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Lefamulin is a novel oral and intravenous (IV) pleuromutilin developed as a twice-daily treatment for community-acquired bacterial pneumonia (CABP). It is a semi-synthetic pleuromutilin with a chemical structure that contains a tricyclic core of five-, six-, and eight-membered rings and a 2-(4-amino-2-hydroxycyclohexyl)sulfanylacetate side chain extending from C14 of the tricyclic core. Lefamulin inhibits bacterial protein synthesis by binding to the 50S bacterial ribosomal subunit in the peptidyl transferase center (PTC). The pleuromutilin tricyclic core binds to a pocket close to the A site, while the C14 side chain extends to the P site causing a tightening of the rotational movement in the binding pocket referred to as an induced-fit mechanism. Lefamulin displays broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria as well as against atypical bacteria that commonly cause CABP. Pleuromutilin antibiotics exhibit low rates of resistance development and lack cross-resistance to other antimicrobial classes due to their unique mechanism of action. However, pleuromutilin activity is affected by mutations in 23S rRNA, 50S ribosomal subunit proteins rplC and rplD, ATP-binding cassette (ABC)-F transporter proteins such as vga(A), and the methyltransferase cfr. The pharmacokinetic properties of lefamulin include: volume of distribution (Vd) ranging from 82.9 to 202.8 L, total clearance (CLT) of 19.5 to 21.4 L/h, and terminal elimination half-life (t1/2) of 6.9–13.2 h; protein binding of lefamulin is high and non-linear. The oral bioavailability of lefamulin has been estimated as 24% in fasted subjects and 19% in fed subjects. A single oral dose of lefamulin 600 mg administered in fasted patients achieved a maximum plasma concentration (Cmax) of 1.2–1.5 mg/L with a time of maximum concentration (Tmax) ranging from 0.8 to 1.8 h, and an area under the plasma concentration-time curve from 0 to infinity (AUC0−∞) of 8.5–8.8 mg h/L. The pharmacodynamic parameter predictive of lefamulin efficacy is the free plasma area under the concentration-time curve divided by the minimum inhibitory concentration (fAUC24h/MIC). Lefamulin efficacy has been demonstrated using various animal models including neutropenic murine thigh infection, pneumonia, lung infection, and bacteremia. Lefamulin clinical safety and efficacy was investigated through a Phase II clinical trial of acute bacterial skin and skin structure infection (ABSSSI), as well as two Phase III clinical trials of CABP. The Phase III trials, LEAP 1 and LEAP 2 established non-inferiority of lefamulin to moxifloxacin in both oral and IV formulations in the treatment of CABP. The United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Health Canada have each approved lefamulin for the treatment of CABP. A Phase II clinical trial has been completed for the treatment of ABSSSI, while the pediatric program is in Phase I. The most common adverse effects of lefamulin include mild-to-moderate gastrointestinal-related events such as nausea and diarrhea. Lefamulin represents a safe and effective option for treating CABP in cases of antimicrobial resistance to first-line therapies, clinical failure, or intolerance/adverse effects to currently used agents. Clinical experience and ongoing clinical investigation will allow clinicians and antimicrobial stewardship programs to optimally use lefamulin in the treatment of CABP.

Dealing with coronavirus disease 2019 (COVID-19) has been a monumental test of medical skills and resources worldwide. The management of community-acquired pneumonia (CAP) can at times be difficult, but treating CAP in the setting of COVID-19 can be particularly trying and confusing and raises a number of challenging questions relating to etiology, diagnosis, and treatment. This article is based on the authors’ experiences and presents an overview of how CAP during COVID-19 is handled in Canada. We touch on the issues of microbial etiology in patients with CAP in the setting of COVID-19 as well as diagnostic, site of care, and treatment approaches. Published guidelines are the basis of management of CAP and are discussed in the context of Canadian data. We also outline the usual treatment approaches to COVID-19, particularly in patients who have been hospitalized.

Community-acquired pneumonia (CAP) is a significant global health problem and leading cause of death and hospitalization in both the US and abroad. Increasing macrolide resistance among Streptococcus pneumoniae and other pathogens results in a greater disease burden, along with changing demographics and a higher preponderance of comorbid conditions. Areas covered: This review summarizes current data on the clinical and economic burden of CAP, with particular focus on community-acquired bacterial pneumonia (CABP). Incidence, morbidity and mortality, and healthcare costs for the US and other regions of the world are among the topics covered. Major factors that are believed to be contributing to the increased impact of CABP, including antimicrobial resistance, the aging population, and the incidence of comorbidities are discussed, as well as unmet needs in current CABP management. Expert commentary: The clinical and economic burden of CABP is staggering, far-reaching, and expected to increase in the future as new antibiotic resistance mechanisms emerge and the world's population ages. Important measures must be initiated to stabilize and potentially decrease this burden. Urgent needs in CABP management include the development of new antimicrobials, adjuvant therapies, and rapid diagnostics.

