Acute COPD Exacerbation

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Management of infection in exacerbations of chronic obstructive pulmonary disease

INTRODUCTION

Most exacerbations of chronic obstructive pulmonary disease (COPD) are caused by respiratory tract infections. Empiric antibiotic therapy is indicated for patients who are most likely to have a bacterial infection causing the exacerbation and for those who are most ill.

The role of antibiotic therapy in exacerbations of COPD will be reviewed here. The evaluation for infection in exacerbations of COPD and other aspects of management (eg, bronchodilators, glucocorticoids, oxygen, and mechanical ventilation) are discussed separately. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease" and "COPD exacerbations: Management".)

DEFINITIONS

The Global Initiative for Chronic Obstructive Lung Disease guidelines define an exacerbation of COPD as an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days, which may be accompanied by tachypnea and/or tachycardia, and is often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insult to the airways [1,2].

The three cardinal symptoms that characterize an exacerbation of COPD are [1,3]:

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023. This topic last updated: Mar 03, 2023.

Other findings that may accompany the cardinal symptoms of an exacerbation of COPD (eg, tachypnea, chest discomfort, fatigue, sleep disturbance, decline in pulmonary function) are discussed separately. (See "COPD exacerbations: Management".)

INDICATIONS FOR ANTIBACTERIAL THERAPY

Our approach — Empiric antibiotic therapy is indicated for patients who are most likely to have a bacterial infection causing the exacerbation and for those who are most ill [1,4]. In general, we determine the need for antibiotics based on the number of cardinal symptoms present, and the need for hospitalization and/or ventilatory support [1,5-7].

Antibiotics are also indicated for patients with concurrent pneumonia (ie, those with fever, signs of consolidation on chest examination and/or chest imaging). Selection of an antibiotic regimen for patients with pneumonia differs from COPD exacerbations and is discussed separately. (See "Overview of community-acquired pneumonia in adults" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

Rationale — Our approach is based upon randomized trials and large cohort studies demonstrating that prompt, appropriate antibiotic use improves clinical outcomes for selected patients with COPD exacerbations [3,9-16]. The benefit is greatest in severely ill patients and those with a greater number of symptoms but appears to diminish as the severity of illness declines. In a meta-analysis of five randomized trials evaluating 803 patients hospitalized with an acute COPD exacerbation, antibiotic use was associated with reduced treatment failure when compared with placebo (risk ratio [RR] 0.76, 95% CI 0.58-1.0) [9]. The benefits of antibiotic treatment were most prominent in a single trial evaluating 93 intensive care unit (ICU) patients,

Increased dyspnea●

Increased sputum volume and/or viscosity●

Increased sputum purulence●

We suggest empiric antibiotic treatment in patients with a COPD exacerbation and ≥2 of 3 cardinal symptoms: increased dyspnea, increased sputum volume/viscosity, or increased sputum purulence or a COPD exacerbation requiring hospitalization and/or ventilatory support (either invasive or noninvasive).

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We do not initiate antibiotic therapy in patients with a COPD exacerbation and only 1 of 3 cardinal symptoms who do not require hospitalization or ventilatory support. New onset of increased wheezing may serve as an additional negative predictor for bacterial infection; therefore, if it is a prominent finding, it steers us away from antibiotic use [8].

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which showed a reduction in all-cause mortality (4 versus 22 percent with placebo) in addition to reductions in treatment failure, duration of mechanical ventilation, length of ICU stay, and need for additional courses of antibiotics [10]. In a cohort study evaluating >84,000 hospitalized patients with COPD exacerbations, the risk of treatment failure was lower when antibiotics were given in the first two hospital days compared with later treatment or no treatment (odds ratio [OR] 0.87, 95% CI 0.82-0.92) [12]. Multivariate analysis of this cohort demonstrated that antibiotic treatment was associated with decreased risk of in-hospital mortality (OR 0.60, 95% CI 0.50-0.73) and a substantial reduction in the risk of 30-day readmission for COPD (OR 0.87, 95% CI 0.79-0.96) [14].

