beratis NG
      • et al.
      Resistance patterns of Streptococcus pneumoniae from carriers attending daycare centers in southwestern Greece.
      • Cizman M
      • Pokorn M
      • Seme K
      • Paragi M
      • Orazem A
      Influence of increased macrolide consumption on macrolide resistance of common respiratory pathogens.
      In the United
      States, only 0.3% of pneumococci from 1979 to 1987 were resistant to macrolides.
      • Spika JS
      • Facklam RR
      • Plikaytis BD
      • Oxtoby MJ
      • Pneumococcal Surveillance Working Group
      Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987.
      By 1996, resistance rates of 6% to 15% were found.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      More recently, the SENTRY program identified macrolide resistance ranging from 11% to 14% for intermediate resistance and 5% to 7% for high resistance.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      Resistance of S pneumoniae to macrolide antibiotics may develop by several mechanisms. The dominant risk factor is selection pressure from previous antibiotic use.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
      • Bernaldo de Quiros JC
      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Tomasz A
      New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.
      • Cizman M
      • Pokorn M
      • Seme K
      • Paragi M
      • Orazem A
      Influence of increased macrolide consumption on macrolide resistance of common respiratory pathogens.
      Other risk factors for macrolide-resistant S pneumoniae include age younger than 5 years, nosocomial acquisition, and penicillin resistance.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
      • Bernaldo de Quiros JC
      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      Erythromycin-resistant strains are usually resistant also to clarithromycin, azithromycin, roxithromycin, and several other antibiotic classes.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
      • Bernaldo de Quiros JC
      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Jacobs MR
      Increasing importance of antibiotic-resistant Streptococcus pneumoniae in acute otitis media.
      • Fasola EL
      • Bajaksouzian S
      • Appelbaum PC
      • Jacobs MR
      Variation in erythromycin and clindamycin susceptibilities of Streptococcus pneumoniae by four test methods.
      Clindamycin resistance occurs less frequently than macrolide resistance in S pneumoniae. In a survey of 1601 isolates of S pneumoniae between November 1997 and April 1998, 1.1% of penicillin-susceptible strains and 12.0% of penicillin-resistant strains were resistant to clindamycin.
      • Doern GV
      • Brueggemann AB
      • Huynh H
      • Wingert E
      Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997-98.
      The presence of high-level resistance to clindamycin (MIC ≥1 μg/ml.) correlated with high-level resistance to macrolides (MIC ≥64 μg/mL).
      • Doern GV
      • Brueggemann AB
      • Huynh H
      • Wingert E
      Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997-98.

      Trimethoprim-Sulfamethoxazole

      Resistance to TMP-SMX has increased along with penicillin resistance.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Syrogiannopoulos GA
      • Grivea IN
      • Beratis NG
      • et al.
      Resistance patterns of Streptococcus pneumoniae from carriers attending daycare centers in southwestern Greece.
      Recent US studies detected TMP-SMX resistance in 20% to 60% of pneumococcal isolates. Several studies Several studies have found that penicillin-resistant pneumococci are also often resistant to TMP-SMX.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      Multidrug-resistant strains of S pneumoniae are even more likely to be resistant to TMP-SMX.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      Thus, TMP-SMX is unreliable empirical therapy for patients with CAP.

      Tetracyclines

      Resistance to tetracyclines has increased worldwide, but the prevalence is highly variable (3%-82%).
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      • Syrogiannopoulos GA
      • Grivea IN
      • Beratis NG
      • et al.
      Resistance patterns of Streptococcus pneumoniae from carriers attending daycare centers in southwestern Greece.
      In the United States, the level of tetracycline resistance has remained relatively stable (2%-10%) from 1979 to 1994, which likely reflects limited use of this class of antimicrobials for routine treatment of respiratory infections.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      Given the relatively low cost and low incidence of resistance, doxycycline has been increasingly advocated as reasonable therapy for CAP.
      • Ailani RK
      • Agastya G
      • Ailani RK
      • Mukunda BN
      • Shekar R
      Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia.

