CASE CONFERENCES The Expert Clinician Section Editor: Peter Clardy, M.D., and Charlie Strange, M.D.
A Noteworthy Case of Acute Bronchitis Patrick R. Aguilar1, Keki Balsara2, Akinobu Itoh2, and Marin H. Kollef1 1 Division of Pulmonary and Critical Care Medicine, and 2Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri
In Brief A middle-aged woman with asthma sought medical attention for fever and shortness of breath in an emergency department. She was given a prescription for azithromycin for suspected bronchitis and sent home. The treatment was ineffective. She became progressively ill, requiring extraordinary care.
Case Vignette A 42-year-old woman with asthma and active tobacco use presented to an emergency room with a 1-day history of dyspnea, cough, and left shoulder pain. Her initial physical examination was notable for a blood pressure of 138/56, heart rate of 105 beats per minute, temperature of 39.68 C, respiratory rate of 23 breaths per minute, and an oxygen saturation of 97% while breathing ambient air. Auscultation revealed no adventitious breath sounds, and a chest radiograph showed clear lung fields. Laboratory analysis demonstrated a white blood cell count of 22,600 cell/ml, serum sodium of 132 mg/dl, and serum creatinine of 0.82 mg/dl. She was discharged home on azithromycin. Blood cultures obtained during her initial visit grew azithromycin-resistant Streptococcus pneumoniae. Despite multiple attempts, the clinical team was unable to contact the patient to communicate those results. Three days after her initial presentation, she returned with progressively worsening dyspnea. A chest radiograph
Figure 1. Chest radiograph (A) on initial evaluation in the emergency department and (B) on subsequent admission to the intensive care unit.
demonstrated bilateral infiltrates, and she was found to be severely hypoxemic, requiring emergent intubation (Figure 1). The woman remained profoundly hypoxemic after intubation despite maximally supportive mechanical ventilation with a partial pressure of arterial oxygen (PaO2) of 49 mm Hg. She was transferred to our center for management of advanced respiratory failure. On arrival, the woman developed hemodynamic and respiratory instability. She underwent urgent cannulation followed by initiation of peripheral venoarterial extracorporeal membrane oxygenation (ECMO). On Day 3, she developed limb ischemia distal to the femoral cannulation site and was converted to a central cannulation strategy. Her ECMO course was complicated by acute kidney injury necessitating renal replacement therapy. After 9 days of support, she was successfully weaned from ECMO. She ultimately underwent tracheostomy to enable
ventilator weaning. Her course was complicated by fungal mediastinitis requiring multiple debridements, partial sternectomies, and muscle flap revisions to achieve eventual chest closure. On hospital day 52, the tracheostomy was removed with maintenance of adequate oxygenation while breathing room air. On day 69, she was transferred to a long-term acute care hospital for continuation of hemodialysis, prolonged antifungal therapy, and rehabilitation.
Questions 1. What was the most likely presenting diagnosis? 2. Did this patient initially warrant inpatient hospitalization? 3. What initial empiric antibiotic regimen would have been most appropriate in this circumstance? [Continue onto next page for answers]
(Received in original form August 13, 2015; accepted in final form November 16, 2015 ) Correspondence and requests for reprints should be addressed to Marin H. Kollef, M.D., Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8052, St. Louis, MO 63110. E-mail: [email protected] Ann Am Thorac Soc Vol 13, No 2, pp 285–287, Feb 2016 Copyright © 2016 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201508-518CC Internet address: www.atsjournals.org
Case Conferences: The Expert Clinician
285
CASE CONFERENCES Clinical Reasoning
Discussion
Differentiating pneumonia from acute bronchitis remains a complex clinical challenge. Both upper and lower tract infections may be associated with cough, dyspnea, and fever, although the degree of fever is typically lower in patients with bronchitis. By convention, infectious complications of the lower respiratory tract are typically thought to constitute pneumonia when radiographic infiltrates are present. However, this distinction is insufficiently sensitive, and lower tract infections may initially be unapparent radiographically. Numerous clinical decision tools are available to inform the proper disposition of patients suspected of having pneumonia (1). For the patient described in this article, the degree of elevation in body temperature, the profound leukocytosis, and the rapid onset of symptoms suggested that a pneumonic process involving the lower respiratory tract was more likely than was uncomplicated acute bronchitis involving only the upper respiratory tract. However, her young age, her blood pressure and other vital signs, and her essentially normal blood chemistry panel suggested that she may be an appropriate candidate for outpatient management. The most recent guidelines for the treatment of community-acquired pneumonia recommend antibiotic therapy with either a respiratory fluoroquinolone, such as moxifloxacin or levofloxacin, or the combination of a b-lactam and macrolide (2). Risk factors for drug-resistant Streptococcal infection include chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; an immunosuppressed state; or the use of antimicrobial drugs within the previous 3 months (Table 1). Macrolide monotherapy may be considered in the absence of any of these risk factors. Given the patient’s history of asthma, the use of macrolide monotherapy was not consistent with published recommendations.
