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Emerging Treatments for Resistant Bacterial Infections and Pathogen-Focused Therapy

Rice, Louis B. MD; Bartlett, John G. MD; Craven, Donald E. MD; Stevens, Dennis L. PhD, MD; Moellering, Robert C. Jr MD, MACP; Eliopoulos, George M. MD

Author Information
Infectious Diseases in Clinical Practice: March 2008 - Volume 16 - Issue 2 - p S1-S20
doi: 10.1097/IPC.0b013e318168c6f9
  • Free


Release Date: March 2008

Expiration Date: March 31, 2009

Estimated time to complete activity: 120 minutes

Media: Monograph supplement

Method of Participation

There are no fees for participating and receiving CME credit for this activity. During the period March 1, 2008 through March 31, 2009, participants must:

  • Read the learning objectives and faculty disclosures
  • Study the educational activity
  • Complete the learning assessment by recording the best answer to each question in the answer key on the evaluation form
  • Complete the evaluation form
  • A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed learning assessment

This CME activity should take approximately 2 hours to complete. The participant should read the objectives and journal supplement. In order to receive CME credit, the participant should take the learning assessment and complete the registration and evaluation online at The evaluation provides each participant with the opportunity to comment on the quality of the instructional process, the perception of enhanced professional effectiveness, the perception of commercial bias, and his/her views on future educational needs. When completed, the participant will be able to immediately access and print his/her certificate for appropriate credit. This credit will be valid through March 31, 2009. No credit will be given after that date.


Louis B. Rice, MD

Professor of Medicine

Case Western Reserve University

Chief, Medical Services

Medical Service III

Cleveland VA Medical Center

Cleveland, OH

John G. Bartlett, MD

Professor of Medicine

John Hopkins University School of Medicine

Director, AIDS Service

Johns Hopkins Hospital

Baltimore, MD

Donald E. Craven, MD

Professor of Medicine

Tufts University School of Medicine

Chair, Department of Infectious Diseases

Lahey Clinic Medical Center

Burlington, MA

Dennis L. Stevens, PhD, MD

Professor of Medicine

University of Washington School of Medicine

Seattle, WA

Associate Chief of Staff, Research and Development

Chief, Infectious Diseases Section

Veterans Affairs Medical Center

Boise, ID

Robert C. Moellering, Jr, MD, MACP

Shields Warren-Mallinckrodt Professor of Medical Research

Harvard Medical School

Department of Medicine

Beth Israel Deaconess Medical Center

Boston, MA

George M. Eliopoulos, MD

Professor of Medicine

Harvard Medical School

Physician, Division of Infectious Diseases

Beth Israel Deaconess Medical Center

Boston, MA

Target Audience

This activity is designed for infectious disease specialists, microbiologists, and other healthcare professionals who participate in the selection of antibiotics for treatment of patients with infections caused by resistant bacterial strains, including MRSA.

Needs Assessment and Program Description

This activity is based on a satellite symposium that was held at the Infectious Diseases Society of America (IDSA) Annual Meeting on Thursday, October 4, 2007, in San Diego, CA. This activity will highlight methicillin-resistant Staphylococcus aureus (MRSA) and other resistant cSSSI and HAP/VAP infections, and will compare and contrast conventional and emerging antimicrobial therapies.

Infectious disease physicians have come to realize that serious, life-threatening infections, such as cSSSIs and HAP/VAP, particularly with highly resistant bacterial strains, continue to result in unacceptably high levels of morbidity and mortality. To help stem the high morbidity and mortality rates associated with MRSA and other resistant bacterial infections, infectious disease specialists require education on the types of infections, potential pathogens involved, current treatment guidelines, and the role of newer antimicrobial agents in the management of MRSA and other resistant bacterial infections. Lastly, "pathogen-focused therapy" is a new concept which uses culture data and clinical findings to define and adjust a patient's antibiotic therapy.

Symposium faculty have been asked to include the shifting epidemiology of MRSA and other resistant bacterial infections, guidelines for the evaluation and treatment of cSSSI and HAP/VAP infections, and the use of newer antimicrobial therapies in the prevention and treatment of these serious, life-threatening infections.

Learning Objectives

Upon completion of this CME activity, participants should be better able to:

  • Describe the growing prevalence of resistant bacterial infections in hospital and community settings
  • Describe the types of infections which are commonly caused by resistant bacterial strains, including cSSSi and HAP/VAP
  • Summarize the efficacy and safety data for current and future treatment for resistant bacterial infections
  • Use the "pathogen-focused therapy" concept to optimize the clinical care of patients with infections

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Dannemiller Memorial Educational Foundation and Exemplar CE, LLC. The Dannemiller Memorial Educational Foundation is accredited by the ACCME to provide continuing medical education for physicians.

Designation Statement

The Dannemiller Memorial Educational Foundation designates this educational activity for a maximum of 1.5 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

To Claim CME Credits

To receive CME credits for this activity, the participant must go to the following URL:, to complete the learning assessment and evaluation form.

Faculty Disclosures

In accordance with the ACCME, the Dannemiller Memorial Educational Foundation requires that any person who is in a position to control the content of a CME activity must disclose all relevant financial relationships they have with a commercial interest. Accordingly:

Louis B. Rice, MD

Speaker Programs: Wyeth, Elan; Consultant/Advisory Board: Merck, Novexel, Johnson & Johnson, Wyeth, Elan

John G. Bartlett, MD

Speaker Programs: Arpida; Consultant/Advisory Board: Abbott, GSK, Pfizer, BMS, Tibotec, Arpida, Johnson & Johnson

Donald E. Craven, MD

Speaker Programs: Arpida, Elan, Merck, Wyeth, sanofi Pasteur, Ortho Johnson & Johnson; Consultant/Advisory Board: Arpida, Pfizer, Cubist, Ortho Johnson & Johnson; Investigator: BARD

Dennis L. Stevens, PhD, MD

Consultant/Advisory Board: Pfizer; Investigator: Arpida, Johnson & Johnson, Cubist

Robert C. Moellering Jr, MD, MACP

Consultant/Advisory Board: Arpida, Pfizer, Cubist, Ortho Johnson & Johnson, Theravance, Targareton, Forest

George M. Eliopoulos, MD

Speaker Programs: Chiron, Novartis; Consultant/Advisory Board: Cubist, Johnson & Johnson; Pfizer Research Grant: Cubist, Novartis, Pfizer

Disclosure and Disclaimer Information

Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, attendees/participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program.

Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of the Dannemiller Memorial Educational Foundation, Arpida, or Exemplar CE, LLC. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

Other Disclosures: The Dannemiller staff and Exemplar staff who were involved in the development of this activity have no financial relationships with any commercial interests that are relevant to this activity.

Resolution of Conflict: To resolve identified conflicts of interest, the educational content was fully peer reviewed by a physician member of the Dannemiller Clinical Content Review Committee who has nothing to disclose. The resulting certified activity was found to provide educational content that is current, evidence-based, and commercially balanced.

Commercial Support

This program is supported by an educational grant from Arpida, Ltd. Jointly sponsored by the Dannemiller Memorial Educational Foundation and Exemplar CE, LLC.



The increasing prevalence of pathogen resistance to currently available antimicrobial agents is of great concern worldwide. The pathophysiologic basis of resistance is complex and includes the overuse and misuse of antibiotics as well as the ability of microbes to share resistance genes. Of equal concern is the limited number of new antibiotics and antibiotics in development. Six prominent infectious disease specialists have contributed to this article, providing information on the changing landscape of bacterial resistance, bacterial resistance in patients with pneumonia, the role of toxins in methicillin-resistant staphylococcal infections and the role of vancomycin in treating these infections, and a review of newly available antibiotics and those in late-stage development.


It is often tempting, for the sake of simplicity, to place all examples of antimicrobial resistance into a single paradigm. Such simplification is ill-advised because the phenotypic expression and genetic complexity of resistance vary considerably. Such is the circumstance with the evolution of resistance in Gram-positive bacteria over the past decade. We have observed clonal expansion of resistance in the community setting, with heterogeneity of clones being the rule (eg, community-acquired methicillin-resistant Staphylococcus aureus [S. aureus] or CA-MRSA). We have realized that what seemed to be a polyclonal expansion of resistance has been the spread of a single virulent and resistant clonal group (vancomycin-resistant enterococci or VRE). Finally, we have reveled in the success of a vaccination strategy to combat resistance, only to find resistance evolving in a manner that eludes the vaccine (eg, penicillin-resistant Streptococcus pneumoniae [S. pneumoniae]).

Community-Acquired Methicillin-Resistant S. aureus

Methicillin was first introduced into clinical practice in 1961. Its use in hospitals was soon followed by the recognition of methicillin-resistant strains of S. aureus (MRSA). In some countries (notably Denmark and some other Scandinavian countries), rates of nosocomial MRSA rose precipitously, prompting concerted efforts to identify and isolate those patients colonized or infected by MRSA.1 These efforts were a dramatic success, and even today, rates of MRSA in these countries are extremely low. The clonal nature of the MRSA spread was not well documented in the 1960s, but fortunately, the strict efforts at infection control were effective in controlling this pathogen.