BACKGROUND: The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) Community-acquired Pneumonia (CAP) guidelines were developed using systematic reviews to inform every recommendation, as suggested by the Institute of Medicine Standards for Trustworthy Guidelines. Recent studies suggest that an expert consensus-based approach, called the Convergence of Opinion on Recommendations and Evidence (CORE) process, can produce recommendations that are concordant with recommendations informed by systematic reviews. PURPOSE: The goal of the study was to evaluate the efficacy of the CORE process had it been used to develop the ATS/IDSA CAP guidelines. METHODS: Experts in CAP who were not on the guideline panel and had no knowledge of the guideline’s systematic reviews or recommendations were recruited to participate in the CORE process, addressing the same questions asked by the guideline panel. Recommendations derived from the CORE process were compared to the guideline recommendations. Concordance of the course of action, strength of recommendation, and quality of evidence were determined. RESULTS: Using a threshold of 70% of experts selecting the same course of action to make a recommendation, the CORE process yielded a recommendation for 20 of 31 (65%) questions. Among the 20 CORE-derived recommendations, 19 (95%) were concordant with the guideline recommendations (kappa agreement 0.88, 95% CI .64–1.00). There was less agreement among the strength of recommendations (58%) and quality of evidence (42%). CONCLUSIONS: If the CORE process had been used, 11 systematic reviews would have been necessary rather than 31, with minimal impact on the recommended courses of action.

SCOPUS: le.j, info:eu-repo/semantics/published

Community-acquired pneumonia is still a significant cause of morbidity and mortality and is often misdiagnosed and inappropriately treated. Although it can be caused by a wide variety of micro-organisms, the pneumococcus, atypicals, such as Mycoplasma pneumoniae and Chlamydophila pneumoniae, Staphylococcus aureus and certain Gram-negative rods are the usual pathogens encountered. The site-of-care decision is critical in determining the site and type of care as well as the extent of diagnostic workup. Antimicrobial therapy should be started as soon as possible particularly in those requiring admission to hospital, but typically the physician does not know with any degree of certainty the identity of the etiologic pathogen. A number of national guidelines have been published to help the physician with this choice. The initial drug(s) can be modified if necessary if the pathogen and its antimicrobial susceptibility pattern becomes known. Adjunctive therapy such as pressors and fluid replacement are of value and macrolides appear to help as well, likely secondary to their immunomodulatory effects. Recent data also suggest a role for steroids.

Community-acquired pneumonia (CAP) has a significant impact in terms of morbidity, mortality, and cost of care. Guidelines play an important role in the management of this disease, and evidence supporting the positive effects of guidelines on outcomes in patients with CAP is substantial. However, evidence supporting many of the CAP quality indicators is low, and pay-for-performance measures do not seem to influence clinically important outcomes. Future CAP quality indicators should incorporate evidence-based interventions.

The title of this article implies that knowledge of the etiological pathogen may be useful in selection of patients for clinical trials for community-acquired pneumonia (CAP). However, this remains to be seen. The clinical course of a patient with CAP admitted to the hospital but not to the intensive care unit depends on a number of variables, including the patient, the pathogen, and the hospital itself. The site-of-care decision can be based on 1 of 2 prediction rules. Neither of these rules, however, correlates with the etiology of CAP, and it is not clear whether they can be used to stratify patients according to prognostic factors. A pathogen may be found in only approximately one-third of hospitalized patients with CAP overall. An etiological diagnosis is more likely to be made for patients with CAP who are hospitalized in the intensive care unit (39%) than for those hospitalized in other wards (20%). The issue of randomization to treatment regimens and possible approaches to randomization are discussed. It seems clear, however, that randomization would have to take place immediately after entry of the patient into the study. The possibility of using risks for specific pathogens or risks for antimicrobial resistance is also addressed. However, there are no data to support the use of such risks as prognostic factors in CAP. The best approach for noninferiority trials involving hospitalized patients with CAP is to randomize patients who meet the inclusion criteria and to stratify them by hospital site, with block randomization within each site. Stratification by site takes into account local epidemiology and can balance differences in unmeasured confounders among sites.

Lionel A. Mandell, Richard G. Wunderink, Antonio Anzueto, John G. Bartlett, G. Douglas Campbell, Nathan C. Dean, Scott F. Dowell, Thomas M. File, Jr. Daniel M. Musher, Michael S. Niederman, Antonio Torres, and Cynthia G. Whitney McMaster University Medical School, Hamilton, Ontario, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, and Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi School of Medicine, Jackson; Division of Pulmonary and Critical Care Medicine, LDS Hospital, and University of Utah, Salt Lake City, Utah; Centers for Disease Control and Prevention, Atlanta, Georgia; Northeastern Ohio Universities College of Medicine, Rootstown, and Summa Health System, Akron, Ohio; State University of New York at Stony Brook, Stony Brook, and Department of Medicine, Winthrop University Hospital, Mineola, New York; and Cap de Servei de Pneumologia i Allergia Respiratoria, Institut Clinic del Torax, Hospital Clinic de Barcelona, Facultat de Medicina, Universitat de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, CIBER CB06/06/0028, Barcelona, Spain.