Although meta-analyses of randomized trials and large cohort studies have also found reduced treatment failure rates with antibiotic use in outpatients [9,11], the benefit appears to be greatest in those with a higher number of cardinal symptoms. This finding is best supported by the Anthonisen trial, one of the largest and more rigorous randomized trials evaluating the efficacy for antibiotics for COPD exacerbations to date [3]. The trial evaluated 173 patients and a total of 362 COPD exacerbations over a three and a half year period. Antibiotic therapy was associated with increased clinical improvement (defined as resolution of symptoms without additional intervention) compared with placebo (68 versus 55 percent). The greatest effect was observed in patients who presented with increased dyspnea, sputum production, and sputum purulence when compared with placebo (63 versus 43 percent); benefit was least evident in patients with only one of these three symptoms (75 versus 70 percent). This observation serves as the foundation for the antibiotic treatment indications outlined above.

Based upon these studies, most clinical practice guidelines recommend antibiotic treatment of moderate to severe exacerbations for outpatients and patients who require hospitalization but not routinely for those with mild exacerbations in the outpatient setting [1]. Our approach is similar to but varies slightly from the strategy outlined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which recommends antibiotic therapy for patients who have the following features: a severe exacerbation requiring mechanical ventilation (noninvasive or invasive), an exacerbation with all three cardinal symptoms, or an exacerbation with two of these three symptoms if sputum purulence is one of the symptoms [1,3,17]. While some studies suggest that sputum purulence is associated with an increased likelihood of infection [18,19], this finding is not consistent across studies [20,21], and we do not consider this finding alone to be clearly predictive of need for antibiotic treatment [22,23].

CRP and procalcitonin — Multiple studies have addressed use of serum biomarkers, such as C- reactive protein (CRP) and procalcitonin, to help determine the need for antibiotic treatment in patients with COPD exacerbations [24-29]. However, study results do not clearly and

consistently demonstrate that use of either assay adds value to clinical judgment alone; we generally do not use them to guide treatment decisions. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'Procalcitonin and C- reactive protein' and "Procalcitonin use in lower respiratory tract infections", section on 'Acute exacerbations of chronic obstructive pulmonary disease'.)

EMPIRIC ANTIBACTERIAL TREATMENT

Risk stratification — We use a "risk stratification" approach when selecting initial empiric antibiotic therapy for the treatment of acute exacerbations of COPD [30,31]. We categorize patients based on treatment setting (eg, outpatient versus inpatient), risk for poor clinical outcomes, and risk for infection with Pseudomonas ( algorithm 1A-B).

This approach to risk stratification promotes judicious antibiotic use by reserving broader spectrum empiric regimens for patients with greater underlying COPD severity [32,39,40].

Risk for poor outcomes – Patients with greater underlying COPD severity are at higher risk for poor outcomes if initial antibiotic therapy is inadequate. We thus use a broader empiric regimen for such patients. Risk factors for poor outcomes include [32-34]:

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Comorbid conditions (especially heart failure or ischemic heart disease)• Severe underlying COPD (forced expiratory volume in one second [FEV ] <50 percent)• 1

Frequent exacerbations of COPD (ie, ≥2 exacerbations per year)• Hospitalization for an exacerbation within the past three months• Receipt of continuous supplemental oxygen•

Older age (eg, age ≥65 years) is also associated with poorer outcomes and/or risk of infection with drug-resistant pathogens. While not a strict indication for broadening antibiotic therapy, we consider older age as additive to the risk factors listed above.

Risk for pseudomonal infection – Patients with greater underlying COPD severity are also at risk for infection with Pseudomonas. Specific factors associated with an increased risk of Pseudomonas infection include [35-38]:

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Chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum• Very severe COPD (FEV <30 percent predicted)• 1

Bronchiectasis on chest imaging (eg, chest radiograph, computed tomography)• Broad-spectrum antibiotic use within the past three months• Chronic systemic glucocorticoid use•

Although it has not been validated in clinical trials, similar approaches are used for the treatment of other infectious diseases (eg, community-acquired pneumonia, acute rhinosinusitis) [41,42].

Antibiotic selection — Empiric antibiotic regimens are designed to target the most likely infecting pathogens ( table 1). Specific antibiotic selection and need for sputum Gram stain and culture vary based on risk for poor clinical outcomes, risk for infection with Pseudomonas, and treatment setting ( algorithm 1A-B) [1,34,37]. Determining need for hospitalization in patients with COPD exacerbations is discussed elsewhere. (See "COPD exacerbations: Management", section on 'Triage to home or hospital'.) (Related Pathway(s): Chronic obstructive pulmonary disease: Identifying patients with an acute exacerbation who warrant hospitalization.)