The spread of MRSA to other areas of the world, including the United States, was slower; not achieving a level of clinical significance until the 1980s. Since that time, MRSA has become a major problem in US hospitals, with more than 55% of S. aureus infections in intensive care units (ICUs) being caused by methicillin-resistant strains.2 Until recently, MRSA was almost exclusively a problem of patients who were either hospitalized or had frequent contact with the health care system.3 It has been recognized for some time that nosocomial MRSA infections were caused by a limited number of clones and that the major mode of transmission is through poor infection control practices.4,5 In contrast, methicillin-susceptible strains of S. aureus (MSSA) from the community were predominantly polyclonal.

MRSA infections have emerged over the past decade in otherwise healthy individuals from the community.6 Soft tissue infections have been the predominant type of MRSA infection, but there are other forms. In some cases, serious and even fatal infections have occurred. Necrotizing MRSA pneumonias have been reported, many of them after infection with influenza virus.7 One MRSA strain, designated USA300, is responsible for the overwhelming number of community-associated infections. In a study by Moran et al6 that incorporated data from 11 emergency rooms from around the country, 78% of staphylococcal soft tissue infections were due to MRSA, and 99% of these infections were caused by USA300. A more recent analysis of invasive MRSA infections (those in which MRSA was isolated from a normally sterile body site) by Klevens et al8 suggests that the prevalence of USA300 is somewhat less than what was suggested by the study of Moran et al and varies across the country (Fig. 1). Overall, 85% of the invasive MRSA infections reported by Klevens et al8 occurred in patients with some connection to the health care system.

Percentage of MRSA identified as USA100 (hospital-associated strains), USA300 (community-associated strains), and others by Pulsed Field Gel Electrophoresis depending on whether they were isolated from sterile body sites (invasive) or from soft tissue infections from patients in the community (skin and soft tissue MRSA infections). Data from Moran et al6 and Klevens et al.8

Data suggest that CA-MRSA strains may be more aggressive than the MSSA strains that typically colonize people. Ellis et al9 reported that 38% of army recruits colonized by MRSA developed infections, compared with 3% of those colonized by MSSA. MRSA may have virulence factors not seen in MSSA. One of the characteristics of the MRSA USA300 strains is the presence of genes encoding the Panton-Valentine leukocidin (PVL) protein, which is toxic to human white blood cells in vitro.6 Animal studies on the contribution of PVL to virulence have been conflicting, so the precise involvement of this protein in causing disease remains to be determined.10,11

Although USA300 is clearly the predominant CA-MRSA strain in the United States, a number of different MRSA clones cause disease worldwide.12 In general, these strains remain susceptible to more antibiotics than the hospital-derived strains, but resistance is increasing in some areas. Although early studies suggested risk factors for infection with CA-MRSA, more recent work casts doubt that any specific epidemiological factors will be predictive.13 Moreover, the "community-acquired" distinction is losing its validity as these strains enter into and become endemic in many hospitals.14

Vancomycin-Resistant Enterococcus

The emergence of transferable vancomycin resistance in enterococci in the late 1980s raised significant concerns that this resistance mechanism would extend from the enterococci to staphylococci. Fortunately, despite a few sporadic cases of vancomycin-resistant MRSA, widespread emergence of vancomycin resistance in staphylococci has not occurred. However, vancomycin resistance is common in Enterococcus faecium (E. faecium), creating treatment difficulties for many immunocompromised patients in the United States and, more recently, across the world.

The epidemiology of VRE has been curious. It was first described in Europe and was found colonizing animals and community-dwelling individuals. European investigators implicated the use of avoparcin, a vancomycin-like antibiotic, in farm animals for the emergence of this resistance.15-17 In the United States, avoparcin was never licensed or used in farm animals, and community reservoirs were never identified. Interestingly, European hospitals reported few VRE infections, whereas hospitals in the United States saw the rapid emergence of vancomycin resistance in clinical strains.18

Recent work by Rob Willems et al19 has shed significant light on the epidemiology of multiresistance in enterococci. These investigators have shown that the overwhelming majority of VRE isolated from clinical infections and outbreaks belong to a single clonal complex, CC-17. CC-17 is characterized by multiresistance, especially high levels of resistance to ampicillin and seems likely to contain several determinants that make it more virulent than non-CC-17 strains. The high levels of ampicillin resistance in these strains is of particular importance because animal studies implicate this resistance in promoting the selection of resistant bacteria by extended-spectrum cephalosporins.20,21

Thus, it seems likely that different clones of VRE emerged in Europe and the United States. In Europe, the VRE that appeared and colonized healthy people was derived from the gastrointestinal tracts of animals and had not developed either the resistance or virulence determinants to promote high rates of clinical infection or outbreak. In the United States, VRE likely developed from pathogenic and resistant nosocomial strains, prompted by the oral use of vancomycin to treat Clostridium difficile (C. difficile) infection. Toward the end of the last century, avoparcin use was banned in European countries. Interestingly, several European countries are now observing significant increases in nosocomial VRE, attributable to the entrance and spread of CC-17 strains.22

There are several treatment alternatives for serious VRE infection. Two antibiotics that have been approved by the US Food and Drug Administration (FDA) for treatment of VRE infections are quinupristin-dalfopristin and linezolid. Daptomycin and tigecycline are also active in vitro against most VRE, but without evidence of their efficacy in treatment of clinical infections. As with any serious infection, appropriate surgical drainage is critical for the success of the antimicrobial regimen.

Penicillin-Resistant S. pneumoniae

Penicillin resistance in pneumococci is conferred by the expression of altered penicillin-binding proteins (PBPs). Pneumococci are naturally transformable (they can take up naked DNA under the right circumstances) and can accept and integrate foreign PBP genes into the pneumococcal genes, leading the production of altered PBPs.23 The level of resistance to penicillin conferred by these mosaic PBPs is generally low, allowing treatment of most infections by parenteral β-lactam antibiotics.24 Resistance is clinically significant for the intravenous (IV) treatment of meningitis, the use of oral β-lactams with limited bioavailability, and the use of β-lactams with unfavorable pharmacokinetics.

For decades after penicillin was introduced into clinical use, pneumococci remained exquisitely susceptible to this antibiotic. However, by the end of the last century, rates of pneumococcal resistance to penicillin and several other commonly used antibiotics were reaching alarming levels.25 In many cases, the spread of penicillin-resistant S. pneumoniae was due to the dissemination of relatively few clones, falling into a few serotypes, prompting intensive efforts to develop an effective vaccine against pneumococci in general and, in particular, the serotypes associated with resistance.

The clinical use of the 7-valent conjugated pneumococcal vaccine has been a major success. In addition to reducing the rates of invasive disease caused by pneumococci in the pediatric population, the vaccine has also been associated with dramatic reductions in the prevalence of antibiotic resistance in pneumococci causing serious disease.26 Interestingly, rates of pneumococcal disease and resistance have also been significantly reduced in adults who did not receive the vaccine, confirming the important role of the pediatric population in the spread of resistant pneumococci.27

More recently, however, resistant pneumococcal strains that consist of serotypes not included in the pediatric vaccine have appeared.28 It is not entirely clear at present whether these strains represent previously susceptible serotype clones that have acquired resistance, or previously resistant serotypes that have acquired new capsular antigens. Either way, this emergence serves as a useful reminder that we must continue to use our antibiotics judiciously if we are to preserve their effectiveness for future generations.


Community-acquired pneumonia (CAP) is one of the most common serious diseases encountered in clinical practice. The increasing incidence of antimicrobial resistance in bacteria causing CAP is of great concern. Therefore, a discussion of methods to reduce or limit the evolution of antibiotic resistance in these organisms is in order.

MRSA: A Study in Emerging Resistance

CA-MRSA, in particular the USA300 strains, is a pathogen whose increasing resistance has attracted great attention. During the course of the past 5 years, there has been an explosive epidemic of CA-MRSA infections in the United States and Europe. The vast majority of these infections have been cutaneous abscesses, although there have been some distinctive, invasive forms, including severe CAP. During the 2003 to 2004 influenza season, 10 cases of severe CA-MRSA CAP associated with suspected or established influenza were reported to the US Centers for Disease Control and Prevention (CDC) from Louisiana and Georgia.29 These 10 patients were relatively young (average age, 18 years), previously healthy children and young adults. They all developed rapidly progressive pneumonia characterized by multilobar infiltrates and a fulminant course. The infection was lethal in 6 patients, with a median duration of 3.5 days from onset of symptoms to death. The putative agent in these cases was the USA300 strain of S. aureus, which is characterized by the mec IV mechanism of methicillin-resistance and the PVL toxin gene.

