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Penicillins for Treatment of Pneumococcal Pneumonia: Does In Vitro Resistance Really Matter?

  1. Lance R. Peterson
  1. Evanston Northwestern Healthcare Research Institute, Evanston Northwestern Healthcare, Department of Pathology and Laboratory Medicine, Division of Microbiology, and Department of Medicine, Division of Infectious Diseases, Northwestern University, Evanston, Illinois
  1. Reprints or correspondence: Dr. Lance R. Peterson, Clinical Microbiology Laboratory, Evanston Northwestern Healthcare, 2650 Ridge Ave., Evanston, IL 60201 (lancer{at}northwestern.edu).
 
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Abstract

Background. The rate of in vitro bacterial resistance to antimicrobial agents is escalating among pathogens that cause the most serious respiratory tract infections. Many reports published during the past few years suggest that this has direct clinical implications. In particular, resistance of Streptococcus pneumoniae to β-lactam antibiotic therapy has assumed a prominent role in the evolution of guidelines for the initial treatment of respiratory tract infection.

Methods. I conducted a critical review of the published medical literature.

Results. There is only a single report of documented microbiologic failure of parenteral penicillin-class antibiotics in the treatment of pneumococcal pneumonia in patients with or without bacteremia, whereas there are numerous well-documented reports of treatment failure with quinolone-class (n ⩾ 21) and macrolide-class (n ⩾ 33) antibiotics in the treatment of pneumococcal pneumonia.

Conclusion. The recommended optimal in-hospital therapy for community-acquired pneumonia should continue to be a β-lactam antibiotic (penicillin, aminopenicillin, cefotaxime, or ceftriaxone) administered with a macrolide or a fluoroquinolone agent for adjunctive treatment of infection with potential atypical pathogens.

Respiratory tract infections caused nearly 125 million adults to visit physicians' offices in the United States during 1997 [1]. Among these infections, Streptococcus pneumoniae caused ∼7 million cases of otitis media, 500,000 cases of pneumonia, 3000 cases of meningitis, and ∼50,000 deaths each year [2]. It is the most frequently detected pathogen responsible for community-acquired pneumonia (CAP), with an overall mortality rate of ∼12% [3, 4]. A meta-analysis of 7000 cases of CAP found that S. pneumoniae was the causative agent in 66% of patients for which a pathogen could be identified and was responsible for nearly two-thirds of all deaths [3]. Other pathogens are associated with CAP, but they do not appear to result in the same degree of illness; thus, proper initial treatment of pneumococcal infection is paramount.

Alexander Fleming and Howard Florey recognized the tremendous ability of bacteria to adapt and survive [5] and wrote about the need for rapid, lethal therapy. To understand the microbial capacity for adaptive survival, one only needs to realize that microbial fossils have been found that date back 3.8 billion years, in earth's 4.5 billion—year history. In contrast, metazoan embryogenesis has existed for 500 million years [6], and we humans, as evidenced by the emergence of our Y chromosome, only have been residents here for ∼50,000–150,000 years [7]. Therefore, it is no surprise that bacteria can adapt in a myriad of exquisite ways, underscoring the need for us to carefully consider our therapeutic decisions regarding which antimicrobial agents to use for treatment of common, serious infections.

The purpose of this commentary is to help improve our understanding of the clinical implications regarding increasing resistance in pneumococci to the earliest and perhaps best of our antibiotics that are used to treat infection due to this key pathogen, and to suggest options for choosing antimicrobial agents in the therapy of hospitalized patients with CAP.

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Emerging in Vitro Resistance

Microbial resistance to therapeutic agents can be either intrinsic or acquired. For pneumococcus, the latter pathway is primarily taken, with the key factor being the use of antimicrobial agents in both the hospital and the community [8]. Unfortunately, surveillance of resistance in pneumococcus has been sporadic. During the early 1980s, this was performed by the Centers for Disease Control and Prevention, and no in vitro resistance against penicillin was detected [9]. Thus, in the late 1980s, surveillance became a low priority and was discontinued. When surveillance resumed in 1992, a full 1% of invasive isolates appeared to be no longer susceptible to penicillin, and the rate of antibiotic resistance has steadily increased since then [9], leading to questions regarding antipneumococcal therapy.

Subsequently, several multicenter surveillance projects were conducted, according to pneumococcal in vitro susceptibility patterns, to determine the percentages of organisms exhibiting resistance [10–12]. All findings reveal continually increasing levels of penicillin resistance in S. pneumoniae. By 2000, rates of high-level enicillin resistance ranged from 5.2% to 56.1%, with other antibiotics faring equally poorly [13]. Compounding the problem was the observation that in vitro macrolide resistance rates ranged from 6.1% to 53.7%, in vitro tetracycline resistance rates ranged from 7.3% to 50%, and in vitro trimethoprim-sulfamethoxazole resistance rates ranged from 13.5% to 50%, with 22.4% of strains being no longer susceptible to multiple classes of antibiotics [13].