Azithromycin, developed in the 1980s, has long been a mainstay of therapy for respiratory tract infections. Azithromycin is prescribed frequently to outpatients with symptoms of cough and dyspnea. During 2011, an estimated 262.5 million prescriptions were written for antibiotics in the United States; azithromycin was the single most commonly prescribed agent, accounting for 54.1 million prescriptions (3). According to the Centers for Disease Control, from 1995 to 1999, macrolide use increased by 320% among children (4). As noted previously, azithromycin monotherapy represents guideline-concordant therapy only in especially low-risk individuals with suspected pneumonia (2). The problem of macrolide resistance is not new, and two major mechanisms of pneumococcal resistance have been described. One pattern of resistance, called the M phenotype, involves the presence of an efflux pump, which results in the extrusion of antibiotic from the cell. A second pattern, called the MLSb phenotype, causes methylation of adenine residues in the pneumococcal 23S ribosomal RNA peptidyl transferase center, resulting in inhibition of macrolide binding (4). Pneumococcal macrolide resistance rates demonstrate substantial geographic variability. Among a series of 2,184 invasive pneumococcal isolates collected by the Asian Network for Surveillance of Resistant Pathogens, the prevalence of macrolide resistance in nonmeningeal isolates was 72.7% (5). The prevalence of macrolide resistance in the United States has been reported to range from 18 to 35% (6). As a result of the increasing prevalence of macrolide resistance among pneumococcal isolates, multiple reports of treatment failure have been associated with the use of azithromycin monotherapy for invasive pneumococcal disease. In one series, patients with macrolide-resistant pneumococcus on macrolide monotherapy were significantly more likely to experience breakthrough bacteremia than were those whose strains were susceptible to macrolide (7). This finding has been validated in separate cohorts, confirming the notion that the in vitro macrolide resistance observed in some pneumococcal isolates plays an important role in determining the clinical response to therapy in patients (8).
Table 1. Risk factors for drug-resistant Streptococcus Cardiac disease Hepatic cirrhosis Diabetes mellitus Alcoholism Immunosuppressed state Chronic lung disease End-stage renal disease Use of antimicrobials in previous 3 mo
286
Provision of azithromycin monotherapy to the patient described above was ultimately suboptimal in the setting of a macrolide-resistant strain of pneumococcus. She developed bacteremia and progressively worsening disease. Use of appropriately targeted antibiotics may have prevented progression of disease in the presented patient and saved her the complex course and prolonged recovery. However, even when adjusted for age, comorbidities, and timing of initial antibiotic dose, tobacco abuse remains an independent risk factor for mortality in patients with pneumococcal pneumonia (9). Antibiotic discovery has been slowed by technological and economic limitations, leading to increasing morbidity and mortality associated with resistant bacteria. Every year, approximately 2 million Americans develop an illness related to antibiotic-resistant organisms, resulting in at least 23,000 attributable deaths (10). There are a number of new antimicrobial medications with activity against macrolide-resistant Streptococcus; however, many of these require parenteral administration. In contrast, omadacycline, a 9-aminomethylcycline antibiotic with activity against Streptococcus, has oral bioavailability and represents a potentially promising option for the outpatient treatment of community-acquired pneumonia (11). More work is needed to identify and develop new antibiotics to decrease the impact of disease caused by resistant organisms. Azithromycin continues to be prescribed commonly for patients with symptoms of upper respiratory infection. Given the increasing incidence of macrolide resistance and the evidence for enhanced resistance in the setting of increased prescribing, a continued increase in the incidence of macrolide-resistant pneumococcus is likely. As a result, those treating patients with suggestive symptoms should be mindful of the risk, and should carefully consider alternative therapies when antibiotic treatment is warranted.