Outpatients — Antibiotic therapy is indicated for outpatients with COPD exacerbations and an increase in ≥2 of 3 cardinal symptoms: dyspnea, sputum volume/viscosity, or sputum purulence ( algorithm 1A) [34,37]. Patients with only one cardinal symptom generally do not require antibiotic therapy. (See 'Indications for antibacterial therapy' above.) (Related Pathway(s): Chronic obstructive pulmonary disease: Empiric antimicrobial therapy for outpatients with acute exacerbations.)

For outpatients who do not have risk factors for poor outcomes or Pseudomonas infection, we target Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis and select among the following options: a macrolide (ie, azithromycin, clarithromycin) or a second- or third-generation cephalosporin (eg, cefuroxime, cefpodoxime, cefdinir). Trimethoprim-sulfamethoxazole is a reasonable alternative to these agents but not first line because trial data suggest it may be less effective [43]. We no longer use doxycycline based on a randomized trial showing minimal benefit [44].

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For outpatients who have risk factors for poor outcomes (but no increased risk for Pseudomonas infection) ( table 2), we broaden the initial regimen to include treatment for macrolide-resistant S. pneumoniae and to enhance eradication of H. influenzae. For these patients, we select either amoxicillin-clavulanate or a respiratory fluoroquinolone (ie, levofloxacin or moxifloxacin).

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For outpatients who have risk factors for poor outcomes and a risk for Pseudomonas infection ( table 3), we generally treat with ciprofloxacin. Because fluoroquinolone resistance is prevalent among P. aeruginosa strains, we also obtain a sputum Gram stain and culture with susceptibility testing for these patients to help guide subsequent

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In most cases, several treatment options are available. We select among antibiotic options based on the patient's previous response to that agent, patient allergies and intolerances, the drug's adverse event profile, drug interactions, susceptibility pattern of organisms isolated in recent sputum cultures (if available), and local antimicrobial resistance patterns. In some instances, local antibiotic resistance rates can be determined by obtaining an antibiogram from a local hospital. However, this information is not always available or readily accessible.

In general, we also avoid using the same antibiotic class more than once within a three-month period. Antibiotic exposure in the previous three months is one of the best predictors of pathogens resistant to that drug class in an individual patient. For example, if a patient has responded well and tolerated a certain antibiotic and that antibiotic was not used within the past three months, then that agent (or one in the same class) is a good choice. However, if that agent was used within the past three months, then an agent of a different class should be selected.

The antibiotic selection outlined above is based on the susceptibility profiles and evolving resistance patterns of the most common pathogens. For example, amoxicillin, which was favored in the past, is no longer a recommended agent because it is inactivated by many nontypeable H. influenzae and most strains of M. catarrhalis. Doxycycline resistance among S. pneumoniae is prevalent in some regions, and it does not appear to improve clinical outcomes when compared with systemic glucocorticoids alone [44,45]; thus, it is also no longer first line. This approach is further supported by a meta-analysis of 12 randomized trials evaluating >2100 patients, which showed that amoxicillin-clavulanic acid, macrolides, second- or third-generation cephalosporins, and fluoroquinolones were more effective than amoxicillin, ampicillin, pivampicillin, trimethoprim-sulfamethoxazole, and doxycycline for the treatment of COPD

management decisions (eg, change in therapy based on susceptibility testing for those who do not respond to empiric treatment). (See 'Follow-up' below.)

Some experts add amoxicillin or another agent with better activity against S. pneumoniae to ciprofloxacin for broader empiric treatment.

Levofloxacin is a reasonable alternative for patients who have risk factors for Pseudomonas infection but no prior history of positive cultures for Pseudomonas. Although levofloxacin is less potent than ciprofloxacin for the treatment of Pseudomonas, it has comparatively greater activity against other common pathogens (S. pneumoniae and M. catarrhalis). Moxifloxacin is not recommended for patients with risk factors for Pseudomonas, as it has little activity against this pathogen.

exacerbations (odds ratio [OR] 0.51, 95% CI 0.34-0.75) [46]. Treatment success was defined as resolution or improvement of symptoms.