Now, the occurrence of multidrug-resistant pneumococci has been documented worldwide, from Asia, where the rate of susceptibility to penicillin is as low as 20.3% [14, 15], to Canada, where the rate of susceptibility to penicillin decreased to 86.4% by 1998 [16]. Findings of longitudinal surveillance studies have demonstrated that the rate of macrolide resistance has increased rapidly, doubling from 16% to 32% between 1994 and 1999 [17], with 68% to 81% of strains tested in Hong Kong having become resistant to erythromycin by the year 2000 [18, 19]. A critical factor not to be overlooked is that in vitro resistance to penicillin and macrolides tends to occur in the same organism [13, 20]. A report from the Centers for Disease Control and Prevention that evaluated 4013 invasive strains of S. pneumoniae found that only 63% of isolates tested in 1998 were still fully susceptible to penicillin and that 15% of isolates were not susceptible to cefotaxime, 16% were not susceptible to meropenem, 16% were not susceptible to erythromycin, and 29% were not susceptible to trimethoprim-sulfamethoxazole [21]. During the period 1995–1998, the prevalence of isolates resistant to ⩾3 drug classes increased from 9% to 14%, suggesting that some cases of pneumonia may be very difficult to treat with standard therapy.

In response to this problem, Austin et al. commented that “Given the observed decline in the rate of development of novel antibiotics [see table 1], in the future more attention must be given to the development of prescribing policies designed to maximize the life expectancy of a given compound” [22, p. 1156]. A key element, which is the focus of this review, is discordant therapy with penicillins, for which there is little reported evidence of an increased rate of treatment failure in patients with penicillin-resistant pneumococcal pneumonia.

Table 1
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Table 1

New antibacterial agents approved in the United States since 1991.

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Clinical Implications of Antibiotic Resistance

Lower respiratory tract infections remain the only communicable illness among the top 10 causes of death in the United States [23]. S. pneumoniae, the most important cause of CAP and meningitis, is resurgent in the form of bacteremic pneumonia [24]. Not only is this pathogen infecting diverse, compromised populations, but its increasing resistance to penicillin is also reported to be associated with an increase in mortality rates [4, 25–27]. Importantly, during the 1930s, the case-fatality rate for pneumococcal pneumonia was 30%–35%, and after the introduction of penicillin, the rate had decreased to 5%–8% [23]. People with bacteremia fared worse, with a mortality rate that approached 85% at 3 weeks after onset, before a specific treatment was introduced, and that decreased to 50% among persons who received serum therapy and to 15% after penicillin became available [28, 29].

How we interpret and apply the information regarding emerging in vitro resistance will be crucial to our evolving use of antimicrobial agents. Virk and Steckelberg began their review of the clinical importance of resistance with the statement, “Antimicrobial resistance is a serious emerging global problem that physicians and patients have to contend with on an almost daily basis” [30, p. 200]. A key to the selection of optimal therapy is knowing how to translate findings of laboratory detection of resistance into an effect on clinical outcome. Although it is clear that S. pneumoniae is gaining resistance to the in vitro action of several antimicrobial agents, questions remain regarding the clinical impact of this “laboratory” phenomenon and the relevant level of resistance to specific β-lactams.

The publication with the most convincing evidence of an increased mortality rate associated with reduced susceptibility to penicillin is from the period after 1995, when the rate of resistance to penicillin has been observed to escalate most dramatically [4]. However, Feikin et al. [4] point out that if severity of illness factors such as age and underlying disease were controlled for, then the overall increased mortality rate would not be associated with penicillin resistance. They also comment that because no treatment data were available and because penicillin-resistant pneumococci are often multidrug-resistant, the small number of cases with poor outcome observed after 4 days were likely caused by more factors than only penicillin or cefotaxime treatment failure [4]. Table 2 summarizes published reports that correlate in vitro (β-lactam) susceptibility of S. pneumoniae with therapeutic outcome. In these reports, several striking observations are made. First, many of the studies that assess outcome of infection with penicillin-resistant pneumococci do not correlate specific therapies with success or failure. Second, prospective trials have been unable to associate discordant penicillin treatment with an adverse outcome. And third, there is only a single case reported in which clinical and microbiologic treatment failure of pneumococcal pneumonia is associated with the use of an (amino) penicillin in a patient infected with a drug-resistant strain [37]. This occurred in a patient who developed an empyema on day 5 of treatment with 2000 mg of amoxicillin and 200 mg of clavulanate administered every 8 h, and the recovered strain of S. pneumoniae had the same in vitro susceptibility (MIC, 8 µg/mL) as that of the initial infecting isolate [37].

Table 2
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Table 2

Summary of reports relating treatment failure of pneumonia with in vitro β-lactam—resistant Streptococcus pneumoniae.

The published reports that correlate in vitro resistance with bacteriologic treatment failure with the β-lactam class of compounds describe failures in the treatment of pneumococcal pneumonia with ceftazidime, cefazolin, cefuroxime, and cefamandole [25, 45–49]. The single report implicating treatment failure with cefotaxime involved a patient with an (undrained) empyema [50], for which antibiotic treatment failure should have been the expected result. Another report links the failure of oral therapy and in vitro susceptibility with the development of bacteremic pneumococcal pneumonia (table 2). These authors concluded that clarithromycin resistance was clinically important and lead to therapeutic failures, whereas nonresponse to treatment with amoxicillin/clavulanate was most likely related to a suboptimal dosage of the antibiotic [31]. Gonzales et al. [34] came to a similar conclusion while studying azithromycin and β-lactam treatment failures (table 2). Thus, although there is anecdotal evidence suggesting that resistance to β-lactam causes failure in the treatment of respiratory tract infection due to S. pneumoniae, documentation of penicillin treatment failure, particularly with aminopenicillins administered at adequate dosages (e.g., parenterally), remains virtually nonexistent.