      Fluoroquinolones

      Historically, the fluoroquinolones (eg, ciprofloxacin, ofloxacin) were considered poor choices for severe CAP because of their marginal MIC (1.0-2.0µ g/mL) against S pneumoniae.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      Levofloxacin has more desirable pharmacokinetics compared with ofloxacin.
      • Turnidge J
      Pharmacokinetics and pharmacodynamics of fluoro-quinolones.
      • Plouffe JF
      • Franklin County Pneumonia Study Group
      Levoflox-acin in vitro activity against bacteremic isolates of Streptococcus pneumoniae.
      and the newer fluoroquinolones (eg, gatifloxacin, moxifloxacin) have improved activity against S pneumoniae, making them better choices for treatment of CAP.
      • Thomson KS
      • Chartrand SA
      • Sanders CC
      • Block L, S
      In-vitro activity of levofloxacin against Streptococcus pneumoniae with various levels of penicillin resistance.
      • Turnidge J
      Pharmacokinetics and pharmacodynamics of fluoro-quinolones.
      • Plouffe JF
      • Franklin County Pneumonia Study Group
      Levoflox-acin in vitro activity against bacteremic isolates of Streptococcus pneumoniae.
      • Baquero F
      • Garcia-Rodriguez JA
      • Garcia de Lomas J
      • Aguilar L
      Spanish Surveillance Group for Respiratory Padtogens. Antimicrobial resistance of 1,113 Streptococcus pneumoniae isolates from patients with respiratory tract infections in Spain: results of a I-year (1996-1997) multicenter surveillance study.
      • Nightingale CH
      Moxifloxacin, a new antibiotic designed to treat community-acquired respiratory tract infections: a review of microbiologic and pharmacokinetic-pharmacodynamic characteristics.
      • Woodcock JM
      • Andrews JM
      • Boswell FJ
      • Brenwald NP
      • Wise R
      In vitro activity of BAY 12-8039, a new fluoroquinolone.
      Importantly, quinolone susceptibilities are usually not affected by resistance to penicillin; resistance to the newer quinolones is rare, even among penicillin-resistant strains of S pne umoniae.
      • Ortqvist A
      • Valtonen M
      • Cars O
      • Wahl M
      • Saikku P
      • Jean C
      • Scandinavian Sparfloxacin Study Group
      Oral empiric treatment of community-acquired pneumonia: a multicenter, double-blind, randomized study comparing sparfloxacin with roxilhromycin.
      • Thomson KS
      • Chartrand SA
      • Sanders CC
      • Block L, S
      In-vitro activity of levofloxacin against Streptococcus pneumoniae with various levels of penicillin resistance.
      • Turnidge J
      Pharmacokinetics and pharmacodynamics of fluoro-quinolones.
      • Baquero F
      • Garcia-Rodriguez JA
      • Garcia de Lomas J
      • Aguilar L
      Spanish Surveillance Group for Respiratory Padtogens. Antimicrobial resistance of 1,113 Streptococcus pneumoniae isolates from patients with respiratory tract infections in Spain: results of a I-year (1996-1997) multicenter surveillance study.
      • Nightingale CH
      Moxifloxacin, a new antibiotic designed to treat community-acquired respiratory tract infections: a review of microbiologic and pharmacokinetic-pharmacodynamic characteristics.
      • Woodcock JM
      • Andrews JM
      • Boswell FJ
      • Brenwald NP
      • Wise R
      In vitro activity of BAY 12-8039, a new fluoroquinolone.
      • Liljequist BO
      • Hoffman BM
      • Hedlund J
      Activity of trovafloxacin against blood isolates of Streptococcus pneumoniae in Sweden.
      However, a recent report from the Canadian Bacterial Surveillance Network found that the prevalence of pneumococci with reduced susceptibility to fluoroquinolones increased from 0% in 1993 to 1.7% by 1998. 19 The authors used a fluoroquinolone MIC of 4 µg/ml. or higher as the definition of reduced susceptibilities.
      • Chen DK
      • McGeer A
      • de Azavedo JC
      • Low DE
      • Canadian Bacterial Surveillance Network
      Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada.
      The clinical importance of this reduced susceptibility is not known.