Several studies have compared the efficacy of macrolides, fluoroquinolones, and amoxicillin- clavulanate with one another [43,47,48]. One meta-analysis of 19 trials, evaluating >7400 patients with COPD exacerbations, compared the effectiveness of macrolides (ie, azithromycin, clarithromycin), fluoroquinolones (ie, levofloxacin, moxifloxacin, ciprofloxacin), and amoxicillin- clavulanate [43]. Antibiotic selection did not affect short-term treatment success, defined as resolution or improvement of symptoms. However, among patients who had a pathogen isolated from sputum at presentation, treatment success was lower for macrolides when compared with fluoroquinolones (OR 0.47, 95% CI 0.31-0.69). Recurrence, in the 26 weeks following therapy, was also less frequent in patients who were treated with fluoroquinolones compared with macrolides. The reduction in treatment success observed with macrolides may be related to their limited ability to eradicate H. influenzae. Amoxicillin-clavulanate had similar efficacy when compared with other agents but was associated with more adverse effects (mostly diarrhea) than the other drugs. In a subsequent randomized trial evaluating >500 patients with exacerbations of COPD, moxifloxacin and amoxicillin-clavulanate appeared to have similar overall efficacy [47]. However, clinical failure rates were lower with moxifloxacin when the analysis was limited to patients with a pathogen isolated from sputum (19 versus 25 percent). Adverse effects associated with fluoroquinolone use are discussed separately. (See "Fluoroquinolones" and "Fluoroquinolones", section on 'Adverse effects'.)

Hospitalized patients — For patients hospitalized for treatment of a COPD exacerbation (who lack clinical and radiographic suspicion for pneumonia), we primarily base empiric antibiotic selection on the risk for Pseudomonas ( algorithm 1B). We select among appropriate options based on the patient's previous response to that agent, patient allergies and intolerances, the drug's adverse event profile, drug interactions, local antimicrobial resistance patterns, and the susceptibility pattern of organisms isolated in recent sputum cultures (if available).

For most inpatients without risk factors for Pseudomonas infection, we select either a respiratory fluoroquinolone (ie, levofloxacin 500 mg orally or intravenously [IV] once daily or moxifloxacin 400 mg orally or IV once daily) or a third-generation cephalosporin (eg, ceftriaxone or cefotaxime).

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For most inpatients with risk factors for Pseudomonas infection, we select one of the following: cefepime, ceftazidime, or piperacillin-tazobactam (4.5 g IV every six hours). For those who cannot tolerate these agents, alternatives include ciprofloxacin, aztreonam, certain carbapenems (eg, meropenem, imipenem), and aminoglycosides. Each comes with relative disadvantages when compared with the antipseudomonal beta-lactams

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For all hospitalized patients who are able to produce a good-quality sputum sample, we obtain a Gram stain and culture to help guide management. For most others, we do not obtain microbiologic testing on sputum because it has limited diagnostic accuracy and results are unlikely to change management. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'When to obtain sputum studies'.)

Patients with clinical concern for concurrent pneumonia should be treated with empiric antibiotic regimens based on the suspected pathogens, severity of illness, and type of pneumonia. (See "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

Additional detail on the antibiotic selection for patients with known or suspected pseudomonal infections are provided separately. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

Duration — The duration of therapy for patients who are clinically improving is generally five days for outpatients and five to seven days for hospitalized patients. However, azithromycin can be given for as few as three days when administered at a dose of 500 mg orally daily because of its long half-life. Patients who are initially started on parenteral antibiotics should be switched to an oral regimen when able to take medications orally.

A meta-analysis that compared five days with seven or more days of antimicrobial therapy (fluoroquinolones, cefixime, or clarithromycin) for exacerbations of COPD found no difference in outcome between the two groups, although there were fewer adverse events among patients who received a five-day course [49].

Some experts use procalcitonin, a biomarker that rises in response to bacterial infections, to guide antibiotic duration. However, clinical utility and safety of using procalcitonin to guide therapy in patients with COPD exacerbations is not firmly established and its use is controversial. (See "Procalcitonin use in lower respiratory tract infections", section on 'Acute exacerbations of chronic obstructive pulmonary disease'.)

RESPIRATORY VIRUS TREATMENT

( table 4). We generally select among them based on local epidemiology, prior susceptibility testing results, drug interactions, and patient comorbidities or intolerances. Two agents are often needed for empiric treatment. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

Influenza — Antiviral therapy is usually indicated for patients whose acute exacerbations of COPD have been triggered by influenza virus. However, the benefits of antiviral therapy diminish with time; thus, for patients presenting ≥72 hours after illness onset, we take the patient's clinical trajectory (eg, worsening/improving) into account when deciding to prescribe. For patients with influenza who also meet criteria for antibacterial treatment (ie, ≥2 cardinal symptoms, need for hospitalization and/or ventilatory support), we treat with both antiviral and antibacterial therapy.