Standard 7-14 day (d) courses of antimicrobial therapy for community-acquired pneumonia (CAP) are thought to have contributed to the emergence of resistant pneumoccoci. Consequently, short-course fluoroquinolone regimens have been proposed to minimize resistance. To test this, we examined 2-day versus 5-day regimens of gemifloxacin and levofloxacin for treatment of pneumonia in a murine model. In doing so, we also investigated whether the enhanced potency of gemifloxacin would influence outcomes. CD1 Swiss mice were infected intratracheally with 10(5)-CFU of a virulent Streptococcus pneumoniae strain. Drugs were administered every 8 h for 2 d and 5 d, starting at 24 h postinfection. Temperature was used to assess disease progression. Gemifloxacin remained effective for 2 d and 5 d, with survival rates of 100%-83% compared with 40%-58% for levofloxacin. Eighty-nine to 100% of gemifloxacin-treated mice were clear of pulmonary bacteria compared with only 0%-20% for levofloxacin. For levofloxacin-treated mice, 2 of 7 (29%) isolates with a levofloxacin minimum inhibitory concentration (MIC) 4 times that of the infecting parent strain had ParC mutations. By contrast, no isolates recovered from gemifloxacin-treated mice were reduced in susceptibility. Gemifloxacin could be effective in shortening duration of therapy for CAP treatment as well as minimize resistance development.

Rashes are a common adverse event observed during antimicrobial therapy. Many rashes are mild to moderate in intensity, however some reactions can be the prelude to much more severe outcomes such as Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necolysis. Several risk or influencing factors are known such as female gender, age and concomitant viral infections, and these may apply to more than one drug class. The incidence of rashes and other cutaneous reactions vary, however rates of >3% are reported with the beta-lactams while serious reactions such as SJS are observed with trimethoprim-sulphamethoxazole. Newer fluoroquinolone agents are devoid of the moiety which caused phototoxic reactions, while rates of rash vary from < 1%-3% or higher if longer courses of therapy are given. Serious systemic events have not been reported with these agents unlike other older, well-accepted antimicrobials. Rashes, while occasionally itchy and sometimes transiently unsightly, have less of an impact on a patient's daily activities than diarrhea, nausea or other more profound adverse events. However, it is essential that any rash be carefully monitored for possible, but rare, serious systemic events ensuing.

Cutaneous adverse events are seen with many antimicrobials. A signal was observed with gemifloxacin in the original clinical research program, however subsequent studies and analysis demonstrated a mild-moderate self-limited macular-papular rash seen most frequently when the duration of exposure was beyond 7 days, a non-approved duration. Following administration for 5 days for community-acquired respiratory tract infections the rash rate is typically less than 1.5%, a rate similar to that for other fluoroquinolones and lower than other frequently used community antimicrobials. The rash associated with gemifloxacin has not been linked with cross or subclinical-sensitization nor any systemic manifestations such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. This review describes the extensive studies conducted to support the use of this agent for short durations in community infections.

Study objectives To demonstrate equivalence in the clinical efficacy of telithromycin vs clarithromycin treatment of outpatients with acute exacerbations of chronic bronchitis (AECB), and to compare the tolerability and respiratory-related health-care resource utilization associated with these treatment regimens. Design and patients A randomized, double-blind, multicenter, clinical study was conducted at 105 centers in 14 countries. Adult outpatients (age ≥ 30 years) received oral telithromycin, 800 mg qd for 5 days (n = 270), or oral clarithromycin, 500 mg bid for 10 days (n = 282), for the treatment of AECB. Clinical and bacteriologic outcomes were assessed at the posttherapy/test-of-cure (TOC) visit (days 17 to 24; per-protocol population). Health-care resource utilization data were collected for each patient by investigators blinded to study medication up to the late posttherapy visit (days 31 to 36). Results Clinical cure rates at the posttherapy/TOC visit were comparable between the groups (telithromycin, 193 of 225 patients [85.8%]; clarithromycin, 206 of 231 patients [89.2%]); bacteriologic outcome was satisfactory for 59 of 72 telithromycin-treated patients (81.9%) vs 63 of 76 clarithromycin-treated patients (82.9%). Health-care resource utilization assessed up to the late posttherapy visit was lower in the telithromycin treatment group than the clarithromycin treatment group, with significantly fewer hospitalizations for respiratory-related causes (one hospitalization vs eight hospitalizations for a total of 4 inpatient days vs 39 inpatient days, respectively), significantly fewer AECB-related emergency department visits (0 vs 8), and fewer unscheduled outpatient visits (11 vs 18). Fewer telithromycin-treated patients reported days lost from work (21 of 91 patients [23.1%]; 133 days) compared with those receiving clarithromycin (30 of 98 patients [30.6%]; 141 days). Telithromycin was well tolerated; adverse events considered possibly related to study medication were reported by 61 of 269 patients (22.7%) and 100 of 280 patients (35.7%) receiving telithromycin and clarithromycin, respectively. Conclusions In this study, 5-day telithromycin treatment was as effective and well tolerated as 10-day clarithromycin treatment for patients with AECB, and was associated with a reduced utilization of health-care resources.