Answers 1. What is the most likely presenting diagnosis?
AnnalsATS Volume 13 Number 2 | February 2016
CASE CONFERENCES Radiographically unapparent community-acquired pneumonia.
b-lactam and a macrolide should have been provided.
2. Did this patient initially warrant inpatient hospitalization?
Follow-Up
Initially, outpatient management would have been reasonable with her presenting vital signs and laboratory findings.
After a prolonged recuperation, the patient was discharged from the long-term acute care to follow-up with physicians in her home community.
3. What initial empiric antibiotic regimen would have been most appropriate in this circumstance?
Insights
With her chronic respiratory disease and tobacco abuse, a course of a respiratory fluoroquinolone or the combination of a
d
d
Macrolide resistance is recognized increasingly in strains of Streptococcus pneumoniae.
References 1 Singanayagam A, Chalmers JD, Hill AT. Severity assessment in community-acquired pneumonia: a review. QJM 2009;102: 379–388. 2 Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, et al.; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44: S27–S72 3 Hicks LA, Chien YW, Taylor TH Jr, Haber M, Klugman KP; Active Bacterial Core Surveillance (ABCs) Team. Outpatient antibiotic prescribing and nonsusceptible Streptococcus pneumoniae in the United States, 1996-2003. Clin Infect Dis 2011;53:631–639. 4 Hyde TB, Gay K, Stephens DS, Vugia DJ, Pass M, Johnson S, Barrett NL, Schaffner W, Cieslak PR, Maupin PS, et al.; Active Bacterial Core Surveillance/Emerging Infections Program Network. Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA 2001;286:1857–1862. 5 Kim SH, Song JH, Chung DR, Thamlikitkul V, Yang Y, Wang H, Lu M, So TM, Hsueh PR, Yasin RM, et al.; ANSORP Study Group. Changing trends in antimicrobial resistance and serotypes of Streptococcus pneumoniae isolates in Asian countries: an Asian
Case Conferences: The Expert Clinician
d
6
7
8
9
10 11
Macrolide-resistant Streptococcus pneumoniae is associated with clinical failure when treated with macrolide monotherapy. Only patients in the absolute lowest risk strata (specifically, those with no other medical problems or risk factors for severe illness) who have had no recent antibiotic exposure should be considered for outpatient macrolide monotherapy for lower respiratory tract infections. n
Author disclosures are available with the text of this article at www.atsjournals.org.
Network for Surveillance of Resistant Pathogens (ANSORP) study. Antimicrob Agents Chemother 2012;56:1418–1426. Cilloniz C, Albert RK, Liapikou A, Gabarrus A, Rangel E, Bello S, Marco F, Mensa J, Torres A. The effect of macrolide resistance on the presentation and outcome of patients hospitalized for Streptococcus pneumoniae pneumonia. Am J Respir Crit Care Med 2015;191: 1265–1272. Lonks JR, Garau J, Gomez L, Xercavins M, Ochoa de Echaguen ¨ A, Gareen IF, Reiss PT, Medeiros AA. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002;35:556–564. Van Kerkhoven D, Peetermans WE, Verbist L, Verhaegen J. Breakthrough pneumococcal bacteraemia in patients treated with clarithromycin or oral beta-lactams. J Antimicrob Chemother 2003; 51:691–696. Bello S, Menendez ´ R, Torres A, Reyes S, Zalacain R, Capelastegui A, Aspa J, Border´ıas L, Martin-Villasclaras JJ, Alfageme I, et al. Tobacco smoking increases the risk for death from pneumococcal pneumonia. Chest 2014;146:1029–1037. Arias CA, Murray BE. A new antibiotic and the evolution of resistance. N Engl J Med 2015;372:1168–1170. Macone AB, Caruso BK, Leahy RG, Donatelli J, Weir S, Draper MP, Tanaka SK, Levy SB. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents Chemother 2014;58:1127–1135.