A major controversy surrounds the question of which CA-MRSA virulence factor is responsible for the devastating consequences noted with invasive infections. The authors of 2 recent articles reached diametrically opposed conclusions. Labandeira-Rey et al10 studied the effects on mice of an intranasal challenge with 2 strains of S. aureus, one PVL-positive and one PVL-negative. The PVL-positive strain produced necrotizing pneumonia and rapid death, whereas the PVL-negative strain only caused a minor inflammatory reaction. The investigators also challenged mice with purified PVL, which caused focal necrotic lesions and death. The authors concluded that PVL is a major virulence determinant in the USA300 strain. In contrast, Voyich et al11 reached a different conclusion as a result of their murine study. These investigators studied both bacteremic (using tail vein injections) and abscess (using subcutaneous injection) models of infection and compared infection with PVL-positive and PVL-negative CA-MRSA strains. They found that the PVL-negative strains produced more bacteremia and larger thigh abscesses than the PVL-positive strains. The authors concluded that PVL is a marker for but not a major virulence factor of the USA300 strain of CA-MRSA and that multiple factors in the genetic makeup of an individual strain are responsible for its virulence. The striking disparity in the results of these 2 studies, which may be due in part to different study designs, highlights the need for continuing studies of bacterial virulence factors.

How Can We Reduce Antibiotic Resistance?

A number of tactics have been suggested to decrease the rate of development of resistance in organisms that cause CAP.

Reduce the Prescribing of Antibiotics to Treat Acute Bronchitis

Population-based studies of physician practice in the United States show that 55% to 75% of patients who seek medical care for acute bronchitis receive an antibiotic.30 Physicians continue to prescribe antibiotics for acute bronchitis despite the guideline recommendation, accepted by multiple authoritative sources, advising against antibiotic use.31 This suggestion is based on the fact that acute bronchitis almost always has a viral etiology, as well as on the lack of any convincing evidence of response to antibiotic treatment.31 Multiple efforts to alter physician behavior have been unsuccessful to date; however, one of the more simple messages is to stop calling this disease "acute bronchitis," instead referring to it as a "chest cold."31 This suggestion derives from the results of surveys showing that both patients and physicians claim that antibiotics are indicated for "acute bronchitis," but not for a "chest cold."31

Use Pathogen-Directed Antibiotic Therapy

There is consensus that CAP can be more effectively treated by the use of pathogen-directed therapy. Although technological advances have led to the development of rapid bedside diagnostic tests for bacterial identification, financial concerns often preclude their use. Indeed, routine microbiological testing has been given a low priority in the 2007 American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines for the management of CAP.32 In this most recent iteration of the guidelines, blood cultures are considered optional for hospitalized patients unless the patient is admitted to the ICU and sputum cultures are advocated only in the event that there is suspicion of a pathogen that would not be treated with the empiric antibiotic recommendations.32 These recommendations are not consistent with the concept of pathogen-directed therapy in CAP. The benefit of pathogen-directed treatment was investigated in a recent clinical study, in which 262 hospitalized CAP patients were randomized either to empiric antibiotic therapy as recommended in the 1993 ATS guidelines or to pathogen-directed treatment using cultures, antigen assays, and serology to define the pathogen.33 The outcome of this study showed no significant difference between the 2 groups in terms of length of stay, rate of clinical failure, mortality, or time to defervescence (Table 1).33 However, compared with patients receiving empiric antibiotics, those randomized to pathogen-directed therapy had a lower rate of adverse drug reactions, which was statistically significant (60% vs 17%, P < 0.001).33 It should be noted that most of the adverse events in this study were related to gastrointestinal intolerance of erythromycin, which is infrequently used in the United States.

Empiric Versus Pathogen-Directed Antibiotic for CAP

Use a Short Course of Antibiotics

In the past, it has been accepted clinical practice to encourage patients to complete 10- to 14-day courses of antibiotics to assure pathogen eradication. Recently, however, many clinicians are using shorter courses of therapy. El Moussaoui et al34 published the results of a study comparing a 3- and 8-day course of antibiotics for the treatment of CAP. In this study, 110 patients hospitalized with CAP were given IV amoxicillin for 3 days. Those that showed substantial improvement at day 3 were randomized to either oral amoxicillin or placebo for an additional 5 days. There were nearly identical rates of clinical success for both groups on days 10 and 28. Radiologic changes on day 10 were also nearly the same as well. The authors concluded that for patients who show an early response to antibiotic therapy, 3 days was an adequate course of treatment.

Vaccinate Patients With Pneumococcal Vaccines

One method that has proven extremely successful for preventing penicillin-resistant pneumonia has been the use of the 7-valent protein conjugated pneumococcal vaccine, which was licensed in 2000 for use in children 2 years or younger. This vaccine contains 7 pneumococcal serotypes, including 5 that account for 78% of all penicillin nonsusceptible strains (6B, 9V, 14, 19F, and 23F).26 In 2006, the CDC published the results of an analysis of a national database of invasive pneumococcal infections from 1996 to 2004.26 The investigators reported a 98% reduction in cases among children younger than 2 years (recipients of the vaccine) and a 79% reduction in these serotypes causing invasive disease in adults older than 65 years (who did not receive the vaccine).26 The authors concluded that this vaccine was highly effective in preventing pneumococcal pneumonia not only in children who were vaccinated but also in persons who were not vaccinated, presumably by eliminating S. pneumoniae infections in young children and their subsequent transmission to older children and adults.26 However, with the decrease in infections due to the strains covered by the vaccine, there has been an increase in CAP cases caused by the 19A strain of S. pneumoniae.35 This strain is relatively resistant to penicillin and macrolides, and efforts are now being made to insert this "replacement strain" into the vaccine for future use.

Antibiotic Use and the Influence of Third-Party Payers

Medicare is the major third-party payer for medical care in the United States. Federal legislation has mandated that Medicare implement programs that reveal relative merits of hospitals through public reporting and reward institutions that score well in selected quality care indicators through "pay-for-performance." One of the indicators selected for audit and payment is the "4-hour rule," which states that hospital emergency rooms must deliver antibiotics to patients with a diagnosis of CAP within 4 hours of registration. This quality measure was selected based on a retrospective analysis of data from more than 13,000 patients admitted to the hospital with CAP, which showed that a delay in delivering antibiotics beyond 4 hours was associated with a significant increase in mortality.36

The efficacy of the Medicare mandate in changing patient care was tested by an analysis of the Perspective Quality Benchmarking database maintained by Premier Healthcare Informatics.37 In this study, public reporting was associated with a 7% increase in compliance with the "4-hour rule," and the "pay-for-performance" was associated with a 12% improvement.37 Although the authors concluded the Medicare plan was successful, other clinicians are concerned with the potential for unintended consequences of the unnecessary use of antibiotics. An example of this was reported by Polgreen et al,38 who described an outbreak of severe C. difficile infection in which 5 patients died. A review of the cases indicated that 6 of the 12 patients who received antibiotics for a presumptive diagnosis of CAP probably had bronchitis.38 Metersky et al39 were also concerned about pressures on clinicians to give patients antibiotics rapidly, and potentially before a diagnosis is made. They performed a chart review of 86 patients with a hospital discharge diagnosis of pneumonia and found that 22% of cases had significant diagnostic uncertainty. The findings of these studies resulted in the "4-hour rule" being dropped as a "pay-for-performance" measure due to the potential for inappropriate use of antibiotics and the ensuing unintended consequences.

It is crucial for clinicians to be aware that although Medicare and other third-party payers may provide powerful incentives to change the standard of care, ongoing analyses of the consequences of these changes should inform choices in patient management.


In 2002, Friedman et al40 proposed a new classification system for infections, differentiating those that were community-acquired, health care-associated, and hospital-acquired. This concept was incorporated into the 2005 ATS/IDSA guideline recommendations for the management of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health care-associated pneumonia (HCAP).41 In contrast to patients with CAP, patients with HAP, VAP, or HCAP are at increased risk for infection with multidrug-resistant (MDR) pathogens.41 The ATS and IDSA noted that although the document was evidence-based, most of the recommendations were based on HAP and VAP because there were considerably less data on patients with HCAP with which to formulate suggestions.41 Subsequently, several studies have confirmed HCAP as a clinical entity that is distinct from CAP and is similar to HAP and VAP in terms of epidemiology and management. Patients with HCAP include those who had been previously hospitalized, persons referred to the hospital from nursing homes or chronic care facilities, individuals undergoing hemodialysis, and those who had received previous antibiotic therapy, all of which increase the risk of colonization and infection with MDR pathogens.41 It has been suggested that pneumonia be classified as CAP or HCAP, with the latter including those clinical entities currently called HCAP, HAP, and VAP. However with the rapid evolution of CA-MRSA, an appropriate pneumonia classification scheme remains a topic of discussion.

How Is HCAP Different From CAP?