PREVIEWRecent years have witnessed the emergence of new pathogens linked to community-acquired pneumonia (CAP) along with new antibiotics designed to combat them. In this article, Dr Mandell presents an expert's view on these developments in the context of treatment guidelines for CAP. He also explores monotherapy versus combination therapy, the efficacy of rapid initiation of treatment, and short-course therapy as a hedge against antimicrobial resistance.

A case-control method was used in the Dutch trial, and ILI was defined as an “acute onset of illness” (duration of prodromal stage, 3‐4 days) and the presence of at least 1 of the following symptoms: cough, rhinitis, sore throat, frontal headache, retrosternal pain, or myalgia. ARTI was defined as an acute respiratory illness other than ILI with at least 1 of the following symptoms: cough, rhinitis, or sore throat. Nose and throat swab specimens were obtained from case patients and control subjects, and viral cultures and PCR tests were performed for detection of adenovirus, coronavirus, enterovirus, hMPV, influenza virus, parainfluenza virus, rhinovirus, and respiratory syncytial virus (RSV), as well as for Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Chlamydophila psittaci. Bacterial cultures of throat swab specimens were also performed to detect all bacterial pathogens that are known to potentially cause “community-acquired” respiratory infection. The findings were then semiquantitatively classified into 5 groups: no colonies, sporadic colonies, few colonies, several colonies, or many colonies.

The seriousness of community-acquired pneumonia (CAP), despite being a reasonably common and potentially lethal disease, often is under estimated by physicians and patients alike. CAP results in more than 10 million visits to physicians, 64 million days of restricted activity, and 600,000 hospitalizations. This article discusses the epidemiology and bacterial causes of CAP in immunocompetent adults and the severe acute respiratory syndrome coronavirus.

The current document bestows an expert synopsis of key new information presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in 2003. Data is presented on the socio-political aspects of and policies on antimicrobial prescribing, novel mechanisms of resistance in Streptococcus pneumoniae, and current epidemiological trends in global resistance. Novel information on new (and existing) antimicrobial agents--new penicillins, cephalosporins, monobactams and oxipenem inhibitors, ketolides, glycopeptides, fluoroquinolones (and hybrids), peptides, daptomycin, aminomethylcyclines, glycylcyclines, and newer formulations of agents such as amoxycillin-clavulanate--provides renewed hope that resistant pathogens can be controlled through use of more potent agents. Improved strategies for the use of existing antimicrobial agents, such as the use of high-dose regimens, short-course therapy, also may delay or reduce the development of resistance and preserve the value of our antibiotic armamentarium.

The Infectious Diseases Society of America (IDSA) produced guidelines for community-acquired pneumonia (CAP) in immunocompetent adults in 1998 and again in 2000 [1, 2]. Because of evolving resistance to antimicrobials and other advances, it was felt that an update should be provided every few years so that important developments could be highlighted and pressing questions answered. We addressed those issues that the committee believed were important to the practicing physician, including suggestions for initial empiric therapy for CAP. In some cases, only a few paragraphs were needed, whereas, in others, a somewhat more in-depth discussion was provided. Because many physicians focus on the tables rather than on the text of guidelines, it was decided that all of the information dealing with the initial empiric treatment regimens should be in tabular format with footnotes (tables 1–3). The topics selected for updating have been organized according to the headings used in the August 2000 CAP guidelines pub

1University of Toronto, Mount Sinai Hospital, Toronto, Ontario; 2Laval University, Hopital Laval, Ste-Foy, Quebec; 3The Toronto Hospital, Toronto Medical Laboratories, Toronto, Ontario; 4McMaster University, Henderson General Hospital, Hamilton, Ontario Correspondence: Dr Meyer Balter, 640 – 600 University Avenue, Toronto, Ontario M5G 1X5. Telephone 416-586-4663, fax 416-586-4736, e-mail mbalter@mtsinai.on.ca Reprints: Core Health Services Inc, 1800 Steeles Avenue West – Second Floor, Concord, Ontario L4K 2P3. Telephone 905-760-1991, fax 905-760-0587, e-mail coremail@idirect.com Acute exacerbations of chronic bronchitis (AECB) account for over 1.5 million physician visits annually in Canada and are a cause of significant morbidity and mortality. Canadian guidelines for the management of chronic bronchitis were published in 1994 (1). The present document is an update of our original guidelines, and is a joint effort by the Canadian Thoracic Society and the Canadian Infectious Disease Society.