287
A Noteworthy Case of Acute Bronchitis Patrick R. Aguilar1, Keki Balsara2, Akinobu Itoh2, and Marin H. Kollef1 1 Division of Pulmonary and Critical Care Medicine, and 2Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri
In Brief A middle-aged woman with asthma sought medical attention for fever and shortness of breath in an emergency department. She was given a prescription for azithromycin for suspected bronchitis and sent home. The treatment was ineffective. She became progressively ill, requiring extraordinary care.
Case Vignette A 42-year-old woman with asthma and active tobacco use presented to an emergency room with a 1-day history of dyspnea, cough, and left shoulder pain. Her initial physical examination was notable for a blood pressure of 138/56, heart rate of 105 beats per minute, temperature of 39.68 C, respiratory rate of 23 breaths per minute, and an oxygen saturation of 97% while breathing ambient air. Auscultation revealed no adventitious breath sounds, and a chest radiograph showed clear lung fields. Laboratory analysis demonstrated a white blood cell count of 22,600 cell/ml, serum sodium of 132 mg/dl, and serum creatinine of 0.82 mg/dl. She was discharged home on azithromycin. Blood cultures obtained during her initial visit grew azithromycin-resistant Streptococcus pneumoniae. Despite multiple attempts, the clinical team was unable to contact the patient to communicate those results. Three days after her initial presentation, she returned with progressively worsening dyspnea. A chest radiograph
Figure 1. Chest radiograph (A) on initial evaluation in the emergency department and (B) on subsequent admission to the intensive care unit.
demonstrated bilateral infiltrates, and she was found to be severely hypoxemic, requiring emergent intubation (Figure 1). The woman remained profoundly hypoxemic after intubation despite maximally supportive mechanical ventilation with a partial pressure of arterial oxygen (PaO2) of 49 mm Hg. She was transferred to our center for management of advanced respiratory failure. On arrival, the woman developed hemodynamic and respiratory instability. She underwent urgent cannulation followed by initiation of peripheral venoarterial extracorporeal membrane oxygenation (ECMO). On Day 3, she developed limb ischemia distal to the femoral cannulation site and was converted to a central cannulation strategy. Her ECMO course was complicated by acute kidney injury necessitating renal replacement therapy. After 9 days of support, she was successfully weaned from ECMO. She ultimately underwent tracheostomy to enable
ventilator weaning. Her course was complicated by fungal mediastinitis requiring multiple debridements, partial sternectomies, and muscle flap revisions to achieve eventual chest closure. On hospital day 52, the tracheostomy was removed with maintenance of adequate oxygenation while breathing room air. On day 69, she was transferred to a long-term acute care hospital for continuation of hemodialysis, prolonged antifungal therapy, and rehabilitation.
Questions 1. What was the most likely presenting diagnosis? 2. Did this patient initially warrant inpatient hospitalization? 3. What initial empiric antibiotic regimen would have been most appropriate in this circumstance? [Continue onto next page for answers]
(Received in original form August 13, 2015; accepted in final form November 16, 2015 ) Correspondence and requests for reprints should be addressed to Marin H. Kollef, M.D., Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8052, St. Louis, MO 63110. E-mail: [email protected] Ann Am Thorac Soc Vol 13, No 2, pp 285–287, Feb 2016 Copyright © 2016 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201508-518CC Internet address: www.atsjournals.org
Case Conferences: The Expert Clinician
285
CASE CONFERENCES Clinical Reasoning
Discussion
Differentiating pneumonia from acute bronchitis remains a complex clinical challenge. Both upper and lower tract infections may be associated with cough, dyspnea, and fever, although the degree of fever is typically lower in patients with bronchitis. By convention, infectious complications of the lower respiratory tract are typically thought to constitute pneumonia when radiographic infiltrates are present. However, this distinction is insufficiently sensitive, and lower tract infections may initially be unapparent radiographically. Numerous clinical decision tools are available to inform the proper disposition of patients suspected of having pneumonia (1). For the patient described in this article, the degree of elevation in body temperature, the profound leukocytosis, and the rapid onset of symptoms suggested that a pneumonic process involving the lower respiratory tract was more likely than was uncomplicated acute bronchitis involving only the upper respiratory tract. However, her young age, her blood pressure and other vital signs, and her essentially normal blood chemistry panel suggested that she may be an appropriate candidate for outpatient management. The most recent guidelines for the treatment of community-acquired pneumonia recommend antibiotic therapy with either a respiratory fluoroquinolone, such as moxifloxacin or levofloxacin, or the combination of a b-lactam and macrolide (2). Risk factors for drug-resistant Streptococcal infection include chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; an immunosuppressed state; or the use of antimicrobial drugs within the previous 3 months (Table 1). Macrolide monotherapy may be considered in the absence of any of these risk factors. Given the patient’s history of asthma, the use of macrolide monotherapy was not consistent with published recommendations.