      Vancomycin

      All strains of S pneumoniae, even those resistant to penicillin and other antimicrobials, have remained susceptible to vancomycin.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Doern GV
      • Pfaller MA
      • Kugler K
      • Freeman J
      • Jones RN
      Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program.
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      • Doern GV
      • Brueggemann A
      • Holley Jr, HP
      • Rauch AM
      Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
      Unfortunately, several clinical isolates of S pneumoniae have been identified that are “tolerant” to vancomycin (ie, inhibited but not killed by a concentration of vancomycin 10-fold higher than the MIC for the isolates)
      • Novak R
      • Henriques B
      • Charpentier E
      • Normark S
      • Tuomanen E
      Emergence of vancomycin tolerance in Streptococcus pneumoniae.
      • McCullers JA
      • English BK
      • Novak R
      Isolation and characterization of vancomycin-tolerant Streptococcus pneumoniae from the cerebrospinal fluid of a patient who developed recrudescent meningitis.
      All tolerant isolates were resistant to penicillin.
      • Novak R
      • Henriques B
      • Charpentier E
      • Normark S
      • Tuomanen E
      Emergence of vancomycin tolerance in Streptococcus pneumoniae.
      Theoretically, just a few mutations could cause these tolerant strains of S pneumoniae to become fully resistant to vancomycin.
      • Novak R
      • Henriques B
      • Charpentier E
      • Normark S
      • Tuomanen E
      Emergence of vancomycin tolerance in Streptococcus pneumoniae.
      Given this worrisome recent development, new antimicrobials with excellent activity against S pneumoniae need to be developed urgently.

      Multiple Drugs

      Resistance to 2 or more antibiotics (eg, penicillins, cephalosporins, TMP-SMX, macrolides) is defined as multiple-drug resistance.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      • Campbell Jr, GD
      • Silberman R
      Drug-resistant Streptococcus pneu moniae.
      Multidrug-resistant strains of S pneumoniae were first noted in South Africa and are now endemic in many countries.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      Risk factors for multidrugresistant S pneumoniae include prior antibiotic use, extremes of age, and hospitalization.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      Of some concern, multiple-drug resistance was found in 9% to 25% of pneumococci in 2 US studies.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Doern GV
      • Brueggemann A
      • Holley Jr, HP
      • Rauch AM
      Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.