(See the Major Article by Moran et al, on pages 1126–33.) Two entities are considered in this editorial: one is a bacterium and the other a clinical infection, but it is their relationship that is the issue of interest. Originally referred to as micrococcus, Staphylococcus aureus has been a recognized problem for well over a century. It is a frequent colonizer of skin and mucosa in animals and humans. In humans, the preferred niche is the anterior nares, although it can also be frequently found in the axillae and perineum. Nasal carriage rates in the general population vary from 10% to 40%. Staphylococcus aureus is also a highly successful pathogen responsible for a variety of clinical problems ranging from folliculitis to endocarditis, osteomyelitis to pneumonia, and food intoxication to septic shock. A number of structural and secreted virulence factors play a role in the pathogenesis of these various conditions and the evasion of host defenses. Penicillinase-resistant semisynthetic penicillins, such as methicillin, became available in the late 1950s. Shortly thereafter, methicillin-resistant strains of S. aureus appeared [1]. The development of such strains is likely related to the acquisition of staphylococcal cassette chromosome (SCC)mec allotypes. SCCmec is an acquired fragment of DNA that carries β-lactam resistance genes and may also carry resistance genes to additional antibiotics. This early appearance of antibiotic resistance was a harbinger of things to come, and methicillin-resistant S. aureus (MRSA) has been a growing problem in hospital-acquired infections for some time. More recently, community-associated MRSA (CA-MRSA) infections have been described in patients with skin and soft tissue infections and pneumonia and is a cause of growing concern. Community-acquired pneumonia (CAP) is not a reportable disease, and therefore accurate figures are not available. Data from the United States suggest that there are >4 million cases per year, resulting in >600 000 hospitalizations, 64 million days of restricted activity, and 50 000 deaths annually [2]. The overall yearly cost associated with CAP in the United States is estimated to be $9–$10 billion dollars. CAP is often misdiagnosed and improperly treated. When confronted with a patient with possible CAP, there are 2 questions to be answered. First, is the clinical syndrome in fact pneumonia or some other clinical entity? Second, if CAP, what is the etiologic pathogen? The diagnosis of pneumonia itself is based on a compatible history and the presence of select clinical features plus a chest radiographic abnormality. The lack of rapid, sensitive, and specific methods to determine the etiologic agent in a particular patient means that the attending physician must often initiate antimicrobial treatment without knowing the pathogen with any degree of certainty. Given the large number of potential pathogens including bacteria, atypical bacteria, and viruses, uncertainty regarding etiology represents a significant problem, particularly for patients ill enough to require admission to hospital. For those requiring management in an intensive care unit (ICU) setting, correct initial selection of an antimicrobial regimen assumes critical importance because of the high mortality rates seen in such cases. Although it was clear that MRSA was becoming an important pathogen in cases of hospital-acquired pneumonia and ventilator-associated pneumonia, it is currently considered to be the etiologic agent in 20%–40% of such cases [3, 4]. As might be expected, the situation seemed to be quite different for CAP; S. aureus was thought to be quite uncommon, typically occurring as a superinfection in patients with influenza and overall accounting for infection in only 1%–5% of all CAP patients. A sharp increase in MRSA infection in patients without obvious exposure to the healthcare system led to the recognition of the new clones referred to as CA-MRSA. CA-MRSA with its SCCmec type IV, and usually with a gene for Panton-Valentine leukocidin, has been responsible for a variety of infections with the majority of isolates in the United States being pulsed-field type USA300 [5]. The prevalence of CA-MRSA varies between countries and even within national boundaries. The community-associated variant has characteristics that distinguish it somewhat from its hospital-acquired counterpart, including susceptibility to certain antibiotics (eg, clindamycin, trimethoprim/sulfamethoxazole, and doxycycline) and differing epidemiologic risk factors such as occurrence in athletes, gay men, and patients with concurrent skin and soft tissue infections. More recently, CA-MRSA infections have begun to move from the community setting into the healthcare setting and no longer seem to be restricted to certain risk groups or to geographic locales where outbreaks first occur [4, 6]. The paper by Moran et al in this issue of Clinical Infectious Diseases provides important information regarding CA-MRSA CAP [7]. This prospective observational study was designed to determine the properties of adults with MRSA-related CAP who were hospitalized through the emergency department and to identify factors associated with such infections. Until very recently, most data on CAP caused by MRSA were provided by case series. According to one paper, “clinical presentation is usually that of a severe pneumonia with high fever, hypotension, and hemoptysis followed by rapid progression to septic shock and requirement for ventilator support” [6]. Papers from the United States and Europe have reported mortality rates >50% [8–10]. A 2010 paper by Lobo et al, however, disputed such findings [11]. In contrast to prior studies, they found (1) significantly lower mortality rates (13.3%), (2) medical care required for only approximately half of patients, (3) an absence of findings previously attributable to CA-MRSA including hemoptysis and neutropenia, and (4) no relationship to influenza. The Moran study adds to the Lobo data by finding that mortality rates (14%) were lower than expected and that clinical and epidemiologic factors thought to be associated with MRSA infection did not help in deciding initial empirical antibiotic therapy. The Moran study appears carefully planned and executed and has a number of positive features. It was carried out in 12 different cities around the United States, which hopefully mitigates regional variations in incidence of MRSA. Most important, by providing both numerator and denominator, they put the frequency of MRSA as a CAP pathogen into perspective by reporting it in only 2.4% of patients and 5% of patients admitted to the ICU. They did note, however, that, in general, patients with infection caused by MRSA tended to be sicker at the time of presentation and were more likely to require intubation or pressors or to die in the emergency department. The few weaknesses of the paper are relatively minor. It would have been nice to know the results of urine antigen or serologic testing for atypical pathogens and nasopharyngeal viral molecular testing to get an idea of their prevalence and to determine if MRSA can be a copathogen with them. The incidence may be slightly underestimated; only the peak pneumonia season was included, and CA-MRSA infections appear to have no seasonal variation [12]. Also, the authors failed to provide a definition of severe CAP used for ICU admission. Are they using the CURB criteria or the Pneumonia Severity Index score or a functional definition based on requirements for mechanical ventilation and/or vasopressors [13–15]? Finally, the fact that all 12 sites were university-affiliated centers may make their data and conclusions less generalizable than if both community-based and academic centers been involved. In the end, however, we still have a problem. The good news seems to be that MRSA CAP may not be as common or severe as previously thought—but how does the average physician decide when to treat with anti-MRSA drugs? Certainly, the risk is higher for those ill enough to require ICU admission; however, should all severe CAP cases be treated for MRSA for an average of only slightly >1 patient per hospital per season? What about those patients who are not as sick? If not treated appropriately initially, will patients who actually have CA-MRSA CAP do significantly worse? In selecting a particular antibiotic regimen, what is the best agent? Because part of the pathogenesis of S. aureus infections is dependent upon exotoxins, then perhaps drugs that suppress toxin production may be important for serious CA-MRSA infections. Lobo et al mention both linezolid and clindamycin because both can inhibit exotoxin production [11]. We are certainly in favor of linezolid for treatment of CAP caused by MRSA. As for clindamycin, however, Moran et al found that 18% of their isolates were clindamycin resistant. While this rate is certainly disconcerting, 49%–76% of such isolates were clindamycin resistant in a Boston healthcare facility [16]. Whether antibiotic sensitivity testing correlates with toxin-suppression activity is also unclear. Only prospective interventional trials will answer the questions of optimal treatment. However, the study of Moran et al presents data critical to the design and powering of such trials. The authors have therefore performed an important service for patients, clinicians, and clinical researchers.