There are a limited number of published observations regarding the use of β-lactam (aminopenicillin)/β-lactamase inhibitor combinations for the treatment of severe CAP (i.e., that which requires hospitalization), and many do not specifically address the issue of discordant therapy. However, the information available indicates that drugs with an aminopenicillin component are highly useful in treating pneumonia. Although most practitioners do not consider β-lactamase inhibitor compounds to be particularly beneficial against non–β-lactamase-producing organisms, such as pneumococcus, experimental evidence has shown that these agents enhance intracellular killing of pneumococcus [51] and in vivo bactericidal action against β-lactamase—negative Staphylococcus aureus [52, 53]. Therefore, their usefulness in treating pneumonia is not surprising. One small study of 75 patients compared treatment with 1–2 mg of ampicillin plus 500–1000 mg of sulbactam every 6 h and treatment with 1–2 g of cefamandole every 6 h [49]. Seven patients presented with pneumococcal pneumonia, and although all patients achieved clinical and microbiological cure on receipt of ampicillin/sulbactam therapy, there was 1 episode of clinical treatment failure involving a patient with S. pneumoniae infection in the cefamandole arm of this prospective trial [49]. Four additional reports describe 110 treated patients infected with S. pneumoniae, 97 of whom were treated with piperacillin/tazobactam (dosage, 4 g of piperacillin plus 500 mg of tazobactam every 8 h or 3 g of piperacillin plus 375 mg of tazobactam every 6 h) and 13 of whom were treated with parenteral amoxicillin/clavulanate (dosage, 2 g of amoxicillin plus 200 mg of clavulanate every 8 h). No patients experienced clinical or bacteriologic treatment failure (1 patient was documented as being infected with a strain that was nonsusceptible to piperacillin), including at least 19 patients with bacteremia [54–57]. Only 1 person died within 30 days after completion of therapy: an 84-year-old man who was dying of cardiorespiratory collapse that occurred 6 days after completion of therapy with piperacillin/tazobactam [57]. The success of this treatment was not unexpected, because piperacillin/tazobactam has antipneumococcal activity within a 2-fold dilution of amoxicillin and is administered at a much higher dose [58]. Additional trials of these agents, in which resistance was assessed, are included in table 2. Altogether, the available information indicates that at least the newer β-lactam/β-lactamase inhibitor combinations are highly effective in the treatment of hospitalized patients with pneumococcal pneumonia.

The mechanisms of macrolide resistance in S. pneumoniae include the following: target-site modification encoded by erythromycin ribosome methylation genes that provide resistance to all macrolides, lincosamides, and streptogramin B (MLSB); active efflux encoded by macrolide efflux genes that causes in vitro resistance to 14- and 15-member ring macrolides; and other, uncommon ribosomal mutation(s) in the 23S rRNA gene for ribosomal protein L4 or L22. MLSB—type-resistance leads to the highest level of resistance and is considered to be most clinically relevant. Importantly, demonstrating the clinical impact of in vitro macrolide resistance has been easier to document. Initially, treatment failure was only described in a single case report [59]. More recently, Lonks et al. [60] reviewed medical records of 76 patients with macrolide-resistant pneumococci in their bloodstream. They found that 18 patients had received treatment with a macrolide and had developed bacteremia after 3–5 days of therapy. Occurrence of treatment failure was evenly divided among patients who received older and newer macrolides and patients infected with pneumococcal strains with resistance based on either drug efflux or target mutation [60]. In 2004, Rzeszutek et al. [61] reviewed 33 published case reports of macrolide treatment failure, 89% of which involved CAP. In the 19 cases for which it was assessed, most (63%) of the reports associated treatment failure with a pneumococcal strain that demonstrated the MLSB phenotype [61]. Thus, the published data make a strong case that in vitro detection of macrolide resistance is relevant.

The problem of clinical treatment failure with fluoroquinolone antimicrobial agents was recently reviewed by Low [62]. Although the reports that document microbiologic treatment failure of this class of drugs are a series of retrospective case reports [63–69], the documented evidence of clinical and microbiologic treatment failure with quinolone antimicrobial agents in the treatment of at least 21 patients infected with pneumococcus is also clear and substantial.

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Current Options for Managing Emerging Resistance

New agent development. One way to manage the development of antimicrobial agent resistance is the development of new, potent drugs with novel antibacterial targets. As can be seen in table 1, this strategy has not been very successful in the past 15 years. Therefore, for the immediate future, we cannot assume that a new class (or classes) of compounds or even novel new drugs in an established class can alone solve the problem of emerging resistance.

Diagnosis as a critical element. Prescription of broad-spectrum therapy in excess of that which is needed is a prevalent and continuing problem for the management of respiratory tract infection in the community. Steinman et al. [70] found that 46% of patients with symptoms of cold (or other nonspecific complaints) received antimicrobial therapy on visiting their physician, and that 51% of patients who were prescribed an antibiotic received a broad-spectrum agent.