      VIRULENCE, PRESENTATION, AND PROGNOSIS IN PATIENTS WITH PENICILLIN - RESISTANT S PNEUMONIAE

      Virulence, clinical features, and disease presentation are similar for patients presenting with illnesses caused by penicillin-susceptible or penicillin-resistant strains.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Kaplan SL
      • Mason Jr, EO
      Management of infections due to antibiotic-resistant Streptococcus pneumoniae.
      However, some factors associated with resistance also worsen prognosis (eg, extremes of age, hospitalization, previous exposure to antibiotics).
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      Although data are limited, pneumonia with resistant strains has not been associated with increased mortality, even though penicillins or cephalosporins have been used.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Clavo Sanchez AJ
      • Giron Gonzalez JA
      • Lopez-Prieto D
      • et al.
      Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study.
      • Kaplan SL
      • Mason Jr, EO
      Management of infections due to antibiotic-resistant Streptococcus pneumoniae.
      • Plouffe JF
      • Breiman RF
      • Facklam RR
      • Franklin County Pneumonia Study Group
      Bactercmia with Streptococcus pneumoniae: implications for therapy and prevention.
      • Heffelfinger JD
      • Dowell SF
      • Jorgensen JH
      • et al.
      Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.
      Pallares et al
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      prospectively reported treatment outcomes in 504 consecutive patients with pneumococcal pneumonia (diagnosis by blood culture in 412, pleural fluid in 46, transthoracic aspiration in 37, and bronchoscopy in 55). Among patients with pneumonia caused by 1 pathogen, the overall percentage of highly penicillin-resistant strains was 10%. The majority of patients were treated with a β-Iactam antibiotic administered intravenously (penicillin, 2 million U every 4 hours; ampicillin, 2 g every 6 hours; ceftriaxone, 1-2 g every 24 hours; or cefotaxime, 1-2 g every 6 hours). Although the overall mortality rate among patients with penicillin-resistant strains was 38% compared with 24% in those with sensitive strains (P=.001), this difference was no longer statistically significant when other predictors of mortality were included (odds ratio, 1.3; P=.32).
      In a recent study of 101 hospitalized patients with pneumococcal pneumonia, penicillin resistance was identified in 49% of isolates. Antibiotic resistance was not associated with longer hospital stay, severity of pneumonia, and other complications.
      • Ewig S
      • Ruiz M
      • Torres A
      • et al.
      Pneumonia acquired in the community through drug-resistant Streptococcus pneumoniae.
      Mortality due to drug-resistant strains was not greatly increased, and discordant antimicrobial treatment was not associated with attributable mortality.
      • Ewig S
      • Ruiz M
      • Torres A
      • et al.
      Pneumonia acquired in the community through drug-resistant Streptococcus pneumoniae.
      Another group of investigators recently evaluated the outcome of 192 adult patients with bacteremic pneumococcal pneumonia.
      • Metlay JP
      • Hofmann J
      • Cetron MS
      • et al.
      Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia.
      The in-hospital mortality due to pneumonia was higher for patients whose pneumococcal isolates were not susceptible to penicillin compared with those patients with susceptible strains of pneumococci (23% vs 11%; relative risk, 2.1). However, after adjustment for difference in severity of illness, there was no increased risk of death associated with infections due to resistant pneumococci. Suppurative complications of pneumonia, however, did occur more frequently with infections due to resistant strains of pneumococci, even after adjustment for severity of illness.
      • Metlay JP
      • Hofmann J
      • Cetron MS
      • et al.
      Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia.
      This potential discrepancy between in vitro sensitivity and clinical outcome in patients with CAP due to penicillin-resistant S pneumoniae is interesting and may depend more on tissue penetration and accumulation of antibiotics in the infected lung than on the antimicrobial levels which can be achieved in serum.
      • Bouza E
      Antibiotic resistance and therapeutic options in lower respiratory tract infections.
      For example, the tissue levels of β-lactam agents may be well above the resistance breakpoints established by the National Committee for Clinical Laboratory Standards.
      • Siegel RE
      The significance of serum vs tissue levels of antibiotics in the treatment of penicillin-resistant Streptococcus pneumoniae and community-acquired pneumonia: are we looking in the wrong place?.
      With macrolides, which exhibit a similar time-dependent killing of bacteria, a similar process has been suggested to explain the discrepancy.
      • Amsden GW
      • Graci DM
      • Cabelus LJ
      • Hejmanowski LG
      A randomized, crossover design study of the pharmacology of extended-spectrum fluoroquinolones for pneumococcal infections.
      The clinical importance of these differences in susceptibility and outcome, however, remains unclear. Thus, the efficacy of β-lactam antibiotics in the treatment of penicillin resistant pneumococci remains controversial, and optimal therapy for serious infections caused by resistant pneumococci has not been clarified. It is quite likely, however, that future studies will be performed with adequate statistical power to detect differences in important clinical outcomes in CAP patients infected with either penicillin-susceptible or penicillin-resistant strains of S pneumoniae.