Gatifloxacin is an advanced-generation fluoroquinolone with demonstrated efficacy and safety as therapy for community-acquired pneumonia (CAP). As part of a phase IV postmarketing surveillance program (TeqCES), 136 outpatients with CAP whose sputum was culture-positive for Streptococcus pneumoniae were enrolled in an open-label trial of oral gatifloxacin 400 mg daily for 7 to 14 days. An antibiogram of isolates showed 100% susceptibility to gatifloxacin (MIC(90) 0.5 micro g/mL) and respective susceptibilities of 67%, 70%, and 80% to penicillin, erythromycin, and tetracycline. Clinical cure was achieved in 95.3% of evaluable patients, including seven patients infected with penicillin-resistant S. pneumoniae (MICor =2 micro g/mL). The bacteriologic eradication rate for S. pneumoniae was 94.5%. Diarrhea, nausea, and dizziness, the most common adverse events in CAP patients (3%), were generally mild to moderate; no serious adverse events were recorded. These results support recommendations to treat CAP, particularly due to S. pneumoniae including multidrug-resistant strains, with the newer 8-methoxy-fluoroquinolone, gatifloxacin.

Background: Gemifloxacin is an enhanced-affinity quinolone with potent activity against lower respiratory tract pathogens. Objective: The efficacy and safety of a 5-day course of gemifloxacin were compared with those of a standard 7-day regimen of clarithromycin in patients with an acute exacerbation of chronic bronchitis (AECB). The impact of treatment on the long-term (26 weeks) clinical outcome was also assessed. Methods: The acute phase of this randomized, double-blind study was performed in 93 centers in 7 countries. Adult patients (age >40 years) with a history of chronic bronchitis and an Anthonisen type 1 acute exacerbation (increased dyspnea, cough, and sputum purulence) were eligible. Patients receiving systemic steroids at a dose of >10 mg prednisone or the equivalent were excluded. Patients were randomized to receive gemifloxacin 320 mg once daily for 5 days or clarithromycin 500 mg twice daily for 7 days. Clinical and bacteriologic response rates were assessed at the end-of-therapy visit (days 8–12), the week 2–3 follow-up visit (days 13–24), and the week 4–5 follow-up visit (days 25–38). The long-term phase (26 weeks), which included US and Canadian participants only, evaluated the proportion of patients who remained free of a recurrence of AECB requiring additional antimicrobial therapy after resolution of the initial episode. Results: Seven hundred twelve patients were randomized to treatment, 351 to gemifloxacin and 361 to clarithromycin. The long-term study included 438 patients, 214 receiving gemifloxacin and 224 receiving clarithromycin. Clinical success rates at the 2–3 week follow-up visit were 85.4% for gemifloxacin and 84.6% for clarithromycin. Bacteriologic success rates were 86.7% for gemifloxacin and 73.1% for clarithromycin. Significantly more patients receiving gemifloxacin than clarithromycin remained free of AECB recurrences (71.0% vs 58.5%, respectively; P = 0.016). Both treatments were well tolerated. Conclusions: In the acute treatment of Anthonisen type 1 AECB, a 5-day course of gemifloxacin was at least as effective as a 7-day regimen of clarithromycin. In this population, significantly more patients receiving gemifloxacin remained free of AECB recurrence after 26 weeks compared with those receiving clarithromycin.