To minimize unnecessary prescribing of antimicrobial compounds, an accurate diagnosis of respiratory symptomatology is crucial [71]. Gram staining of properly collected sputum specimens was recently reassessed [72]. Although sensitivity for the detection of pneumococci and Haemophilusspecies was modest (57% and 82%, respectively), the specificity was high (97% and 99%, respectively), making specific therapy possible if the typical organism was observed on a Gram stain [72]. The Infectious Diseases Society of America's guidelines for the treatment of CAP [73] endorse the use of this simple, rapid test, combined with the use of culture, for patients who require hospitalization. Novel use of a new, commercially available urine test for the detection of pneumococcal antigen was reported by Guchev et al. [74] as a means to target treatment of CAP. However, they found that detection was only successful for 48 (63%) of 76 patients with pneumococcal pneumonia, once again indicating that this test should be used to augment standard diagnostic testing [73, 74]. Rapid testing for influenza virus is available as well, but it also has low sensitivity, as noted in the evaluation by Cazacu et al. [75], who found its sensitivity to be <45% during the 2002–2003 influenza season. Expanded use of even basic laboratory testing can be a step in the right direction while we await a future in which enhanced diagnostics may improve therapeutics [76].

Treatment options. With the increasing complexity of health care, there are no easy answers to the selection of treatment options. One must begin with an understanding of resistance in important pathogens in the community and of what the in vitro detection of resistance means in relation to clinical response. Many treatment guidelines appear to have evolved largely on the basis of trends of diminishing in vitro activity of penicillin. An example of this trend is shown in table 3, in which frequent updates of the Medical Letter Guide [77–84] demonstrate how changes have occurred in response to in vitro development of resistance. Current recommendations for the prescription of a β-lactam combined with a macrolide or a newer respiratory fluoroquinolone (gatifloxacin or moxifloxacin) are reasonable for ambulatory patients with documented cases of pneumonia. However, on the basis of the clinical efficacy of selected β-lactam antibiotics, it appears that choosing 1 of these compounds (table 4) combined with another agent active against atypical pathogens is still considered to be optimal treatment for hospitalized patients with pneumonia. This recommendation is supported by the recent report by Baddour et al. [85], who observed a 3-fold reduction in mortality when critically ill patients with pneumococcal bacteremia received combination therapy, most often a β-lactam combined with a macrolide. Importantly, the impact on mortality was most pronounced when a second agent was added to β-lactam treatment [85]. On the basis of my review, the choice of the β-lactam should be limited to penicillin, an aminopenicillin, ceftriaxone, or cefotaxime. Nuermberger and Bishai [87] have recently reviewed the kinetics of orally administered agents for the treatment of pneumococcal pneumonia; table 4 contains a similar review of the parenteral β-lactam agents available for this infection, with correlations of dose that provide for the antimicrobial drug concentration in the blood to be above the MIC for ⩾50% of the dosing interval, where clinical success should be expected. The specific agent selected for initial therapy is dependent on which other microbial etiologies are suspected as the cause of pneumonia. It should be remembered that abscess collections, such as empyema, must be drained. Also, if endocarditis, meningitis, or other disseminated infections are suspected, use of ceftriaxone and/or inclusion of vancomycin as an additional agent should be considered whenever penicillin-resistant pneumococci are prevalent, until bacterial identification and susceptibility testing are complete.

Table 3
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Table 3

Summary of evolving recommendations for the therapy of pneumonia by The Medical Letter.

Table 4
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Table 4

Suitable β-lactam agents for the treatment of hospitalized patients with pneumonia when Streptococcus pneumonia infection is part of the differential diagnosis.

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Conclusion

A recent review by Dagan et al. [88] emphasized the mounting clinical evidence that supports the need for bacterial eradication as part of treatment of respiratory tract infection. They conclude that “The aim of antimicrobial therapy in respiratory tract infections should be the eradication of the infecting organism” [88, p. 129]. In the case of pneumococcus, it appears that penicillins are still most capable of accomplishing this goal, clinically outperforming both macrolides and quinolones in the treatment of pneumococcal pneumonia.

The era of antibiotics has now matured for >60 years. However, we still have much to learn about how to use them effectively to preserve this precious resource that has served us so well. We need to fully comprehend our microbial adversaries' capacity for survival when they invade to cause infection. The emergence of significant resistance in many pathogenic bacterial species does have direct, serious, clinical, and economic implications that must be effectively dealt with as we plan for future management of infectious diseases.

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Acknowledgments

I thank Kyle D. Gadbois and Glenn S. Tillotson for their critique of portions of this article.

Financial support. Evanston Northwestern Healthcare.

Potential conflicts of interest. L.R.P.: no conflicts.

  • Received August 12, 2004.
  • Revision received August 2, 2005.
  • Accepted December 13, 2005.
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References