Two epidemiologic studies validated the concept of HCAP as a separate category of pneumonia. In 2005, Kollef et al42 published the results of a retrospective cohort analysis of data from a total of 4,543 patients in the United States with culture-positive pneumonia who were admitted to 59 acute-care hospitals from 2002 to 2003. The goal of this study was to characterize the microbiology and outcomes in patients with CAP, HCAP, HAP, and VAP. More than 20% of these patients had HCAP. The major pathogen in all pneumonia categories was S. aureus, which was more common in the non-CAP pneumonias. Of note is that length of stay and mean hospital charges were dependent on the category of pneumonia (in descending order of length of stay and cost-VAP, HAP, HCAP, CAP; P < 0.0001). Furthermore, the mortality rate was 10% for CAP patients, 19.8% for HCAP, 18.8% for HAP, and 29.3% for VAP (Fig. 2). These data support the concept of HCAP as an entity distinct from CAP and more closely resembling HAP and VAP. Further supportive data for distinguishing HCAP from CAP was recently provided by Carratalà et al43 in Spain, who studied patients with a diagnosis of pneumonia admitted to the hospital through the emergency department from January 2001 through December 2004. Of the 727 patients studied, the 126 with HCAP (17.3%) were significantly different from the 601 that had CAP (82.7%). Patients with HCAP were significantly older than those with CAP (mean age, 69.5 vs 63.7 years; P < 0.001), more frequently had high-risk pneumonia (67.5% vs 48.8%; P < 0.001), and had a higher 30-day fatality rate (10.3% vs 4.3%; P = 0.007). More comorbidity was seen in the HCAP group (95.2% vs 74.7%, P < 0.001), including cardiovascular disease, cerebrovascular disease, cancer, impaired consciousness, corticosteroid use, and recent antibiotic use. The most common pathogen isolated in both groups was S. pneumoniae, but patients with HCAP were more often infected with MDR pathogens. In addition, infections with Haemophilus influenzae (H. influenzae), S. aureus, and Gram-negative bacilli were more common in patients with HCAP. The authors concluded that HCAP is a separate entity from CAP and that a significant number of patients diagnosed with pneumonia in the emergency department have HCAP.

Mortality data for CAP, HCAP, and VAP. Reprinted with permission from Kollef et al.42.

These studies and others have demonstrated important distinctions between HCAP and CAP as well as the greater similarity between HCAP, HAP, and VAP. Similarities include an increased risk for infection with MDR pathogens, the need to use broader spectrum antibiotics for initial coverage, and patient mortality rates. Patients with HCAP may be infected with non-MDR bacterial pathogens including S. pneumoniae, H. influenzae, MSSA, anaerobes, and Legionella species. However, delays in initiating appropriate antibiotic therapy for MDR pathogens such as Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii (A. baumannii), extended-spectrum β-lactamase-producing Gram-negative rods, and MRSA contribute to significant patient morbidity and mortality.41 These trends are likely to continue, and further studies are needed to better define the evolving risk factors for MDR infections and to develop better techniques for diagnosing pneumonia and identifying specific etiologic agents.

Nursing Home-Acquired Pneumonia and HCAP

There is a spectrum of nursing home residents who develop pneumonia. Many are at low risk for infection with MDR pathogens. These low-risk patients may be managed in the nursing home with oral or intravenous antibiotics, with greater convenience and less cost than those who are referred to the hospital emergency department for evaluation and treatment.41

Nursing home-acquired pneumonia (NHAP) is the most common cause of patient transfers to an acute care facility.44 Patients who present to the hospital with NHAP are a diverse group, with a spectrum of comorbid disorders and pneumonia severity. Nursing homes differ widely in their ability to diagnose pneumonia to assess its severity in the availability of IV fluids and antibiotics, and in their criteria for referral to the hospital. Patients with severe NHAP who present to the emergency department are often those who have received a course of empiric antibiotic therapy without symptom resolution. These patients are at increased risk for pneumonia due to MDR pathogens; however, distinguishing which individuals with NHAP are infected with MDR pathogens can be challenging. To address this issue, El Solh et al44 defined criteria to facilitate identification of these patients. Their study enrolled 88 patients with severe NHAP that was confirmed by bronchoalveolar lavage and found that 17 (19%) had MDR infections.44 Major risk factors for predicting infection with MDR pathogens include recent antibiotic use and an activities of daily living score indicative of increased disability.44 El Solh et al44 used study data to create a classification tree for predicting the risk of MDR pathogens in NHAP that varied from 0% with neither risk factor to 90% in those who had both recent antibiotic use and a high disability score (Fig. 3). The investigators validated this information, finding it 100% sensitive for predicting MDR with a specificity of 69%.44 These results provide additional criteria to use when considering which nursing home patients with severe pneumonia need acute care and broader spectrum IV antibiotics to treat MDR pathogens, which have less severe pneumonia, and which could be effectively cared for in the nursing home setting (Fig. 4).

Classification tree for predicting risk of MDR pathogens in patients with NHAP. ADL indicates activities of daily living; DRP, drug-resistantStreptococcus pneumonia. Reprinted with permission from El Solh et al.44
Recommendations for initial, antibiotic therapy based on the risk factors for infection with a MDR Gram-negative bacilli or methicillin-resistantS. aureus. Debility and severity should be considered as additional risk factors for broader spectrum initial empiric antibiotic therapy for HCAP.41 FQ indicates fluoroquinolone (third or fourth); AG indicates aminoglycoside. Data from American Thoracic Society,41 with permission. Official Journal of the American Thoracic Society. ©American Thoracic Society.

Assessing Pneumonia Severity Correlates With Patient Mortality

Severity of disease may be an important variable in the initial selection of appropriate antibiotics in patients with HCAP. Several scoring systems have been developed to predict the severity of CAP, the need for hospital admission, and mortality. These include the Pneumonia Severity Index (PSI), Confusion, Urea, Respiratory rate, Blood pressure, and Age ≥ 65 years (CURB-65) and Confusion, Respiratory rate, Blood pressure, and Age ≥ 65 years (CRB-65). These scoring systems may help determine the site of care, the extent of diagnostic testing needed, and the choice of initial antibiotics.

Pneumonia Severity Index

The PSI score uses 19 criteria, including age, chronic underlying disease, clinical signs, and laboratory values.45 Each criterion is assigned points, and the sum of the point scores determines the risk category.45 The risk of mortality is 0.1% for those in risk group I, the lowest group, and rises to 29.2% for those with the highest risk, group V. The PSI is complex and difficult to use. Details are available on the Agency for Healthcare Research and Quality Web site,

Confusion, Urea, Respiratory Rate, Blood Pressure, and Age ≥ 65 Years

CURB-65 is simpler than PSI. Patients score 1 point for each of the following: confusion, urea > 7 mmol/L, respiratory rate ≥ 30 breaths/min, systolic blood pressure < 90 mm/Hg or diastolic blood pressure ≤ 60 mm/Hg, and age ≥ 65 years.46 Patients are divided into 3 groups based on this score. Those in group 1 (score = 0-1) have a low mortality rate of approximately 1.5%, those in group 2 (score = 2) have an intermediate mortality rate of 9.2%, and those in group 3 (score ≥ 3) have a high mortality rate of 22%.46

Confusion, Respiratory Rate, Blood Pressure, and Age ≥ 65 Years

CRB-65 is similar to CURB-65 except that the patient's urea level is not a criterion; therefore, scores range from 0 to 4. A CRB-65 score can be calculated without laboratory testing. Mortality for patients in group 1 (score = 0) is 1.2%; in group 2 (score = 1-2), 8.2%; and in group 3 (score = 3-4), 31%.46

All 3 of these scoring systems have similar sensitivity and specificity in predicting mortality.47 The severity of disease and increased risk of mortality underscore the need to obtain cultures immediately and to begin IV antibiotic therapy as early as possible with an agent that addresses all potential pathogens and is given at an adequate dose. Disease severity may also be used as a criterion for referral to a hospital or for the need for admission to an ICU.

HCAP Treatment: ATS/IDSA Guideline Recommendations

To facilitate the use of the algorithm for management of HCAP, the ATS/IDSA guidelines provided a list of risk factors for infection with MDR pathogens. These include41:

  • Antimicrobial therapy in the preceding 90 days
  • High frequency of antibiotic resistance in the community
  • Hospitalization for ≥2 days in the preceding 90 days
  • Residence in a nursing home or extended-care facility
  • Home infusion therapy
  • Chronic dialysis within the previous 30 days
  • Home wound care
  • Previous infection with an MDR pathogen
  • A family member with MDR pathogen
  • Immunosuppressive disease or therapy
  • Late onset HAP or VAP

As previously mentioned, it may also be useful to consider the level of patient disability, underlying disease, and the severity of acute disease when choosing an initial antibiotic regimen as outlined in Figure 4.

Recommendations for Initial Therapy

For patients with no risk factors for infection with MDR, the ATS/IDSA guidelines recommend the initial use of limited spectrum antibiotics.41 These are ceftriaxone and azithromycin or third- or fourth-generation fluoroquinolones, or ampicillin/sulbactam with or without azithromycin for atypical pathogens (Fig. 4).41

Patients with risk factors for MDR pathogens should receive broader spectrum antibiotics directed against MDR Gram-negative bacilli and possible MRSA.41 Recommendations for Gram-negative bacilli include a third- or fourth-generation cephalosporin (ceftazidime or cefepime) or carbapenem (imipenem or meropenem), or a β-lactam/β-lactamase inhibitor combination (piperacillin plus tazobactam) plus an aminoglycoside (gentamycin, tobramycin, or amikacin) or a fluoroquinolone with activity against P. aeruginosa (ciprofloxacin or levofloxacin) for Gram-negative bacilli, with or without vancomycin or linezolid, if MRSA is a possibility.41 Patients who have previously received an antibiotic should not be given an agent from this class as part of initial empiric therapy.