The use of quinolones in respiratory tract infection (RTI) has developed from unpromising origins. A number of differing pathogens cause community-acquired pneumonia (CAP), which is not a homogeneous clinical entity. Fluoroquinolones refer primarily to three currently available agents: levofloxacin, gatifloxacin and moxifloxacin. A recent comprehensive review of in vitro and ex vivo models of pneumococcal infection found most to indicate positive outcomes at AUC/MIC values of 20 to 50, thus explaining the paradox of certain fluoroquinolones, such as levofloxacin, which failed to attain AUC/MIC ratios in keeping with previously recommended levels (125 or greater) yet proved highly effective in human infection. Analysis of bacteriologic results according to specific pathogens has shown that the quinolones, in particular, agents such as levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin, are at least comparable with control drugs for the treatment of infections caused by Streptococcus pneumoniae, Haemophilus influenzae, and other common pathogens. Of the various community-acquired RTIs, pharyngitis is one of the most common and carries a significant burden of illness. Of the infections described in this chapter, pharyngitis is the only one affecting the upper respiratory tract and it is responsible for 200 physician visits per 1,000 population annually. Acute bronchitis is primarily a viral or noninfective, pollution-related entity which occurs in patients with normal airways and, as such, does not routinely justify antibiotic therapy.

We report on amino acid substitutions in the quinolone resistance-determining region of type II topisomerases and the prevalence of reserpine-inhibited efflux for 70 clinical isolates of S. pneumoniae for which the ciprofloxacin MIC is ≥4 μg/ml and 28 isolates for which the ciprofloxacin MIC is ≤2 μg/ml. The amino acid substitutions in ParC conferring low-level resistance (MICs, 4 to 8 μg/ml) included Phe, Tyr, and Ala for Ser-79; Asn, Ala, Gly, Tyr, and Val for Asp-83; Asn for Asp-78; and Pro for Ala-115. Isolates with intermediate-level (MICs, 16 to 32 μg/ml) and high-level (MICs, 64 μg/ml) resistance harbored substitutions of Phe and Tyr for Ser-79 or Asn and Ala for Asp-83 in ParC and an additional substitution in GyrA which included either Glu-85-Lys (Gly) or Ser-81-Phe (Tyr). Glu-85-Lys was found exclusively in isolates with high-level resistance. Efflux contributed primarily to low-level resistance in isolates with or without an amino acid substitution in ParC. The impact of amino acid substitutions in ParE was minimal, and no substitutions in GyrB were identified.

John G. Bartlett,1 Scott F Dowell,2 Lionel A. Mandell,6 Thomas M. File, Jr.,3 Daniel M. Musher,4 and Michael J. Fine5 'Johns Hopkins University School of Medicine, Baltimore, Maryland, 2Centers for Disease Control and Prevention, Atlanta, Georgia, 3Northeastern Ohio Universities College of Medicine, Cleveland, Ohio, 4Baylor College of Medicine and Veterans Affairs Medical Center, Houston, Texas, and 5University of Pittsburgh, Pennsylvania, USA; and 6McMaster University, Toronto, Canada

Lionel A Mandell MD FRCPC1, Thomas J Marrie MD FRCPC2, Ronald F Grossman MD FRCPC FACP3, Anthony W Chow MD FRCPC FACP4, Robert H Hyland MD FRCPC5, and the Canadian CAP Working Group* McMaster University, Hamilton, Ontario; Dalhousie University, Halifax, Nova Scotia; QEII Health Sciences Centre, Halifax, Nova Scotia; University of British Columbia, Vancouver, British Columbia; St Michael’s Hospital, Toronto, Ontario

Pneumonia remains a serious medical problem, and its diagnosis and management is the source of considerable controversy. To date, 3 sets of guidelines have been published in Canada and the United States to help physicians deal with this disease in an organized manner [1-3]. Initially, there were enthusiastic and often heated discussions about the value of such guidelines, but now data support the value of regimens recommended in the guidelines and show reductions in cost, mortality, and length of hospital stay [4-6]. The guidelines have also pointed out the glaring gaps in our knowledge of the epidemiology, diagnosis, and treatment of pneumonia and have helped to direct research efforts in these areas. The latest contribution to the literature of community-acquired pneumonia (CAP) is the 2 guidelines from the United States and Canada [7, 8]. The former represents the efforts of the Infectious Diseases Society of America (IDSA) and the latter is a joint effort by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. John Bartlett (Johns Hopkins University School of Medicine, Baltimore) and I were stereoisomers of each other in these endeavors; Dr. Bartlett chaired the American effort and served on the Canadian panel, while I cochaired the Canadian opus and served on the IDSA board. It was a pleasure and a privilege to work with Dr. Bartlett and with my colleagues from across Canada and the United States.