  1. ↵
    1. Weis MS
    . Proceedings of the Ochsner Clinic Symposium. 2000. The impact of antimicrobial resistance on the primary care physician: resistance and the use and misuse of antimicrobial therapy; p. 29-35.
  2. ↵
    1. Centers for Disease Control and Prevention
    . Defining the public health impact of the drug-resistant Streptococcus pneumoniae: report of a working group. MMWR Morbid Mortal Weekly Rep 1996;45(RR-1):1-21.
    Medline
  3. ↵
    1. Fine MJ,
    2. Smith MA,
    3. Carson CA,
    4. et al
    . Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996;275:134-41.
    Abstract/FREE Full Text
  4. ↵
    1. Feikin DR,
    2. Schuchat A,
    3. Kolczak M,
    4. et al
    . Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995–1997. Am J Public Health 2000;90:223-9.
    Abstract/FREE Full Text
  5. ↵
    1. Moberg CL
    . Rene Dubos: a harbinger of microbial resistance to antibiotics. Microb Drug Resist 1996;2:287-97.
    MedlineWeb of Science
  6. ↵
    1. Saier MH Jr
    . Bacterial diversity and the evolution of differentiation. ASM News 2000;66:337-43.
    Web of Science
  7. ↵
    1. Cavalli-Sforza LL
    . The DNA revolution in population genetics. TIG 1998;14:60-5.
    CrossRefMedline
  8. ↵
    1. Tenover FC,
    2. McGowan JE Jr
    . Reasons for the emergence of antibiotic resistance. Am J Med Sci 1996;311:9-16.
    CrossRefMedlineWeb of Science
  9. ↵
    1. Butler JC,
    2. Hoffman J,
    3. Centron MS,
    4. Elliott JA,
    5. Facklam RR,
    6. 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. J Infect Dis 1996;174:986-93.
    Abstract/FREE Full Text
  10. ↵
    1. Butler DL,
    2. Gagnon RC,
    3. Miller LA,
    4. Poupard JA,
    5. Felmingham D,
    6. Grüneberg RN
    . Differences between the activity of penicillin, amoxicillin, and co-amoxyclav against 5,252 Streptococcus pneumoniae isolates tested in the Alexander Project, 1992–1996. J Antimicrob Chemother 1999;43:777-82.
    Abstract/FREE Full Text
    1. Chen DK,
    2. McGeer A,
    3. de Azavedo JC,
    4. Low DE
    . Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med 1999;341:233-9.
    CrossRefMedlineWeb of Science
  12. ↵
    1. Doern GV,
    2. Pfaller MA,
    3. Kugler K,
    4. Freeman J,
    5. Jones RN
    . Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY Antimicrobial Surveillance Program. Clin Infect Dis 1998;27:764-70.
    Abstract/FREE Full Text
  13. ↵
    1. Doern GV,
    2. Heilmann KP,
    3. Huynh HK,
    4. Rhomberg PR,
    5. Coffman SL,
    6. Brueggemann AB
    . Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999–2000, including a comparison of resistance rates since 1994–1995. Antimicrob Agents Chemother 2001;45:1721-9.
    Abstract/FREE Full Text
  14. ↵
    1. J.-Song H,
    2. Lee NY,
    3. Ichiyama S,
    4. et al
    . Spread of drug-resistant Streptococcus pneumoniae in Asian countries: Asian network for surveillance of resistant pathogens (ANSORP) study. ANSORP Study Group. Clin Infect Dis 1999;28:1206-11.
    Abstract/FREE Full Text
  15. ↵
    1. Ho P-L,
    2. Que T-L,
    3. Tsang DN-C,
    4. Ng T-K,
    5. Chow K-H,
    6. Seto W-H
    . Emergence of fluoroquinolone resistance among multiple resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1999;43:1310-3.
    Abstract/FREE Full Text
  16. ↵
    1. Jetté LP,
    2. Delage G,
    3. Ringuette L,
    4. et al
    . Surveillance of invasive Streptococcus pneumoniae infection in the province of Quebec, Canada, from 1996 to 1998: serotype distribution, antimicrobial susceptibility, and clinical characteristics. Pneumococcus Study Group. J Clin Microbiol 2001;39:733-7.
    Abstract/FREE Full Text
  17. ↵
    1. Gay K,
    2. Baughman W,
    3. Miller Y,
    4. et al
    . The emergence of Streptococcus pneumoniae resistant to macrolide antimicrobial agents: a 6-year population-based assessment. J Infect Dis 2000;182:1417-24.
    Abstract/FREE Full Text
  18. ↵
    1. Ho PL,
    2. Yung RW,
    3. Tsang DN,
    4. et al
    . Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicentre study in 2000. J Antimicrob Chemother 2001;48:659-65.
    Abstract/FREE Full Text
  19. ↵
    1. The Alexander Network
    . Microbiologists' forum: resistance today (slide series). 2001. Available at: http://www.alexander-network.com/. Accessed on 29 April 2003.
  20. ↵
    1. Doern GV,
    2. Brueggemann A,
    3. Holley HP Jr,
    4. 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. Antimicrob Agents Chemother 1996;40:1208-13.
    Abstract/FREE Full Text
  21. ↵
    1. Whitney CG,
    2. Farley MM,
    3. Hadler J,
    4. et al
    . Increasing prevalence in the United States of multidrug-resistant Streptococcus pneumoniae. N Engl J Med 2000;343:1917-24.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Austin DJ,
    2. Kristonsson KG,
    3. Anderson RM
    . The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Natl Acad Sci 1999;96:1152-6.