Azithromycin, developed in the 1980s, has long been a mainstay of therapy for respiratory tract infections. Azithromycin is prescribed frequently to outpatients with symptoms of cough and dyspnea. During 2011, an estimated 262.5 million prescriptions were written for antibiotics in the United States; azithromycin was the single most commonly prescribed agent, accounting for 54.1 million prescriptions (3). According to the Centers for Disease Control, from 1995 to 1999, macrolide use increased by 320% among children (4). As noted previously, azithromycin monotherapy represents guideline-concordant therapy only in especially low-risk individuals with suspected pneumonia (2). The problem of macrolide resistance is not new, and two major mechanisms of pneumococcal resistance have been described. One pattern of resistance, called the M phenotype, involves the presence of an efflux pump, which results in the extrusion of antibiotic from the cell. A second pattern, called the MLSb phenotype, causes methylation of adenine residues in the pneumococcal 23S ribosomal RNA peptidyl transferase center, resulting in inhibition of macrolide binding (4). Pneumococcal macrolide resistance rates demonstrate substantial geographic variability. Among a series of 2,184 invasive pneumococcal isolates collected by the Asian Network for Surveillance of Resistant Pathogens, the prevalence of macrolide resistance in nonmeningeal isolates was 72.7% (5). The prevalence of macrolide resistance in the United States has been reported to range from 18 to 35% (6). As a result of the increasing prevalence of macrolide resistance among pneumococcal isolates, multiple reports of treatment failure have been associated with the use of azithromycin monotherapy for invasive pneumococcal disease. In one series, patients with macrolide-resistant pneumococcus on macrolide monotherapy were significantly more likely to experience breakthrough bacteremia than were those whose strains were susceptible to macrolide (7). This finding has been validated in separate cohorts, confirming the notion that the in vitro macrolide resistance observed in some pneumococcal isolates plays an important role in determining the clinical response to therapy in patients (8).
Table 1. Risk factors for drug-resistant Streptococcus Cardiac disease Hepatic cirrhosis Diabetes mellitus Alcoholism Immunosuppressed state Chronic lung disease End-stage renal disease Use of antimicrobials in previous 3 mo
286
Provision of azithromycin monotherapy to the patient described above was ultimately suboptimal in the setting of a macrolide-resistant strain of pneumococcus. She developed bacteremia and progressively worsening disease. Use of appropriately targeted antibiotics may have prevented progression of disease in the presented patient and saved her the complex course and prolonged recovery. However, even when adjusted for age, comorbidities, and timing of initial antibiotic dose, tobacco abuse remains an independent risk factor for mortality in patients with pneumococcal pneumonia (9). Antibiotic discovery has been slowed by technological and economic limitations, leading to increasing morbidity and mortality associated with resistant bacteria. Every year, approximately 2 million Americans develop an illness related to antibiotic-resistant organisms, resulting in at least 23,000 attributable deaths (10). There are a number of new antimicrobial medications with activity against macrolide-resistant Streptococcus; however, many of these require parenteral administration. In contrast, omadacycline, a 9-aminomethylcycline antibiotic with activity against Streptococcus, has oral bioavailability and represents a potentially promising option for the outpatient treatment of community-acquired pneumonia (11). More work is needed to identify and develop new antibiotics to decrease the impact of disease caused by resistant organisms. Azithromycin continues to be prescribed commonly for patients with symptoms of upper respiratory infection. Given the increasing incidence of macrolide resistance and the evidence for enhanced resistance in the setting of increased prescribing, a continued increase in the incidence of macrolide-resistant pneumococcus is likely. As a result, those treating patients with suggestive symptoms should be mindful of the risk, and should carefully consider alternative therapies when antibiotic treatment is warranted.