      THERAPY

      Although the prevalence of antimicrobial resistance in the community is important in choosing antimicrobial therapy, clinicians often do not know the specific etiology of CAP in an individual patient at the time of treatment decisian.
      • Marston BJ
      • Plouffe JF
      • File Jr, TM
      • et al.
      Community-Based Pneumonia Incidence Study Group. Incidence of community-acquired pneumonia requiring hospitalization: results of a population-based active surveillance study in Ohio.
      • Ruiz-Gonzalez A
      • Falguera M
      • Nogues A
      • Rubio-Caballero M
      Is Streptococcus pneumoniae the leading cause of pneumonia of unknown etiology? a microbiologie study of lung aspirates in consecutive patients with community-acquired pneumonia.
      • Rhew DC
      • Riedinger MS
      • Sandhu M
      • Bowers C
      • Greengold N
      • Weingarten SR
      A prospective, multicenler study of a pneumonia practice guideline.
      • Fine MJ
      • Stone RA
      • Singer DE
      • et al.
      Processes and outcomes of care for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team (PORT) cohort study.
      Even when a pathogen is isolated, antibiotic susceptibilities are not usually available for at least several hours. Decisions regarding empirical treatment of CAP are often based on institution-specific clinical practice guidelines, which are usually based on guidelines developed by prominent national organizations.
      • Rhew DC
      • Riedinger MS
      • Sandhu M
      • Bowers C
      • Greengold N
      • Weingarten SR
      A prospective, multicenler study of a pneumonia practice guideline.
      • Bartlett JG
      • Breiman RF
      • Mandell LA
      • File Jr, TM
      • Infectious Diseases Society of America
      Community-acquired pneumonia in adults: guidelines for management.
      • Niederman MS
      • Bass Jr, JB
      • Campbell GD
      • et al.
      American Thoracic Society, Medical Section of the American Lung Association. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy.
      • Heffelfinger JD
      • Dowell SF
      • Jorgensen JH
      • et al.
      Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.
      • Gilbert K
      • Gleason PP
      • Singer DE
      • et al.
      Variations in antimicrobial use and cost in more than 2,000 patients with community-acquired pneumonia.
      In a recent study of 12,945 elderly patients with CAP, 3 empirical antimicrobial regimens (recommended in the 1993 American Thoracic Society CAP guidelines), which included a secondgeneration cephalosporin plus a macrolide, a third-generation cephalosporin plus a macrolide, or a fluoroquinolone alone, were associated with lower 30-day mortality.
      • Gleason PP
      • Meehan TP
      • Fine JM
      • Galusha DH
      • Fine MJ
      Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia.
      Another study revealed that additional microbiological studies did not change the outcome in hospitalized patients initially treated with use of the American Thoracic Society guidelines, suggesting the effectiveness of the guideline-based empirical therapy.
      • Sanyal S
      • Smith PR
      • Saha AC
      • Gupta S
      • Berkowitz L
      • Homel P
      Initial microbiologic studies did not affect outcome in adults hospitalized with community-acquired pneumonia.
      Given the prevalence of resistant pneumococci in patients presenting with CAP, it is important that institutions implement practice guidelines for empirical CAP treatment, taking into consideration treatment effectiveness, future resistance issues, and economic feasibility.
      If pneumococcal disease is confirmed, penicillins remain the mainstay of therapy for infections due to susceptible strains (eg, penicillin G for parenteral use; highdose amoxicillin, 875 mg twice a day, for oral use).
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      • Campbell Jr, GD
      • Silberman R
      Drug-resistant Streptococcus pneu moniae.
      Oral β-lactam antibiotics may be adequate for mild to moderate infections caused by susceptible strains.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      Of the oral penicillins, amoxicillin is the most active agent against S pneumoniae; the addition of clavulanate to amoxicillin does not improve the activity.
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      Of the extended-spectrum penicillins, piperacillin is most active against S pneu moniae
      • Appelbaum PC
      Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae.
      Among the cephalosporin antibiotics, cefuroxime axetil and cefpodoxime have excellent intrinsic activity against susceptible S pneumoniae (similar to amoxicillin).
      • Doern GV
      • Brueggemann A
      • Holley Jr, HP
      • Rauch AM
      Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
      Thus, oral penicillins or cephalosporins may be adequate for mild infections caused by strains that have high or intermediate penicillin susceptibility, but these agents cannot be considered reliable for more serious infections.
      Optimal therapy for serious pneumococcal infections caused by pneumococci that are penicillin-resistant or have only intermediate susceptibility is controversial.
      • Doern GV
      • Brueggemann A
      • Holley Jr, HP
      • Rauch AM
      Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
      • Kaplan SL
      • Mason Jr, EO
      Management of infections due to antibiotic-resistant Streptococcus pneumoniae.