    Abstract/FREE Full Text
  23. ↵
    1. Wenzel RP,
    2. Edmond MB
    . Managing antibiotic resistance. N Engl J Med 2000;343:1961-3.
    CrossRefMedlineWeb of Science
  24. ↵
    1. Mufson MA,
    2. Stanek RJ
    . Bacteremic pneumococcal pneumonia in one American city: a 20-year longitudinal study, 1978–1997. Am J Med 1999;107:34-43.
  25. ↵
    1. Carratalà J,
    2. Marron A,
    3. Fernández-Sevilla A,
    4. Liñares J,
    5. Gudiol F
    . Treatment of penicillin-resistant pneumococcal bacteremia in neutropenic patients with cancer. Clin Infect Dis 1997;24:148-52.
    Abstract/FREE Full Text
    1. Turett GS,
    2. Blum S,
    3. Fazel BA,
    4. Justman JE,
    5. Telzak EE
    . Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high human immunodeficiency virus seroprevalence. Clin Infect Dis 1999;29:321-7.
    MedlineWeb of Science
  27. ↵
    1. Metlay JP,
    2. Hofmann J,
    3. Cetron MS,
    4. et al
    . Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2000;30:520-8.
    Abstract/FREE Full Text
  28. ↵
    1. Austrian R,
    2. Gold E
    . Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964;60:759-76.
    Abstract/FREE Full Text
  29. ↵
    1. Metlay JP,
    2. Singer DE
    . Outcomes in lower respiratory tract infections and the impact of antimicrobial drug resistance. Clin Microbiol Infect 2002;8(Suppl 2):1-11.
  30. ↵
    1. Virk A,
    2. Steckelberg JM
    . Clinical aspects of antimicrobial resistance. Mayo Clin Proc 2000;75:200-14.
    Abstract/FREE Full Text
  31. ↵
    1. Van Kerkhoven D,
    2. Peetermans WE,
    3. Verbist L,
    4. Verhaegen J
    . Breakthrough pneumococcal bacteremia in patients treated with clarithromycin or oral beta-lactams. J Antimicrob Chemother 2003;51:691-6.
    Abstract/FREE Full Text
    1. Pallares R,
    2. Linares J,
    3. Vadillo M,
    4. et al
    . Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995;333:474-80.
    CrossRefMedlineWeb of Science
    1. Yu VL,
    2. Chiou CC,
    3. Feldman C,
    4. et al
    . An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. International Pneumococcal Study Group. Clin Infect Dis 2003;37:230-7.
    Abstract/FREE Full Text
  34. ↵
    1. Gonzalez BE,
    2. Martinez-Aguilar G,
    3. Mason EO Jr,
    4. Kaplan SL
    . Azithromycin compared with beta-lactam antibiotic treatment failures in pneumococcal infections of children. Pediatr Infect Dis J 2004;23:399-405.
    CrossRefMedlineWeb of Science
    1. Rosón B,
    2. Carratalà J,
    3. Tubau F,
    4. et al
    . Usefulness of beta-lactam therapy for community-acquired pneumonia in the era of drug-resistant Streptococcus pneumoniae: a randomized study of amoxicillin-clavulanate and ceftriaxone. Microb Drug Resist 2001;7:85-96.
    CrossRefMedlineWeb of Science
    1. Song JH,
    2. Jung SI,
    3. Ki HK,
    4. et al
    . Clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in Asian countries: a study by the Asian Network for Surveillance of Resistant Pathogens. Asian Network for Surveillance of Resistant Pathogens Study Group. Clin Infect Dis 2004;38:1570-8.
    Abstract/FREE Full Text
  37. ↵
    1. Aspa J,
    2. Rajas O,
    3. Rodriguez de Castro F,
    4. et al
    . Drug-resistant pneumococcal pneumonia: clinical relevance and related factors. Pneumococcal Pneumonia in Spain Study Group. Clin Infect Dis 2004;38:787-98.
    Abstract/FREE Full Text
    1. Pallares R,
    2. Capdevila O,
    3. Linares J,
    4. et al
    . The effect of cephalosporin resistance on mortality in adult patients with nonmeningeal systemic pneumococcal infections. Am J Med 2002;113:120-6.
    CrossRefMedlineWeb of Science
    1. Rosón B,
    2. Carratalà J,
    3. Fernández-Sabé N,
    4. Tubau F,
    5. Manresa F,
    6. Gudiol F
    . Causes and factors associated with early failure in hospitalized patients with community-acquired pneumonia. Arch Intern Med 2004;164:502-8.
    Abstract/FREE Full Text
    1. Falcó V,
    2. Almirante B,
    3. Jordano Q,
    4. et al
    . Influence of penicillin resistance on outcome in adult patients with invasive pneumococcal pneumonia: is penicillin useful against intermediately resistant strains? J Antimicrob Chemother 2004;54:481-8.
    Abstract/FREE Full Text
    1. File TM Jr,
    2. Jacobs MR,
    3. Poole MD,
    4. Wynne B
    . Outcome of treatment of respiratory tract infections due to Streptococcus pneumoniae, including drug-resistant strains, with pharmacokinetically enhanced amoxycillin/clavulanate. 546, 547, 548, 549, 550, 551, 556, 557, and 592 Clinical Study Groups. Int J Antimicrob Agents 2002;20:235-47.
    CrossRefMedlineWeb of Science
    1. File TM Jr,
    2. Lode H,
    3. Kurz H,
    4. et al
    . Double-blind, randomized study of the efficacy and safety of oral pharmacokinetically enhanced amoxicillin-clavulanate (2,000/125 milligrams) versus those of amoxicillin-clavulanate (875/125 milligrams), both given twice daily for 7 days, in treatment of bacterial community-acquired pneumonia in adults. 600 Study Group. Antimicrob Agents Chemother 2004;48:3323-31.