De-Escalation Therapy and When to Stop

It is of critical importance to de-escalate therapy whenever possible. At days 2 and 3 of therapy, the culture results should be checked and the patient's clinical response assessed.41 Patients with clinical improvement and microbiologic data should be treated with the narrowest appropriate antibiotic regimen possible for a total of 7 days.41 If there is no clinical improvement in patients with negative cultures, testing should be done for other pathogens (such as Legionella, viruses, or MDR pathogens), other diagnoses that are either infectious (empyema or abscess) or noninfectious (drug fever, pulmonary emboli), or other sites of infection (C. difficile, occult abscess).41 No clinical improvement in patients with positive cultures may warrant a change in antibiotic coverage, a search for other pathogens, and consideration that the patient may have complications, other diagnoses, or another site of infection.41

Controversy: What Is the Impact of S. pneumoniae Resistance on Outcomes?

Pneumococcal resistance to penicillin, both high-level and low-level, is increasing rapidly, as is high- and low-level resistance to macrolides.32 Pneumococcal resistance to quinolones, while still rare, is increasing due to their widespread use. A major contributor to the development of pneumococcal antibiotic resistance is previous antibiotic use. Ruhe and Hasbun48 found that exposure to β-lactams within the previous month increased the risk of penicillin resistance 3.3-fold, and within the previous 6 months it increased the risk by 6.4-fold. If 2 or more courses were prescribed, the risk increased 34.4-fold (P < 0.001 for all comparisons). These investigators found similar results for the development of penicillin resistance after the use of macrolides.

The impact of increasing pneumococcal resistance on patient outcomes remains controversial, as is illustrated by the following studies. The first was a multicenter study of 638 patients with community-acquired S. pneumoniae.49 The investigators found that 36% of organisms had a penicillin minimum inhibitory concentration (MIC) > 0.12 μg/mL, 24% had an erythromycin MIC > 128 μg/mL, and 22% of patients had MDR pathogens. Of note is that disseminated intravascular coagulation, empyema, and bacteremia were seen more frequently in patients with penicillin-susceptible isolates. The authors concluded that resistance does not correlate with increased morbidity. Conversely, a meta-analysis of selected, prospective cohort studies found a mortality rate of 19.4% in the group with penicillin-nonsusceptible S. pneumoniae and 15.7% for the penicillin-susceptible group, with a relative risk of 1.29 (95% confidence interval, 1.04-1.59) when adjusted for age, comorbidity, and severity of illness.50 These investigators concluded that penicillin resistance is associated with a higher mortality rate than penicillin susceptibility. The correlation between in vitro resistance and clinical outcomes continues to be investigated. In these clinical studies, a number of factors other than the worldwide increase in resistance to β-lactam and macrolide antibiotics contribute to results.51 Other variables that contribute to morbidity and mortality in these clinical trials include patient characteristics that increase risk (eg, more severe underlying disease), the presence of multilobar pneumococcal pneumonia (with and without secondary bacteremia), specific pneumococcal capsular types being studied, the antibiotic prescribed, and the study design and interpretation.51,52

Bacterial resistance is defined by in vitro testing, a process that is complex both in methodology and interpretation.32 Recently, Peterson53 conducted a literature review and found only 1 report of documented microbiologic failure of parenteral penicillins to treat pneumococcal pneumonia. However, there were 21 reports of treatment failure with quinolones and 33 reports of failure with macrolides.53 This underscores the importance of considering not only laboratory resistance patterns but also clinical outcomes when discussing the impact of increasing resistance in frequently prescribed antibiotics.

Controversy: Combination Therapy for Severe Pneumococcal Pneumonia?

The results of 3 retrospective studies indicated that treatment with a combination of antibiotics is associated with reduced mortality compared with monotherapy.54 This led to a prospective, multicenter study of patients with pneumococcal bacteremia comparing treatment with combination therapy to monotherapy.54 For the entire study population, mortality rates were not significantly different between the groups. However, when evaluating severely ill patients with pneumococcal bacteremia (Pittsburgh Bacteremia Score > 4), the 14-day mortality rate was significantly lower in the group that received combination antibiotic therapy versus monotherapy (23% vs 55%; P = 0.0015). The resultsfor this subset of patients were independent of the antibiotic regimen used or the presence of microbial resistance in vitro.

In summary, HCAP is a new classification of pneumonia, which is distinct from CAP and is more similar to HAP and VAP in terms of epidemiology, microbiology, and management. HCAP is seen in patients who are older and have comorbidities. It is associated with a higher risk for MDR pathogens and increased mortality. Risk factors for MDR HCAP include residing in nursing homes or chronic care facilities, antibiotic therapy or hospitalization in the previous 90 days, and possibly severity of underlying disease and level of debility. With the aging of our population, this group of patients will increase dramatically in the coming decade. Recommendations for the treatment of HCAP/HAP/VAP are summarized in the 2005 ATS/IDSA guidelines. Pneumococci remain a common cause of CAP, HCAP, and HAP. In vitro high-level resistance of pneumococci to penicillin and macrolides is increasing, but the impact on clinical outcomes remains controversial. In patients who are seriously ill with severe pneumococcal pneumonia and bacteremia, combination therapy seems to lower the crude mortality rate. Finally, the ATS/IDSA guideline also emphasizes the importance of modifiable risk factors for the prevention of HCAP, HAP, and VAP. Clearly, all patients with risk factors for HCAP, HAP, and VAP should be vaccinated with pneumococcal-23 and influenza vaccines, and those with a history of smoking should be educated on its inherent risks and be offered a smoking cessation program.


The increase in hospital-acquired methicillin-resistant S. aureus (HA-MRSA) infections has been a slowly progressive process that began in the 1970s soon after the introduction of penicillinase-resistant antibiotics such as nafcillin, methicillin, and oxacillin. In contrast, the increase in the prevalence of CA-MRSA has been explosive during a period of several years. CA-MRSA strains have several distinctive characteristics. Most contain a unique gene locus (SCCmec cassette type IV) coding for an altered PBP. Many share distinctive pulse gel electrophoretic patterns (eg, USA300) and harbor a number of virulence genes such as PVL, enterotoxins, and toxic shock syndrome toxin-1 (TSST-1). In addition, CA-MRSA has been associated with several novel clinical syndromes (Table 2).

Types of CA-MRSA Infections

The emergence of these novel staphylococcal syndromes and their severity suggested that MRSA infections might be associated with higher mortality than those caused by MSSA. To answer this question, Cosgrove et al55 performed a meta-analysis of outcomes associated with MSSA and MRSA and clearly demonstrated that MRSA infections are indeed associated with worse outcomes than MSSA. Similarly, van der Mee-Marquet et al56 recently demonstrated that in Holland, the mortality rate for MSSA infection was 13% compared with 20% for MRSA.

The higher mortality rate seen with MRSA may be explained by 3 factors:

  • Higher mortality could be associated with inappropriate antimicrobial treatment. Studies have documented that patients with CA-MRSA infections are frequently prescribed antibiotics to which the organism is resistant. In a retrospective population-based analysis by the CDC, this happened 73% of the time.57 The investigators also contacted study patients to determine if receiving therapy with microbiologically ineffective antibiotics led to worse clinical outcomes and found that this was not the case. However, the authors noted that most cases were minor in nature, incision and drainage were performed on many of these patients, and not all patients could be reached by telephone to verify their status. In a recent CDC report of 10 cases of hemorrhagic/necrotizing pneumonitis, inappropriate antibiotics (specifically ceftriaxone) were prescribed 80% of the time and 60% of patients died.29
  • Vancomycin, which has been the principal antimicrobial used to effectively treat MRSA infections for 4 decades, could be losing its effectiveness against MRSA. Supporting this idea is the emergence of vancomycin-resistant S. aureus (VRSA), vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), the rising MICs of vancomycin needed to treat MRSA, and the appearance of MRSA strains which are tolerant to vancomycin.
  • The virulence of MRSA in general, and CA-MRSA in particular, may be increasing due to acquisition of a variety of genes coding for extracellular protein toxins (Table 3).
The Prevalence of Toxin Genes in CA-MRSA and HA-MRSA

Toxins and Toxin-Related Syndromes in MRSA

TSST-1 and Enterotoxins

Staphylococcal toxic shock syndrome (StaphTSS) caused by MRSA has been reported in numerous studies.56,59-64 In the past, StaphTSS has been caused by TSST-1 in tampon-associated menstrual cases and by staphylococcal extotoxin B in postsurgical cases associated with wound-packing material; however, toxin profiles were not available for most of these reports. Until recent reports describing the USA300 strains, the gene for TSST-1 was rarely found in CA-MRSA. However, in 2007, the TSST-1 gene was found in 3% of MRSA and in 14% of MSSA of blood isolates from Holland.56 Classical StaphTSS was rarely associated with bacteremia; in fact, the original CDC definition of StaphTSS excluded patients with positive blood cultures. These data suggest that the prevalence of TSST-1 and other superantigens, such as the enterotoxins, may be increasing in prevalence in MRSA and that infections associated with bacteremia could be complicated by an associated StaphTSS.