      • Campbell Jr, GD
      • Silberman R
      Drug-resistant Streptococcus pneu moniae.
      Although controlled therapeutic trials have not been done, favorable responses have been cited with cefotaxime or ceftriaxone for pneumococcal bacteremia or pneumonia, even for strains that are penicillin-resistant or have only intermediate susceptibility.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Pallares R
      • Gudiol F
      • Liñares J
      • et al.
      Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.
      • Kaplan SL
      • Mason Jr, EO
      Management of infections due to antibiotic-resistant Streptococcus pneumoniae.
      • Campbell Jr, GD
      • Silberman R
      Drug-resistant Streptococcus pneu moniae.
      • Heffelfinger JD
      • Dowell SF
      • Jorgensen JH
      • et al.
      Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.
      Interestingly, favorable responses have also been noted with high-dose penicillin, even in bacteremic pneumonia caused by pneumococci that are penicillin-resistant or have only intermediate susceptibility.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Pallares R
      • Gudiol F
      • Liñares J
      • et al.
      Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci.
      • Kaplan SL
      • Mason Jr, EO
      Management of infections due to antibiotic-resistant Streptococcus pneumoniae.
      • Campbell Jr, GD
      • Silberman R
      Drug-resistant Streptococcus pneu moniae.
      • Heffelfinger JD
      • Dowell SF
      • Jorgensen JH
      • et al.
      Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.
      It should be emphasized that data regarding the efficacy of penicillins or cephalosporins for penicillin-resistant strains are limited, and additional data are required to clarify optimal therapy in this context.
      Macrolide antibiotics are effective for treatment of CAP caused by susceptible strains of pneumococci. Clarithromycin has more activity than either erythromycin or azithromycin against pneumococci in vitro.
      • Doern GV
      • Brueggemann AB
      • Huynh H
      • Wingert E
      Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997-98.
      • Edniel M
      • Visalli MA
      • Jacobs MR
      • Appelbaum PC
      Comparative activities of clariehromycin, crythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci.
      However, resistance to all macrolides, based on current National Committee for Clinical Laboratory Standards breakpoints, should be assumed among isolates displaying erythromycin resistance. The high prevalence of macrolide resistance in some areas raises concern for the use of macrolides for empirical treatment of serious pneumococcal infections.
      • Rahav G
      • Toledano Y
      • Engelhard D
      • et al.
      Invasive pneumococcal infections: a comparison between adults and children.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
      • Bernaldo de Quiros JC
      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      • Doern GV
      • Brueggemann A
      • Holley Jr, HP
      • Rauch AM
      Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
      • Syrogiannopoulos GA
      • Grivea IN
      • Beratis NG
      • et al.
      Resistance patterns of Streptococcus pneumoniae from carriers attending daycare centers in southwestern Greece.
      • Heffelfinger JD
      • Dowell SF
      • Jorgensen JH
      • et al.
      Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.
      The newer fluoroquinolones (eg, levofloxacin, gatifloxacin, moxifloxacin) may have a role for infections due to penicillin- or macrolide-resistant pneumococci.
      • Thomson KS
      • Chartrand SA
      • Sanders CC
      • Block L, S
      In-vitro activity of levofloxacin against Streptococcus pneumoniae with various levels of penicillin resistance.
      • Turnidge J
      Pharmacokinetics and pharmacodynamics of fluoro-quinolones.
      • Plouffe JF
      • Franklin County Pneumonia Study Group
      Levoflox-acin in vitro activity against bacteremic isolates of Streptococcus pneumoniae.
      • Nightingale CH
      Moxifloxacin, a new antibiotic designed to treat community-acquired respiratory tract infections: a review of microbiologic and pharmacokinetic-pharmacodynamic characteristics.
      Quinolone susceptibilities are generally not affected by susceptibility or resistance to penicillin.
      • Thomson KS
      • Chartrand SA
      • Sanders CC
      • Block L, S
      In-vitro activity of levofloxacin against Streptococcus pneumoniae with various levels of penicillin resistance.
      • Plouffe JF
      • Franklin County Pneumonia Study Group
      Levoflox-acin in vitro activity against bacteremic isolates of Streptococcus pneumoniae.
      • Liljequist BO
      • Hoffman BM
      • Hedlund J
      Activity of trovafloxacin against blood isolates of Streptococcus pneumoniae in Sweden.
      Fluoroquinolone monotherapy for patients with CAP has been associated with high cure rates (>90%), even when S pneumoniae was thought to be the causative agent.
      • Ortqvist A
      • Valtonen M
      • Cars O
      • Wahl M
      • Saikku P
      • Jean C
      • Scandinavian Sparfloxacin Study Group
      Oral empiric treatment of community-acquired pneumonia: a multicenter, double-blind, randomized study comparing sparfloxacin with roxilhromycin.
      • Plouffe JF
      • Franklin County Pneumonia Study Group
      Levoflox-acin in vitro activity against bacteremic isolates of Streptococcus pneumoniae.