    Abstract/FREE Full Text
    1. Friedland IR,
    2. Klugman KP
    . Antibiotic-resistant pneumococcal disease in South African children. Am J Dis Child 1992;146:920-3.
    Abstract/FREE Full Text
    1. Plouffe JF,
    2. Breiman RF,
    3. Facklam RR
    . Bacteremia with Streptococcus pneumoniae: implications for therapy and prevention. Franklin County Pneumonia Study Group. JAMA 1996;275:194-8.
    Abstract/FREE Full Text
  45. ↵
    1. Daum RS,
    2. Nachman JP,
    3. Leitch CD,
    4. Tenover FC
    . Nosocomial epiglottitis associated with penicillin- and cephalosporin-resistant Streptococcus pneumoniae bacteremia. J Clin Microbiol 1994;32:246-8.
    Abstract/FREE Full Text
    1. Sacho H,
    2. Klugman KP,
    3. Koornhof HJ,
    4. Ruff P
    . Community-acquired pneumonia in an adult due to a multiply-resistant pneumococcus. J Infect 1987;14:188-9.
    CrossRefMedlineWeb of Science
    1. Buckingham SC,
    2. Brown SP,
    3. Joaquin VH
    . Breakthrough bacteremia and meningitis during treatment with cephalosporins parenterally for pneumococcal pneumonia. J Pediatr 1998;132:174-6.
    CrossRefMedlineWeb of Science
    1. Dowell SF,
    2. Smith T,
    3. Leversedge K,
    4. Snitzer J
    . Failure of treatment of pneumonia associated with highly resistant pneumococci in a child. Clin Infect Dis 1999;29:462.
    MedlineWeb of Science
  49. ↵
    1. Williams D,
    2. Perri M,
    3. Zervos MJ
    . Randomized comparative trial with ampicillin/sulbactam versus cefamandole in the therapy of community acquired pneumonia. Eur J Clin Microbiol Infect Dis 1994;13:293-8.
    CrossRefMedlineWeb of Science
  50. ↵
    1. Arancibia F,
    2. Ewig S,
    3. Martinez JA,
    4. et al
    . Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications. Am J Respir Crit Care Med 2000;162:154-60.
    Abstract/FREE Full Text
  51. ↵
    1. Finlay J,
    2. Miller L,
    3. Poupard JA
    . A review of the antimicrobial activity of clavulanate. J Antimicrob Chemother 2003;52:18-23.
    Abstract/FREE Full Text
  52. ↵
    1. Fasola EL,
    2. Fasching CE,
    3. Peterson LR
    . Molecular correlation between in vitro and in vivo activity of β-lactam and β-lactamase inhibitor combinations against methicillin-resistant Staphylococcus aureus (MRSA). J Lab Clin Med 1995;125:200-11.
    MedlineWeb of Science
  53. ↵
    1. Yokota T
    . Inactivation of beta-lactamases by sulbactam and enhanced clinical activity due to target-site binding of the combination of sulbactam and ampicillin. APMIS 1989;5(Suppl):9-16.
  54. ↵
    1. Shlaes DM,
    2. Baughman R,
    3. Boylen CT,
    4. et al
    . Piperacillin/tazobactam compared with ticarcillin/clavulanate in community-acquired bacterial lower respiratory tract infection. J Antimicrob Chemother 1994;34:565-77.
    Abstract/FREE Full Text
    1. Mouton Y,
    2. Leroy O,
    3. Beuscart C,
    4. et al
    . Efficacy, safety and tolerance of parenteral piperacillin/tazobactam in the treatment of patients with lower respiratory tract infections. J Antimicrob Chemother 1993;31(Suppl A):87-95.
    Abstract/FREE Full Text
    1. Sifuentes-Osornio J,
    2. Ruíz-Palacios GM,
    3. Jakob E,
    4. Rojas JJ,
    5. Jáuregui A,
    6. Villalobos Y
    . Piperacillin/tazobactam in the treatment of lower respiratory tract infections: an open non-comparative and multicentered trial. Latin American Clinical Research Group. J Chemother 1994;6:197-203.
    MedlineWeb of Science
  57. ↵
    1. Speich R,
    2. Imhof E,
    3. Vogt M,
    4. Grossenbacher M,
    5. Zimmerli W
    . Efficacy, safety, and tolerance of piperacillin/tazobactam compared to co-amoxiclav plus an aminoglycoside in the treatment of severe pneumonia. Eur J Clin Microbiol Infect Dis 1998;17:313-7.
    MedlineWeb of Science
  58. ↵
    1. Bassetti M,
    2. Dembry LM,
    3. Farrel PA,
    4. Callan DA,
    5. Andriole VT
    . Antimicrobial activities of BMS-284756 compared with those of fluoroquinolones and β-lactams against gram-positive clinical isolates. Antimicrob Agents Chemother 2002;46:234-8.
    Abstract/FREE Full Text
  59. ↵
    1. Schut RL,
    2. Peterson LR,
    3. Shanholtzer CJ,
    4. Janoff EN
    . Development of erythromycin-resistant pneumococcal endocarditis in a patient receiving erythromycin for community-acquired pneumonia. Inf Dis Clin Pract 1994;3:108-10.
  60. ↵
    1. Lonks JR,
    2. Garau J,
    3. Gomez L,
    4. et al
    . Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002;35:565-9.
    FREE Full Text
  61. ↵
    1. Rzeszutek M,
    2. Wierzbowski A,
    3. Hoban DJ,
    4. Conly J,
    5. Bishai W,
    6. Zhanel GG
    . A review of clinical failures associated with macrolide-resistant Streptococcus pneumoniae. Int J Antimicrob Agents 2004;24:95-104.
    CrossRefMedlineWeb of Science
  62. ↵