Inhaled zanamivir is contraindicated in this patient population due to the risk of airway reactivity. Other agents, such as oral oseltamivir, oral baloxavir, or, in certain situations, intravenous peramivir or zanamivir (not available in the United States) can be used. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Coronavirus disease 2019 — COPD increases the morbidity and mortality associated with coronavirus disease 2019 (COVID-19; caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) and we test all COPD patients with symptoms of an exacerbation for COVID-19.

Standard treatment of the exacerbation with bronchodilators, systemic corticosteroids, and antibiotics should not be altered in patients with both COPD and COVID-19 [50]. However, these patients need to be observed closely for deterioration. Given their age and comorbidity, patients with COPD and COVID-19 are likely to be candidates for COVID-19 specific therapy. (See "COVID-19: Management of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults".)

FOLLOW-UP

Most patients should demonstrate some improvement in 48 to 72 hours of starting antibiotic therapy. For those who fail to improve, we generally obtain a sputum culture (if not already obtained) to help guide any subsequent changes in antibiotic treatment, reevaluate our approach to other aspects of care (eg, bronchodilators, need for mechanical ventilation), consider potential contributing comorbidities, and broaden our differential diagnosis to include other cardiopulmonary disorders (eg, pneumonia, heart failure, lung cancer). (See "COPD exacerbations: Management", section on 'Adjusting therapy for poor response' and "Approach to the patient with dyspnea".)

PREVENTION

Vaccination — Patients with COPD should be vaccinated against seasonal influenza virus (annually), SARS CoV-2, and pneumococcus ( table 5).  

The evidence supporting vaccination of patients with COPD includes the following:

Patients with COPD should also receive other vaccines according to the schedule summarized in the following figure ( figure 1); in particular, vaccine uptake for pertussis is low and incidence is rising. (See "Pertussis infection in adolescents and adults: Treatment and prevention", section on 'Vaccination'.)

All patients who lack contraindications should be vaccinated against SARS-CoV-2. (See "COVID- 19: Vaccines".)

Prophylactic macrolides — We do not routinely use prophylactic macrolides or other antibiotics for the long-term care of patients with COPD. For most patients, the benefits of long- term antibiotic use do not outweigh the risks. However, for selected patients with severe COPD with frequent exacerbations (≥2 per year) despite optimal medical management (long-acting bronchodilators, inhaled glucocorticoids, pulmonary rehabilitation, smoking cessation), macrolide prophylaxis may be advantageous. The risks associated with the development of antibiotic resistance should be taken into account when deciding to use long-term prophylaxis. When considering prescription, we carefully weigh the potential benefit against the risk of long- term macrolide use (eg, QT prolongation, other cardiovascular events, Clostridioides difficile infection). (See "Azithromycin and clarithromycin", section on 'Adverse reactions'.)

When prescribing a macrolide for long-term prophylaxis, we typically use azithromycin, which can be given as 250 mg daily [53] or at a lower dose of 250 to 500 mg three times per week [54-

The utility of influenza vaccination is well established for reducing both the rate and severity of symptoms due to influenza, including respiratory symptoms. A meta-analysis of 11 trials, including 6 specifically performed in patients with COPD, found a significant reduction in the number of exacerbations per patient compared with placebo [51]. (See "Seasonal influenza vaccination in adults".)

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For pneumococcal vaccination, a meta-analysis of 12 randomized trials evaluated the efficacy of PPSV23 on 2171 patients with COPD [52]. Analysis of five trials showed a reduction in the rates of community-acquired pneumonia with vaccination (odds ratio [OR] 0.61, 95% CI 0.42-0.89), and four trials showed a reduction in rates of COPD exacerbation (OR 0.60, 95% CI 0.39-0.93). There were no significant differences in all-cause or cardiorespiratory mortality, although event rates were low. (See "Pneumococcal vaccination in adults".)

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57]. We often use 250 mg three times per week to reduce adverse effects, although this dose is less well studied. Erythromycin (500 mg two times per day) is an alternative [1]. While the optimal duration of therapy is not known, a 12-month course is commonly used [1]. If there is suspicion for Mycobacterium avium complex (MAC) infection based on symptoms or radiological signs (bronchiectasis, tree in bud, chronic opacities on chest radiograph or computed tomography), sputum or bronchoscopic cultures for MAC should be obtained prior to initiation of macrolides; their use is not recommended if the cultures are positive. (See "Overview of nontuberculous mycobacterial infections", section on 'Clinical manifestations'.)