      • File Jr, TM
      • Segreli J
      • Dunbar L
      • et al.
      A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroximc axctil in treatment nf adults with community-acquired pneumonia.
      Enthusiasm for fluoroquinolones should be tempered, however, by the potential for evolution of antimicrobial resistance.
      • Chen DK
      • McGeer A
      • de Azavedo JC
      • Low DE
      • Canadian Bacterial Surveillance Network
      Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada.
      For highly resistant pneumococci, vancomycin may be used for treatment of pneumonia, as all strains of pneumococci (both penicillin-susceptible and penicillin-resistant) remain susceptible to vancomycin.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Pallares R
      • Liñares J
      • Vadillo M
      • et al.
      Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
      • Bernaldo de Quiros JC
      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      • Butler JC
      • Hofmann J
      • Cetron MS
      • Elliott JA
      • Facklam RR
      • Breiman RF
      The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
      • Doern GV
      • Brueggemann A
      • Holley Jr, HP
      • Rauch AM
      Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
      However, given the concern for the development and spread of vancomycin resistance in pneumococci and other gram-positive cocci, this antibiotic must be used cautiously.
      • Gold HS
      • Moellering Jr, RC
      Antimicrobial-drug resistance.
      • Novak R
      • Henriques B
      • Charpentier E
      • Normark S
      • Tuomanen E
      Emergence of vancomycin tolerance in Streptococcus pneumoniae.
      • McCullers JA
      • English BK
      • Novak R
      Isolation and characterization of vancomycin-tolerant Streptococcus pneumoniae from the cerebrospinal fluid of a patient who developed recrudescent meningitis.
      • Jones RN
      • Pfaller MA
      • Doem GV
      • Erwin ME
      • Hollis RJ
      • Cefepime Study Group
      Antimicrobial activity and spectrum investigation of eight broad-spectrum β-lactam drugs: a 1997 surveillance trial in 102 medical centers in the United States.
      The newly released oxazolidinone linezolid has good in vitro activity against those strains both susceptible and not susceptible to it and may have a use in the treatment of S pneumoniae caused by resistant strains.
      • Clemett D
      • Markham A
      Linezolid.
      Carbapenems, both imipenem-cilastatin and meropenem, are highly active against both penicillin-susceptible and penicillin-resistant strains.
      • Hofmann J
      • Cetron MS
      • Farley MM
      • et al.
      The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
      • Jones RN
      • Low DE
      • Pfaller MA
      Epidemiologie trends in nosocomial and community-acquired infections due to antibiotic-resistant gram-positive bacteria: the role of streptogramins and other newer compounds.
      • Moreno S
      • Garcia-Leoni ME
      • Cercenado E
      • Diaz MD
      • Bernaldo de Quiros JC
      • Bouza E
      Infections caused by erythromycin-resistanl Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study.
      • Jones RN
      • Pfaller MA
      • Doem GV
      • Erwin ME
      • Hollis RJ
      • Cefepime Study Group
      Antimicrobial activity and spectrum investigation of eight broad-spectrum β-lactam drugs: a 1997 surveillance trial in 102 medical centers in the United States.
      Meropenem has been approved for treatment of bacterial meningitis. Clinical studies of these agents to treat serious pneumococcal infections are limited. Given their broad spectrum of antibacterial activity and increased incremental costs compared with other potential agents, studies rigorously evaluating their use for appropriate empirical treatment of CAP are needed.

      SUMMARY AND CONCLUSIONS

      Streptococcus pneumoniae resistance to available antimicrobial agents is an important clinical problem, the magnitude of which is projected to worsen. The most common resistance is that to penicillin, with prevalence rates reaching 45% in some geographical areas. Maybe more worrisome than the penicillin experience are the emerging resistance patterns of this organism to several other previously effective antimicrobial classes. Decelerating the rate of antibiotic resistance is particularly problematic because of the fact that development of future resistance correlates substantially with current antibiotic use. Thus, a clear tradeoff is recognized between choosing an effective therapy now and the resultant pressure for future resistance as broad-spectrum agents are more frequently used empirically for patients with CAP. At present, no method to stop this vicious cycle has emerged. However, an evidence-based approach can minimize the tension between optimizing care for an individual patient today and ensuring effective therapy for future patients with S pneumoniae infection. Increasing the appropriate use of antibiotics is essential for success. For those patients with indications for antibiotic therapy, practice guidelines should be implemented that take into account both patient characteristics and local resistance patterns. Further studies that include clinical effectiveness, future resistance patterns, and economic impact to define the optimal treatment of CAP due to S pneumoniae are warranted.

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