Alpha Hemolysin

Older studies have shown that alpha hemolysin is a potent virulence factor, causing dermonecrosis in experimental infections and has a deleterious effect upon human leukocyte viability and function.65 We have found this toxin gene in 100% of S. aureus USA300 strains (unpublished results).

Panton-Valentine Leukocidin

The PVL gene is commonly found in CA-MRSA (Table 3); however, in certain categories of severe infection, the prevalence of PVL is particularly elevated (Table 4). Nevertheless, a clear causal relationship between PVL production and severe infection has not been established. In fact, the PVL gene is found in most CA-MRSA strains that cause simple abscesses, carbuncles, and furuncles (Table 4). This raises several questions:

  • Do strains that are positive for the PVL toxin gene actually produce the toxin?
  • Is there diversity in the amount of toxin produced among PVL-positive strains?
  • Is there a correlation between the quantity of toxin produced and the severity of infection?
Association of PVL With Clinical Infections Caused by MRSA

In our studies, we found that all CA-MRSA strains with PVL genes produced the toxin and that the quantity of toxin varied between 50 and 800 ng/mL.71 Interestingly, the CA-MRSA strains that yielded the most PVL toxin were those isolated from abscesses, whereas strains isolated from patients with hemorrhagic/necrotizing pneumonia or necrotizing fasciitis produced only moderate amounts of PVL toxin. This diversity of PVL production in vitro suggests that either PVL is necessary but not sufficient to cause severe infections or that there are unknown factors that regulate production in vivo.

Two recent studies have investigated the role of PVL in bacterial virulence. Both studies used wild-type MRSA that were PVL-positive and compared their virulence to strains that had the PVL genes deleted. In 1 study, experimental soft tissue infections in mice showed no difference in lesion size or the course of the infection, leading the investigators to conclude that PVL had no role in the pathogenesis of skin and soft tissue infection.11 Other investigators used a mouse model of pneumonia and found that the wild-type PVL-positive MRSA strains were markedly more virulent than the PVL knockout strain. Furthermore, these investigators demonstrated that recombinant PVL aerosolized into the airways of mice directly caused hemorrhagic necrotizing pneumonia.10

Antibiotic Effects on Toxin Production

One factor that could affect the expression of bacterial toxins is the administration of inappropriate antimicrobial agents (eg, ceftriaxone or nafcillin). This is especially relevant when considering infections with CA-MRSA, where 70% to 80% of patients receive antibiotics to which the infecting MRSA strains are resistant.

In minor infections (eg, furuncles), the effect of inappropriate treatment is not well defined, but it likely has little relevance to outcomes. In a randomized, double-blind, placebo-controlled study, Rajendran et al72 found that surgical drainage alone was sufficient treatment for uncomplicated skin and soft tissue abscesses, with no added benefit or deleterious effects with the addition of cephalexin. In contrast, a larger retrospective cohort study by Ruhe et al73 found that antimicrobial therapy (including β-lactams, tetracyclines, fluoroquinolones, and sulfonamides), in addition to surgical drainage, was associated with a statistically significant positive impact on clinical outcome. However, some patients receiving surgical drainage and antibiotics (cephalexin or vancomycin) experienced treatment failure.

Inappropriate antibiotic therapy for more severe CA-MRSA infections has a much more striking effect on clinical outcomes, as was seen when ceftriaxone was used to treat hemorrhagic necrotizing pneumonia, which led to a high mortality rate.29 These results are related not only to lack of bactericidal activity but also to the effects of certain antibiotics on bacterial virulence factor expression, such as increased toxin production. Subinhibitory concentrations of β-lactams have been shown to upregulate alpha hemolysin expression in vitro.74,75 Based on these results, we examined the effect of increasing concentrations of nafcillin on the expression of alpha hemolysin, TSST-1, and PVL by several strains of MRSA (Table 5).76

Effects of Various Antimicrobial Agents onS. aureus Toxin Production

These data suggest that the inappropriate treatment of a toxin-producing MRSA strain infection with nafcillin (and perhaps with other β-lactams) not only delays appropriate therapy but also upregulates all 3 toxin genes, prolongs their expression, and increases the quantities of toxin produced. These results provide some initial insight as to how the use of the wrong antibiotics may have contributed to the poor outcomes seen in patients with hemorrhagic necrotizing pneumonia due to CA-MRSA and perhaps even to the failure of cephalexin to treat minor infections.

Strategies to Attenuate Toxins

It would seem prudent to develop strategies to attenuate the production of toxins in CA-MRSA infections such as toxic shock syndrome, hemorrhagic necrotizing pneumonia, necrotizing fasciitis, and other potentially severe infections. Although some have advocated using immune globulin, there is little clinical evidence to support or refute this premise. Difficulties with this solution are the relatively low concentration of neutralizing antibodies in any 1 batch as well as the between-batch variations in the quantities of antitoxin.

Other classes of antibiotics may be beneficial. As seen in Table 5, linezolid and clindamycin markedly attenuated the production of TSST-1, PVL, and alpha hemolysin. Although both affect protein synthesis, linezolid prevents the formation of the ribosomal initiation complex, whereas clindamycin affects release of the nascent polypeptide chain.

In summary, there has been a rapid increase in the reporting of CA-MRSA infections during the last few years. Some studies suggest that CA-MRSA skin and soft tissue infections are now more common than MSSA infections, at least among patients seeking care in emergency departments. In addition, novel types of staphylococcal infections have been described in association with CA-MRSA strains. This, and the worse outcomes with MRSA compared with MSSA, suggest that CA-MRSA strains may be more virulent. Certainly, CA-MRSA strains have a greater assortment of toxin genes such as enterotoxins, PVL, and alpha hemolysin than either MSSA or HA-MRSA strains. For minor and complicated skin and soft tissue infections, there is a variety of new and old agents that are effective. For more complex CA-MRSA infections such as StaphTSS, necrotizing fasciitis, and hemorrhagic/necrotizing pneumonitis, the ideal agent has yet to be determined. Our data suggest that in vitro, β-lactam antibiotics upregulate expression of multiple toxin genes and that such upregulation is associated with enhanced toxin production. In contrast, protein synthesis inhibitors markedly suppress toxin synthesis despite the fact that they also stimulate toxin gene transcription.


Vancomycin has been available for clinical use for more than 50 years.77 It was discovered in the early 1950s during a natural products screening program looking for new antimicrobial agents. The organism that produced vancomycin, originally named Streptomyces orientalis but now called Amycolatopsis orientalis, was found in Indonesia.78 Vancomycin is a large glycopeptide with a molecular weight of 1448 Da.79 It inhibits bacterial cell wall synthesis by binding to the terminal d-alanyl-d-alanine of the pentapeptide building blocks of the cell wall.79 In so doing, it inhibits both the transglycosylation and transpeptidation steps in cell wall synthesis and for that reason was originally bactericidal against most of its target organisms.77 Its spectrum of activity includes the majority of pathogenic Gram-positive bacteria, but it is not active against Gram-negative bacilli because of its inability to penetrate the outer-cell envelope of these organisms.

Vancomycin is not appreciably absorbed when given orally, is not tolerated intramuscularly, and therefore must be given intravenously. Excretion is via renal glomerular filtration. Vancomycin has relatively low (≈55%) serum protein binding. The terminal half-life is approximately 6 to 8 hours; thus, vancomycin can be dosed every 12 to 24 hours. For many years, the standard dose has been 1 g every 12 hours, but this must be adjusted downward in patients with impaired renal function.80 The dose in such patients can be determined by the use of published nomograms (Fig. 5).81

Dosage nomogram for vancomycin in patients with impaired renal function. The nomogram is not valid for functionally anephric patients on dialysis. For such patients, the dose is 1.9 mg/kg every 24 hours. Reprinted with permission from Moellering et al.81 Copyright © 1981, Annals of Internal Medicine, American College of Physicians. All rights reserved. (The American College of Physicians is not responsible for the translation accuracy of the printed material being used).