The benefit of macrolides is attributed to their immunomodulatory effects in addition to their potential to prevent infection [58,59]. In a systematic review of 14 randomized trials evaluating 3932 patients with moderate-to-severe COPD, the proportion of patients experiencing ≥1 exacerbation was reduced when comparing prophylactic antibiotic use (primarily macrolides) with placebo (OR 0.57, 95% CI 0.42-0.78) [58]. A marginal improvement in quality-of-life measures was detected; trends toward improvement in the number of hospital admissions, change in forced expiratory volume in one second (FEV ), serious adverse events, and all-cause mortality were observed but were not statistically significant.

The benefits and risks of long-term macrolide use are well illustrated in one of the randomized trials included in the meta-analysis [53,58]. In this trial, 1142 patients with COPD were randomly assigned to receive azithromycin 250 mg orally daily or placebo for one year in addition to their usual COPD regimen [53]. The following findings were observed:

1

The median time to first COPD exacerbation was significantly longer among the patients who received azithromycin compared with those who received placebo (266 versus 174 days).

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Patients who received azithromycin had a significant (but modest) reduction in the frequency of COPD exacerbations compared with those who received placebo (1.48 versus 1.83 exacerbations per patient-year; hazard ratio 0.73, 95% CI 0.63-0.84).

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Patients who received azithromycin had a significantly higher rate of nasopharyngeal colonization with macrolide-resistant bacteria (Staphylococcus aureus, S. pneumoniae, Haemophilus spp, Moraxella spp) than those who received placebo (81 versus 41 percent). Lower airway and enteric microbiology were not monitored, so the emergence of macrolide-resistant strains in these relevant sites was not assessed.

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Hearing decrements (assessed by audiometry) were more common in the azithromycin group than the placebo group (25 versus 20 percent). However, hearing loss associated with azithromycin usually results from long-term use and is reversible.

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Patients with resting tachycardia, hearing impairment, and those with or at risk for a prolonged QT interval were excluded from participating. Thus, the risks of long-term use may be higher when used in the general COPD population.

Other antibiotics, particularly moxifloxacin, also have demonstrated some efficacy for preventing COPD exacerbations [17]. However, we typically reserve their use for the treatment of infections in order to avoid fluoroquinolone-related adverse effects and the selection of fluoroquinolone-resistant bacteria [60]. In one trial comparing pulsed moxifloxacin (400 mg orally daily for five days every eight weeks for six cycles [total duration of 48 weeks]) in 1157 patients with COPD at high risk for recurrent exacerbations, the risk of COPD exacerbation was lower with moxifloxacin, both in the per-protocol analysis (OR 0.75, 95% CI 0.565-0.994) and in the intent-to-treat analysis (OR 0.81, 95% CI 0.645-1.008) [17]. A larger benefit was observed in those with purulent or mucopurulent sputum production (OR 0.55, 95% CI 0.36-0.84) in post-hoc analysis. Gastrointestinal adverse effects were more frequent with moxifloxacin; however, C. difficile infections were not observed. Sustained emergence of moxifloxacin-resistant strains was not observed in sputum or in enteric flora.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)

SUMMARY AND RECOMMENDATIONS

Background – Most exacerbations of chronic obstructive pulmonary disease (COPD) are caused by respiratory tract infections. Empiric antibiotic therapy is indicated for patients who are most likely to have a bacterial infection causing the exacerbation and for those who are most ill. (See 'Introduction' above.)

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Clinical characteristics – An exacerbation of COPD is an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days and is often associated with increased airway or systemic inflammation. Most exacerbations of COPD are due to respiratory infection. Cardinal symptoms of a COPD exacerbation include (see 'Introduction' above and 'Definitions' above):

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Increase in dyspnea• Increase in sputum volume and/or viscosity•

Increase in sputum purulence•

When to treat with antibiotics – We typically determine the need for antibiotics based on the number of cardinal symptoms present and the need for hospitalization and/or ventilatory support. The benefit of empiric antibiotic treatment is greatest in severely ill patients and those with a greater number of symptoms but appears to diminish as the severity of illness declines. (See 'Indications for antibacterial therapy' above.)

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We suggest empiric antibiotic treatment in patients with a COPD exacerbation and ≥2 of 3 cardinal symptoms: increased dyspnea, increased sputum volume/viscosity, or increased sputum purulence or a COPD exacerbation requiring hospitalization and/or ventilatory support (either invasive or noninvasive) (Grade 2C).