The in vitro activity of gemifloxacin against 316 bloodstream isolates of staphylococci, pneumococci, and enterococci was compared with the activities of six fluoroquinolones and three other antimicrobial agents. Of the antimicrobial agents tested, gemifloxacin was the most potent against penicillin-intermediate and -resistant pneumococci, methicillin-susceptible and -resistant Staphylococcus epidermidis isolates, and coagulase-negative staphylococci.

Difficult-to-treat infections caused by gram-negative pathogens are common in the hospital setting, particularly those caused by Pseudomonas aeruginosa, Acinetobacter species, and extended-spectrum beta-lactamase-producing Enterobacteriaceae, all of which are capable of developing resistance to common antimicrobial agents. New drugs are urgently needed to combat this threat. In this supplement, researchers in infectious diseases discuss the role of doripenem, a newly approved carbapenem, in the treatment of serious nosocomial infections and review new data on doripenem for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. The topics addressed include antimicrobial resistance and the available therapeutic options against gram-negative pathogens, the in vitro activity of doripenem, the efficacy and safety of intravenous infusion of doripenem, and the clinical and economic consequences of ventilator-associated pneumonia. Based on the strength of the clinical evidence presented, doripenem appears to provide broad-spectrum coverage and antipseudomonal activity, leading to advantageous clinical outcomes, particularly in patients at risk of infection with drug-resistant pathogens.

This article takes a broad perspective of community-acquired pneumonia (CAP). The arguments and data that support or refute the current approaches to initial antimicrobial treatment of CAP as outlined in the American Thoracic Society and Infectious Disease Society of America documents are provided. The complex issues involved in the decision of how to properly treat CAP are addressed.

OBJECTIVE: To describe outbreaks of infection caused by Legionella sainthelensi occurring in older residents of two nursing homes and to determine risk factors for the development of infection. DESIGN: Descriptive epidemiology and a case-control study. SETTING: Two nursing homes (140 beds and 254 beds in nursing homes A and B, respectively) located in southern Ontario, Canada, experiencing outbreaks of respiratory tract infection in July and August 1994. SUBJECTS: Case-residents of the two nursing homes who met clinical and laboratory criteria for Legionella infection. Control-residents were defined as those who were in the homes during the outbreaks and were asymptomatic. MEASUREMENTS: Active surveillance was conducted in both nursing homes to identify symptomatic residents. Residents with fever or respiratory tract symptoms had nasopharyngeal swabs taken for viral antigen detection and culture, urine for Legionella antigen detection, and acute and convalescent serology for viruses, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella. Chest X-rays were performed, and an attempt was made to obtain blood and sputum cultures. Water samples from shower heads, faucets, and air conditioning units were collected for Legionella culture and polymerase chain reaction (PCR) assay. A case-control study was done to assess possible risk factors for legionellosis. RESULTS: Twenty-nine cases — 17 in nursing home A; 12 in nursing home B — were identified. Four (14%) case-residents had documented pneumonia and four case-residents died. Univariate analysis revealed that a history of stroke (odds ratio (OR) 2.3 (95% CI, 1.0–5.3)), eating pureed food (OR 4.6 (95% CI, 1.6–12.7)), and having fluids administered with medication (OR 2.5 (95% CI, 1.0–5.9)) were significant risk factors. Cases were less likely to wear dentures (OR .4 (95% CI, .2-.9)) or to eat solid food (OR .3, (95% CI, .1-.6)). Only eating pureed food remained significant in a multivariable analysis (OR 4.6 (95% CI, 1.6–13.0, P = .01)). CONCLUSION: This report describes outbreaks of legionellosis in two nursing homes, representing the first reported outbreaks of infection caused by Legionella sainthelensi. The association with illness of dietary characteristics indicative of swallowing disorders suggests that aspiration was the most likely mode of infection. The diagnosis of legionellosis should be considered during outbreaks of respiratory infection in nursing homes. J Am Geriatr Soc 47:547–552, 1999.

pirical in nature rather than directed against a specific pathogen. In an attempt to address this problem and to optimize the care of patients with CAP, a number of societies around the world have developed guidelines for the treatment of CAP. Beyond the immediate and obvious benefit of providing physicians with an approach to the initial treatment of these patients, some of the guidelines have helped to highlight the gaps and deficiencies in our knowledge about this disease, thereby helping to direct future studies. The guidelines have also codified our treatment of patients with CAP and have resulted in a reduction in mortality, length of hospital stay, and cost [3].