Answers 1. What is the most likely presenting diagnosis?
AnnalsATS Volume 13 Number 2 | February 2016
CASE CONFERENCES Radiographically unapparent community-acquired pneumonia.
b-lactam and a macrolide should have been provided.
2. Did this patient initially warrant inpatient hospitalization?
Follow-Up
Initially, outpatient management would have been reasonable with her presenting vital signs and laboratory findings.
After a prolonged recuperation, the patient was discharged from the long-term acute care to follow-up with physicians in her home community.
3. What initial empiric antibiotic regimen would have been most appropriate in this circumstance?
Insights
With her chronic respiratory disease and tobacco abuse, a course of a respiratory fluoroquinolone or the combination of a
d
d
Macrolide resistance is recognized increasingly in strains of Streptococcus pneumoniae.
References 1 Singanayagam A, Chalmers JD, Hill AT. Severity assessment in community-acquired pneumonia: a review. QJM 2009;102: 379–388. 2 Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, et al.; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44: S27–S72 3 Hicks LA, Chien YW, Taylor TH Jr, Haber M, Klugman KP; Active Bacterial Core Surveillance (ABCs) Team. Outpatient antibiotic prescribing and nonsusceptible Streptococcus pneumoniae in the United States, 1996-2003. Clin Infect Dis 2011;53:631–639. 4 Hyde TB, Gay K, Stephens DS, Vugia DJ, Pass M, Johnson S, Barrett NL, Schaffner W, Cieslak PR, Maupin PS, et al.; Active Bacterial Core Surveillance/Emerging Infections Program Network. Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA 2001;286:1857–1862. 5 Kim SH, Song JH, Chung DR, Thamlikitkul V, Yang Y, Wang H, Lu M, So TM, Hsueh PR, Yasin RM, et al.; ANSORP Study Group. Changing trends in antimicrobial resistance and serotypes of Streptococcus pneumoniae isolates in Asian countries: an Asian
Case Conferences: The Expert Clinician
d
6
7
8
9
10 11
Macrolide-resistant Streptococcus pneumoniae is associated with clinical failure when treated with macrolide monotherapy. Only patients in the absolute lowest risk strata (specifically, those with no other medical problems or risk factors for severe illness) who have had no recent antibiotic exposure should be considered for outpatient macrolide monotherapy for lower respiratory tract infections. n
Author disclosures are available with the text of this article at www.atsjournals.org.
Network for Surveillance of Resistant Pathogens (ANSORP) study. Antimicrob Agents Chemother 2012;56:1418–1426. Cilloniz C, Albert RK, Liapikou A, Gabarrus A, Rangel E, Bello S, Marco F, Mensa J, Torres A. The effect of macrolide resistance on the presentation and outcome of patients hospitalized for Streptococcus pneumoniae pneumonia. Am J Respir Crit Care Med 2015;191: 1265–1272. Lonks JR, Garau J, Gomez L, Xercavins M, Ochoa de Echaguen ¨ A, Gareen IF, Reiss PT, Medeiros AA. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002;35:556–564. Van Kerkhoven D, Peetermans WE, Verbist L, Verhaegen J. Breakthrough pneumococcal bacteraemia in patients treated with clarithromycin or oral beta-lactams. J Antimicrob Chemother 2003; 51:691–696. Bello S, Menendez ´ R, Torres A, Reyes S, Zalacain R, Capelastegui A, Aspa J, Border´ıas L, Martin-Villasclaras JJ, Alfageme I, et al. Tobacco smoking increases the risk for death from pneumococcal pneumonia. Chest 2014;146:1029–1037. Arias CA, Murray BE. A new antibiotic and the evolution of resistance. N Engl J Med 2015;372:1168–1170. Macone AB, Caruso BK, Leahy RG, Donatelli J, Weir S, Draper MP, Tanaka SK, Levy SB. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents Chemother 2014;58:1127–1135.
287