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We do not initiate antibiotic therapy in patients with a COPD exacerbation and only one of three cardinal symptoms who do not require hospitalization or ventilatory support. New onset of increased wheezing may serve as an additional negative predictor for bacterial infection; therefore, if it is a prominent finding, it steers us away from antibiotic use.

•

Risk stratification to guide antibiotic selection – We use a "risk stratification" approach when selecting initial empiric antibiotic therapy for the treatment of acute exacerbations of COPD. We categorize patients based on treatment setting (eg, outpatient versus inpatient), risk for poor clinical outcomes ( table 2), and risk for infection with Pseudomonas ( table 3). (See 'Risk stratification' above.)

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Empiric antibiotic regimens – Empiric antibiotic regimens are designed to target the most likely infecting pathogens ( table 1); specific selection varies based on the patient's risk status ( algorithm 1A-B). When selecting an antibiotic, we take into account the patient's prior antibiotic exposure, prior clinical response to specific antibiotics, allergies and intolerances, drug interactions, the drug's adverse event profile, and the susceptibility pattern of organisms isolated in recent sputum cultures (if available). (See 'Antibiotic selection' above.)

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Duration of antibiotics – The duration of therapy is generally five days for outpatients and five to seven days for most hospitalized patients. However, azithromycin can be given for as few as three days when administered at a dose of 500 mg orally daily because of its long half-life. (See 'Duration' above.)

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Antiviral treatment – Patients with COPD are at increased risk for complications of influenza, so antiviral therapy (eg, oral oseltamivir or an intravenous agent) may be

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ACKNOWLEDGMENT

UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

Use of UpToDate is subject to the Terms of Use.

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appropriate for exacerbations triggered by influenza virus, depending on timing and susceptibility patterns. Inhaled zanamivir is contraindicated in this patient population due to the risk of airway reactivity. Similarly, patients with COPD and COVID-19 are likely to be candidates for COVID-19-specific therapy. (See 'Respiratory virus treatment' above.)

Vaccination – To prevent future exacerbations, patients with COPD should be vaccinated against influenza and pneumococcus, according to the following schedule ( figure 1). All patients who lack contraindications should also be vaccinated against SARS-CoV-2. (See 'Vaccination' above.)

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Macrolide prophylaxis for selected patient with severe COPD – We do not routinely use prophylactic macrolides or other antibiotics for the long-term care of patients with COPD. For most patients, the benefits of long-term antibiotic use do not outweigh the risks. However, for selected patients with severe COPD and frequent exacerbations (≥2 per year) despite optimal medical management (bronchodilators, inhaled glucocorticoids, pulmonary rehabilitation, smoking cessation), macrolide prophylaxis may be advantageous. Azithromycin can be given as 250 mg daily or at a lower dose of 250 to 500 mg three times per week. We often use 250 mg three times per week to reduce adverse effects. (See 'Prophylactic macrolides' above.)

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10. Nouira S, Marghli S, Belghith M, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo- controlled trial. Lancet 2001; 358:2020.

11. Roede BM, Bresser P, Prins JM, et al. Reduced risk of next exacerbation and mortality associated with antibiotic use in COPD. Eur Respir J 2009; 33:282.

12. Rothberg MB, Pekow PS, Lahti M, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA 2010; 303:2035.

13. Daniels JM, Snijders D, de Graaff CS, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 181:150.

14. Stefan MS, Rothberg MB, Shieh MS, et al. Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids. Chest 2013; 143:82.

15. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 12:CD010257.

16. Llor C, Moragas A, Hernández S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:716.

17. Sethi S, Jones PW, Theron MS, et al. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Respir Res 2010; 11:10.

18. Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000; 117:1638.

19. Miravitlles M, Kruesmann F, Haverstock D, et al. Sputum colour and bacteria in chronic bronchitis exacerbations: a pooled analysis. Eur Respir J 2012; 39:1354.

20. Brusse-Keizer MG, Grotenhuis AJ, Kerstjens HA, et al. Relation of sputum colour to bacterial load in acute exacerbations of COPD. Respir Med 2009; 103:601.

21. Daniels JM, de Graaff CS, Vlaspolder F, et al. Sputum colour reported by patients is not a reliable marker of the presence of bacteria in acute exacerbations of chronic obstructive pulmonary disease. Clin Microbiol Infect 2010; 16:583.