Rapid intravenous administration of vancomycin may cause histamine release, resulting in so-called "Red Man Syndrome."77 Although it was originally thought that high doses of vancomycin might be ototoxic, with the purer preparations of the drug currently available, ototoxicity does not occur.77 Nephrotoxicity is uncommon with standard doses of vancomycin, but the incidence of this complication increases with the concomitant administration of nephrotoxic agents including the aminoglycosides.80 Several recent studies suggest that vancomycin doses above 4 g/d have enhanced nephrotoxic potential.82,83

When vancomycin was first available for clinical use, it exhibited excellent in vitro bactericidal activity against most Gram-positive organisms, with the exception of enterococci.84,85 In recent years, vancomycin seems to have lost its bactericidal activity against many strains of staphylococci; however, until a short time ago, the bacteriostatic activity (as measured by MIC) remained unchanged.86,87 During the past decade, a number of medical centers have documented a "creep" upward in the MICs of vancomycin for S. aureus.88-90 Moreover, the Clinical and Laboratory Standards Institute has recently altered the breakpoints for susceptibility to vancomycin.91 Although strains for which the MIC of vancomycin was 4 μg/mL were previously considered susceptible, these strains are now considered to have "intermediate" susceptibility, and the cutoff for true susceptibility is ≤2 μg/mL. Supporting these changes are a number of recent publications documenting the failure of standard doses of vancomycin to treat infections due to organisms for which the MIC of vancomycin is 4 μg/mL.92 The increasing resistance to vancomycin is highlighted by the fact that even in "susceptible" organisms, there seems to be a gradient of responses to vancomycin as the MIC increases from 0.5 to 2 μg/mL.93

The issue of increasing vancomycin resistance is complicated by the fact that many strains of MRSA which test as intermediate or susceptible in vitro may harbor subpopulations of resistant organisms, a phenomenon known as heteroresistance.94 These organisms are difficult to detect using standard laboratory susceptibility test methods, but their presence has been associated with therapeutic failure of vancomycin.95 The prevalence of strains exhibiting heteroresistance to vancomycin in the United States is unknown; however, a recent study in Western Australia showed that as the MIC for vancomycin increased from 1 to 4 μg/mL, the prevalence of heteroresistance increased from 57% to 100%.96

Investigators have attempted to overcome heteroresistance by using increased doses of vancomycin. A number of recent studies have shown that inhibition and killing of staphylococci by vancomycin are concentration independent. Therapeutic effectiveness correlates best with an area under-the-curve (AUC)/MIC ratio of at least 400 (or 200 if one uses predrug concentrations).97,98 Effective AUC/MIC ratios are easily obtained with standard doses (2 g/d) of vancomycin for organisms for which the MIC of vancomycin is ≤0.5 μg/mL. For strains with an MIC of 1 μg/mL, it would take 4 g/d to attain therapeutic AUC/MIC ratios, and for an MIC of 2 μg/mL, the effective dose is 8 g/d. Unfortunately, recent data suggest that doses of vancomycin above 4 g/d are intrinsically nephrotoxic.82,83 Thus, increasing the dose, as has been suggested by certain national standard-setting organizations, is unlikely to result in increased therapeutic efficacy without significant toxicity.41 Whether or not maintaining adequate trough levels of vancomycin will prevent further emergence of resistance is unknown, but anecdotal evidence suggests that it might be at least partially effective in achieving this end.99

A multitude of data suggests that vancomycin is slowly losing its effectiveness. It is likely that this decreased effectiveness will be manifest most clearly when the drug is used to treat endocarditis, bacteremias, or serious deep-seated infections including pneumonia and osteomyelitis. For the moment, it seems less likely to be a problem when vancomycin is used for less serious infections including skin and skin structure infections. Because of potential nephrotoxicity, there are limitations as to how high the dose can be raised without significant collateral damage to the patient. Avoiding the use of concomitant nephrotoxic agents will likely help to mitigate the nephrotoxic potential of the vancomycin, but certainly cannot eliminate it entirely.


The increasing incidence of bacterial resistance to antimicrobials, including multidrug resistance, is becoming a worldwide health problem.100 The growing number of cases of MRSA is widely publicized, and infections with VISA and VRSA have been observed. Other antimicrobial-resistant organisms that are proving challenging to treat include VRE and multiresistant Gram-negative bacteria, including Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp. This section of the supplement will focus on newer approved and investigational antimicrobial agents targeting Gram-positive bacteria.

Despite the clear need for novel antimicrobial agents, there are few new drugs in development.100 Agents that have been approved by the FDA and have joined the antimicrobial armamentarium include linezolid, daptomycin, and tigecycline. Investigational agents that are in late-stage development and that have important activity against Gram-positive bacteria are the glycopeptides telavancin, dalbavancin and oritavancin; the β-lactams ceftobiprole and ceftaroline; and an antifolate (iclaprim).

Antimicrobial Agents Approved by the FDA


Linezolid is an oxazolidinone antibiotic that is active against a vast array of Gram-positive species.101 It has been shown to be useful in treating patients with serious infections caused by vancomycin-resistant or vancomycin-intermediate organisms, although it is not specifically approved for the latter.

The efficacy of linezolid was evaluated in a retrospective study of 25 patients treated for serious infections due to MRSA with reduced sensitivity to vancomycin.95 Seventeen patients had bacteremia and 6 had osteomyelitis and/or septic arthritis without bacteremia. All had previous glycopeptide therapy, which had failed for 19 patients (76%). The MIC of vancomycin for all isolates was 2 to 4 μg/mL. All isolates were susceptible to linezolid. Twenty-one patients received antibiotic therapy to treat MRSA with reduced sensitivity to vancomycin. Linezolid, the most commonly used agent, was given to 18 patients (9 linezolid alone, 8 sequentially with rifampicin and fusidic acid, and 1 sequentially with chloramphenicol and fusidic acid). Treatment with linezolid was effective in 14 patients (78%). Of the 8 patients with endocarditis, linezolid was effective in 4.

Linezolid was effective against vancomycin-resistant E. faecium in an open-label, noncomparative, nonrandomized, compassionate use program.102 Linezolid performed well against bacteremia (clinical cure, 78%; microbiological cure, 85%), endocarditis (clinical cure, 77%; microbiological cure, 64%), abdominal abscesses (clinical cure, 91%; microbiological cure, 89%), skin and soft tissue infections (clinical cure, 79%; microbiological cure, 83%), bone infections (clinical cure, 75%, microbiological cure 81%), and urinary tract infections (clinical cure, 92%; microbiological cure, 94%). Because linezolid is a bacteriostatic agent, however, it is not a first-line antimicrobial in situations where bactericidal therapy is desired.

Postmarketing studies have better defined the safety profile of linezolid. Case reports describe patients who developed lactic acidosis after treatment with linezolid; this has been attributed to the drug's interference with mitochondrial protein synthesis.101,103,104 Linezolid may also be associated with serotonin syndrome, a progressive syndrome characterized by mental status changes, autonomic hyperactivity, and neuromuscular signs.105 Linezolid is a weak, nonselective, reversible inhibitor of monoamine oxidase and should be used with caution in patients concurrently taking drugs that increase serotonin concentrations.105,106 Among reported cases of serotonin syndrome in patients receiving linezolid, selective serotonin reuptake inhibitors were frequently reported concomitant agents.105,106


Daptomycin is the first agent in a new class, the cyclic lipopeptides.107 It has activity against a broad range of Gram-positive organisms.107 Daptomycin can inhibit many organisms that are resistant to oxacillin, vancomycin, or linezolid.107

Two large, randomized clinical trials evaluated the efficacy of daptomycin for the treatment of complicated skin and skin structure infections (cSSTIs).107 Infecting organisms included MSSA, MRSA, groups A and B streptococci, and Enterococcus faecalis (E. faecalis).107 Overall, the clinical success rate was 83.4% for daptomycin and 84.2% for the comparator (either a penicillinase-resistant penicillin or vancomycin).

An open-label, randomized, noninferiority trial compared daptomycin with either an antistaphylococcal penicillin or vancomycin for the treatment of S. aureus bacteremia or right-sided endocarditis.108 Patients randomized to the comparator agents also received 4 days of low-dose gentamicin. Approximately 38% of patients in both the daptomycin and comparator groups had MRSA. The primary end point was clinical success at 42 days after the end of therapy. A successful outcome was seen in 44.2% of the daptomycin patients and 41.7% of the comparator patients. Success rates for daptomycin were similar for MSSA (44.6%) and MRSA (44.4%) infections. A smaller proportion of patients with MRSA infections responded to treatment with comparator agents compared with daptomycin (31.8% vs 44.4%), but this difference did not reach statistical significance. Rates of treatment failure for both groups were similar. Daptomycin treatment failure was more frequently attributed to persistent or relapsing infection (daptomycin 15.8%, comparator 9.6%; P = 0.17). Most of these patients had deep-seated infections and did not have required surgical intervention. Failure of the comparator therapy was more frequently associated with treatment-limiting adverse events (daptomycin 6.7%, comparator 14.8%; P = 0.06). An increase from baseline in daptomycin MIC was seen in 7 patients; however, there was no significant correlation between microbiological failure and the plasma drug concentrations in either treatment group. In this trial, creatinine kinase elevations occurred in significantly more patients in the daptomycin group than in the comparator group (daptomycin 6.7%, comparator 0.9%; P = 0.04) and led to discontinuation of therapy in 2.5% of daptomycin patients. Renal impairment occurred significantly more often in patients on comparator therapy (daptomycin 6.7%, comparator 18.1%; P = 0.009) and led to discontinuation of therapy in 4.3% of comparator patients.


Tigecycline is a broad-spectrum antimicrobial of the glycylcycline class. It is a first-in-class agent designed to avoid bacterial resistance to tetracyclines by efflux and ribosomal protection.109

The efficacy and safety of tigecycline for the treatment of cSSTI was evaluated in a pooled analysis of 2 large, double-blind studies.109 Tigecycline was compared with a regimen of vancomycin plus azetreonam for up to 14 days. A clinical response was seen in 86.5% of tigecycline patients and 88.6% of comparator patients. In bacteremic patients, a clinical cure was reported for 82.6% of tigecycline patients and 87.5% of comparator patients. Microbiologic eradication was seen in patients with MRSA (tigecycline 78.1%, comparator 75.8%), MSSA (tigecycline 88.8%, comparator 90.8%), group A streptococci (tigecycline 93.8%, comparator 92.6%), and group B streptococci (tigecycline 87.5%, comparator 84.6%), among others.