    1. Low DE
    . Quinolone resistance among pneumococci: therapeutic and diagnostic implications. Clin Infect Dis 2004;38(Suppl 4):357-62.
    Abstract/FREE Full Text
  63. ↵
    1. Ho PL,
    2. Tse WS,
    3. Tsang KW,
    4. et al
    . Risk factors for acquisition of levofloxacin-resistant Streptococcus pneumoniae: a case-control study. Clin Infect Dis 2001;32:701-7.
    Abstract/FREE Full Text
    1. Kuehnert MJ,
    2. Nolte FS,
    3. Perlino CA
    . Fluoroquinolone resistance in Streptococcus pneumoniae. Ann Intern Med 1999;131:312-3.
    FREE Full Text
    1. Empey PE,
    2. Jennings HR,
    3. Thornton AC,
    4. Rapp RP,
    5. Evans ME
    . Levofloxacin failure in a patient with pneumococcal pneumonia. Ann Pharmacother 2001;35:687-90.
    Abstract
    1. Weiss K,
    2. Restieri C,
    3. Gauthier R,
    4. et al
    . A nosocomial outbreak of fluoroquinolone-resistant Streptococcus pneumoniae. Clin Infect Dis 2001;33:517-22.
    Abstract/FREE Full Text
    1. Kays MB,
    2. Smith DW,
    3. Wack ME,
    4. Denys GA
    . Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. Pharmacotherapy 2002;22:395-9.
    CrossRefMedlineWeb of Science
    1. Ross JJ,
    2. Worthington MG,
    3. Gorbach SL,
    4. et al
    . Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;347:65-7.
    CrossRefMedlineWeb of Science
  69. ↵
    1. Davidson R,
    2. Cavalcanti R,
    3. Brunton JL,
    4. et al
    . Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747-50.
    CrossRefMedlineWeb of Science
  70. ↵
    1. Steinman MA,
    2. Landefeld CS,
    3. Gonzales R
    . Predictors of broad-spectrum antibiotic prescribing for acute respiratory tract infections in adult primary care. J Am Med Assoc 2003;289:719-25.
    Abstract/FREE Full Text
  71. ↵
    1. Metlay JP,
    2. Fine MJ
    . Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003;138:109-18.
    Abstract/FREE Full Text
  72. ↵
    1. Rosón B,
    2. Carratalà J,
    3. Verdaguer R,
    4. Dorca J,
    5. Manresa F,
    6. Gudiol F
    . Prospective study of the usefulness of sputum gram stain in the initial approach to community-acquired pneumonia requiring hospitalization. Clin Infect Dis 2000;31:869-74.
    Abstract/FREE Full Text
  73. ↵
    1. Mandell LA,
    2. Bartlett JG,
    3. Dowell SF,
    4. File TM Jr,
    5. Musher DM,
    6. Whitney C
    . Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 2003;37:1405-33.
    FREE Full Text
  74. ↵
    1. Guchev IA,
    2. Yu VL,
    3. Sinopalnikov A,
    4. Klochkov OI,
    5. Kozlov RS,
    6. Stratchounski LS
    . Management of nonsevere pneumonia in military trainees with the urinary antigen test for Streptococcus pneumoniae: an innovative approach to targeted therapy. Clin Infect Dis 2005;40:1608-16.
    Abstract/FREE Full Text
  75. ↵
    1. Cazacu AC,
    2. Chung SE,
    3. Greer J,
    4. Demmler GJ
    . Comparison of the directigen flu A + B membrane enzyme immunoassay with viral culture for rapid detection of influenza A and B viruses in respiratory specimens. J Clin Microbiol 2004;42:3707-10.
    Abstract/FREE Full Text
  76. ↵
    1. Peterson LR,
    2. Dalhoff A
    . Towards targeted prescribing: will the cure for antimicrobial resistance be specific, directed therapy through improved diagnostic testing? J Antimicrob Chemother 2004;53:902-5.
    Abstract/FREE Full Text
  77. ↵
    The choice of antibacterial drugs. Med Lett Drugs Ther 1990;32:41-8.
    Medline
  78. The choice of antibacterial drugs. Med Lett Drugs Ther 1992;34:49-56.
    Medline
  79. The choice of antibacterial drugs. Med Lett Drugs Ther 1994;36:53-60.
    Medline
  80. The choice of antibacterial drugs. Med Lett Drugs Ther 1996;38:25-34.
    Medline
  81. The choice of antibacterial drugs. Med Lett Drugs Ther 1998;40:33-42.
    MedlineWeb of Science
  82. The choice of antibacterial drugs. Med Lett Drugs Ther 1999;41:95-104.
    MedlineWeb of Science
  83. The choice of antibacterial drugs. Med Lett Drugs Ther 2001;43:69-78.
    MedlineWeb of Science
  84. ↵
    The choice of antibacterial drugs. Med Lett Drugs Ther 2004;2:13-26.
  85. ↵
    1. Baddour LM,
    2. Yu VL,
    3. Klugman KP,
    4. et al
    . Combination antibiotic therapy lowers mortality in severely ill patients with pneumococcal bacteremia. International Pneumococcal Study Group. Am J Respir Crit Care Med 2004;170:440-4.
    Abstract/FREE Full Text
  86. Physicians' desk reference. 59th ed. Montvale, NJ: Thomson PDR; 2005.
  87. ↵
    1. Nuermberger EL,
    2. Bishai WR
    . Antibiotic resistance in Streptococcus pneumoniae: what does the future hold? Clin Infect Dis 2004;38(Suppl 4):363-71.
    Abstract/FREE Full Text
  88. ↵
    1. Dagan R,
    2. Klugman KP,
    3. Craig WA,
    4. Baquero F
    . Evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy. J Antimicrob Chemother 2001;47:129-40.
    Abstract/FREE Full Text
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