Adverse events seen in clinical trials of tigecycline include nausea and vomiting in a substantial minority of patients. Itching, rash, and elevated transaminases were among the less commonly encountered events.109,110

Investigational Agents in Late-Stage Development


Dalbavancin is a glycopeptide antimicrobial that, like vancomycin, inhibits bacterial wall synthesis.111 The effect is typically bactericidal. Dalbavancin has linear, dose-dependent pharmacokinetics and a half-life of 170-210 hours, making once-weekly dosing possible.111 A phase 3 noninferiority study compared once-weekly dalbavancin with twice-daily linezolid for the treatment of cSSTI.112 MRSA was identified in 51% of patients. At the test-of-cure visit, clinical efficacy was demonstrated for 88.9% of dalbavancin patients and 91.2% of linezolid patients. Microbiological response was 89.5% for dalbavancin and 87.5% for linezolid. MRSA was eradicated in 91% of dalbavancin patients and 89% of linezolid patients. Thus, dalbavancin was comparable to linezolid. Overall, the type and severity of adverse events were similar between the 2 groups. The most frequent adverse events in both groups were nausea and diarrhea; these were seen in 3.2% and 2.5% of the dalbavancin-treated patients.


Telavancin is a rapidly-acting bactericidal lipoglycopeptide.113 It acts in 2 ways: it inhibits transglycosylation, thus inhibiting cell wall synthesis, and it also causes bacterial cell membrane depolarization leading to changes in cell permeability.114 Telavancin has predictable, linear pharmacokinetics, with an elimination half-life ranging from 6.9 to 9.1 hours, that supports the feasibility of once-daily dosing.115

An in vitro study comparing telavancin with other glycopeptide antimicrobials found that it was broadly active against Gram-positive organisms tested, and 90% of isolates were inhibited by telavancin at concentrations ≤1 mg/L.116 Because of its multiple modes of action, telavancin also demonstrated in vitro activity against vancomycin-resistant enterococci. The MIC90 of telavancin against both vancomycin-resistant E. faecium and E. faecalis was 4 mg/L.116 In a randomized, double-blind, active control, phase 2 trial comparing telavancin with standard therapy (either an antistaphylococcal penicillin or vancomycin) for the treatment of cSSTI, the clinical cure rates in the microbiologically evaluable patients with S. aureus infections were 96% for telavancin and 90% for standard therapy.117 In the subgroup of these patients infected with MRSA, clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbial eradication rates were 92% for telavancin versus 78% for standard therapy (P = 0.07); for patients with MRSA, they were 92% and 68%, respectively (P = 0.04). Adverse events seen significantly more common in the telavancin group included nausea, taste disturbance, insomnia, and decreased serum potassium levels; elevated serum creatinine concentrations were also seen more frequently, but this was not statistically significant (P = 0.06). Two patients in the telavancin arm developed rashes leading to discontinuation, but no patients developed Red Man Syndrome. There was a mean change from baseline in QTc of 12.5 milliseconds in the telavancin group (P ≤ 0.0001) and more outliers with prolongation of QTc > 60 milliseconds; however, there were no cardiac events associated with the prolonged QTc. A similar proportion of patients in both groups were removed from the trial due to adverse events (telavancin 6%, standard 3%).


Oritavancin is a semisynthetic glycopeptide that has a very long plasma terminal half-life (360 hours), making once-daily to once-weekly administration feasible.118,119 Its activity against vancomycin-intermediate and resistant organisms has been demonstrated in a number of studies. In a study using E. faecalis JH2-2 and transconjugants bearing either vanA or vanB resistance genes, MICs of vancomycin and oritavancin against the parent strain were 2 and 0.25 μg/mL, respectively.120 Against both vancomycin-resistant strains, the vancomycin MICs exceeded 128 μg/mL, whereas the oritavancin MICs remained at 0.25 μg/mL.120 Similarly, against a vancomycin-resistant strain of S. aureus (MIC = 32 μg/mL), the MIC of oritavancin was 0.25 μg/mL.121 A study examining in vitro activity against vancomycin-intermediate isolates of S. aureus found oritavancin MICs of 0.5 to 1 μg/mL, whereas vancomycin MICs ranged from 4 to 8 μg/mL.122 Oritavancin data were obtained with media supplemented with polysorbate 80 to prevent the drug from binding to plastic surfaces. Clinical trials of oritavancin in cSSTI have been completed.


Ceftobiprole is an extended-spectrum β-lactam that binds tightly to and inhibits PBP2a, a protein that is responsible for staphylococcal resistance to β-lactams.123,124 Ceftobiprole is delivered as a prodrug, which is hydrolyzed to the active molecule in vivo.123,125 This drug is active against both MSSA and MRSA. Ceftobiprole inhibits 90% of oxacillin-susceptible and oxacillin-resistant S. aureus at concentrations of 0.5 and 2 μg/mL, respectively.125 Ninety percent of coagulase-negative MRSA were inhibited by ceftobiprole at 2 μg/mL.125


Ceftaroline is a broad-spectrum cephalosporin, administered as a prodrug, which also targets the low-affinity PBP, PBP2a.126 An in vitro study found its MIC for MSSA to be 0.12 to 0.25 μg/mL and for MRSA to be 0.5 to 2.0 μg/mL.126 The MIC for methicillin-susceptible coagulase-negative staphylococci was 0.06 to 0.12 μg/mL and for methicillin-resistant coagulase-negative staphylococci was 0.25 to 2 μg/mL.126 When tested against E. faecalis, the MIC for ceftaroline was ≤8 μg/mL, whereas that for E. faecium was ≥16 μg/mL.126 A randomized, observer-blinded study investigated its efficacy and safety compared with vancomycin with or without aztreonam for the treatment of cSSTI.127 A penicillinase-resistant penicillin could be substituted for vancomycin for susceptible organisms. The clinical cure rate was 96.7% for ceftaroline and 88.9% for the comparator. Of the 5 MRSA patients who were treated with ceftaroline, 4 were cured. The only adverse event seen more often with ceftaroline than with comparator was nausea (6% vs 0%).


Iclaprim is a potent inhibitor of bacterial dihydrofolate reductase (DHFR) and is highly selective for bacterial over human DHFR.128 Compared with trimethoprim, it has better binding to DHFR, possibly due to lipophilic interactions.128 Iclaprim is active in vitro against trimethoprim-resistant S. aureus.128 It is in clinical development to be used as monotherapy, and phase 3 trials for the use of the IV formulation to treat cSSTI have been completed.128 A study examined the distribution of iclaprim in healthy volunteers after an infusion of 1.6 mg/kg IV for 60 minutes.129 At 2 hours, the plasma concentration was 0.59 μg/mL and the concentration in epithelial lining fluid was 12.6 μg/mL; at 3.5 hours, the concentrations were 0.24 μg/mL and 6.4 μg/mL, respectively; and at 6.5 hours, they were 0.14 mL and 2.7 μg/mL. Microbiological studies have demonstrated an MIC for both MSSA and MRSA of 0.06 μg/mL.130 Trial results released at the Interscience Conference on Antimicrobial Agents and Chemotherapy 2007 include data on the testing of 4516 isolates of S. aureus for which the MIC50 of iclaprim was found to be 0.06 μg/mL and the MIC90 was 0.125 μg/mL.131 The molecular biology of the cell (MBC)/MIC ratio was ≤4 for 85.4% of isolates in this trial.131 In the Arpida Skin and Skin Structure Infection Studies-1 (ASSIST-1) clinical trial of the use of iclaprim in cSSTI, iclaprim eradicated MRSA in 84.7% of patients, whereas the comparator (linezolid) eradicated MRSA in 85.3%.132

In summary, currently available antimicrobials are still relatively effective against prevalent pathogens, but the increasing incidence of MRSA is of great concern. Several drugs in late-stage development may be useful additions to the antimicrobial armamentarium because of their increased potency, ease of use, and novel mechanisms of action.


The growing phenomenon of antimicrobial resistance is complex, and the basis for resistance varies with the microbe being considered. Antibiotic overuse and misuse have undoubtedly contributed to resistance, but the prevalence of resistant organisms makes avoidance of antibiotic use difficult. Resistance is of concern in both minor and serious infections, including skin and skin structure infections and pneumonia. Investigations to better define the causes of bacterial virulence and toxin production is ongoing but have already shown that the choice of antibiotics can influence the upregulation of toxin gene expression and toxin production. Linezolid, daptomycin, and tigecycline are now available to treat organisms resistant or less susceptible to previously effective agents such as vancomycin. Antimicrobials in late-stage development (dalbavancin, telavancin, oritavancin, ceftobiprole, ceftaroline, and iclaprim) will be welcomed into the antimicrobial armamentarium when available. Resistance to newly introduced antimicrobials will no doubt emerge as use expands over time. We must strive to learn how to use these powerful tools optimally to extend their longevity as we explore alternative strategies to control infections.


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