22. Soler N, Esperatti M, Ewig S, et al. Sputum purulence-guided antibiotic use in hospitalised patients with exacerbations of COPD. Eur Respir J 2012; 40:1344.

23. Sethi S. Personalised medicine in exacerbations of COPD: the beginnings. Eur Respir J 2012; 40:1318.

24. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2017; 10:CD007498.

25. Daubin C, Valette X, Thiollière F, et al. Procalcitonin algorithm to guide initial antibiotic therapy in acute exacerbations of COPD admitted to the ICU: a randomized multicenter study. Intensive Care Med 2018; 44:428.

26. Mathioudakis AG, Chatzimavridou-Grigoriadou V, Corlateanu A, Vestbo J. Procalcitonin to guide antibiotic administration in COPD exacerbations: a meta-analysis. Eur Respir Rev 2017; 26.

27. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007; 131:9.

28. Prins HJ, Duijkers R, van der Valk P, et al. CRP-guided antibiotic treatment in acute exacerbations of COPD in hospital admissions. Eur Respir J 2019; 53.

29. Butler CC, Gillespie D, White P, et al. C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations. N Engl J Med 2019; 381:111.

30. Stoller JK. Clinical practice. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002; 346:988.

31. Snow V, Lascher S, Mottur-Pilson C, Joint Expert Panel on Chronic Obstructive Pulmonary Disease of the American College of Chest Physicians and the American College of Physicians-American Society of Internal Medicine. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 2001; 134:595.

32. Balter MS, La Forge J, Low DE, et al. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can Respir J 2003; 10 Suppl B:3B.

33. Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. DAFNE Study Group. Eur Respir J 2001; 17:928.

34. Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis. Thorax 2006; 61:337.

35. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: a prospective study. Eur Respir J 2009; 34:1072.

36. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012; 7:1129.

37. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: characterization and risk factors. BMC Pulm Med 2014; 14:103.

38. Boixeda R, Almagro P, Díez-Manglano J, et al. Bacterial flora in the sputum and comorbidity in patients with acute exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:2581.

39. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008; 359:2355.

40. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: new developments concerning microbiology and pathophysiology--impact on approaches to risk stratification and therapy. Infect Dis Clin North Am 2004; 18:861.

41. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community- acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019; 200:e45.

42. Chow AW, Benninger MS, Brook I, et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis 2012; 54:e72.

43. Siempos II, Dimopoulos G, Korbila IP, et al. Macrolides, quinolones and amoxicillin/clavulanate for chronic bronchitis: a meta-analysis. Eur Respir J 2007; 29:1127.

44. van Velzen P, Ter Riet G, Bresser P, et al. Doxycycline for outpatient-treated acute exacerbations of COPD: a randomised double-blind placebo-controlled trial. Lancet Respir Med 2017; 5:492.

45. Golden AR, Baxter MR, Davidson RJ, et al. Comparison of antimicrobial resistance patterns in Streptococcus pneumoniae from respiratory and blood cultures in Canadian hospitals from 2007-16. J Antimicrob Chemother 2019; 74:iv39.

46. Dimopoulos G, Siempos II, Korbila IP, et al. Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis: a metaanalysis of randomized controlled trials. Chest 2007; 132:447.

47. Wilson R, Anzueto A, Miravitlles M, et al. Moxifloxacin versus amoxicillin/clavulanic acid in outpatient acute exacerbations of COPD: MAESTRAL results. Eur Respir J 2012; 40:17.

48. Nouira S, Marghli S, Besbes L, et al. Standard versus newer antibacterial agents in the treatment of severe acute exacerbation of chronic obstructive pulmonary disease: a randomized trial of trimethoprim-sulfamethoxazole versus ciprofloxacin. Clin Infect Dis 2010; 51:143.

49. Falagas ME, Avgeri SG, Matthaiou DK, et al. Short- versus long-duration antimicrobial treatment for exacerbations of chronic bronchitis: a meta-analysis. J Antimicrob Chemother 2008; 62:442.

50. Halpin DMG, Criner GJ, Papi A, et al. Global Initiative for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease. The 2020 GOLD Science Committee Report on COVID-19 and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2021; 203:24.

51. Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006; :CD002733.

52. Walters JA, Tang JN, Poole P, Wood-Baker R. Pneumococcal vaccines for preventing pneumonia in chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2017; 1:CD001390.

53. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365:689.

54. Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014; 2:361.

55. Blasi F, Bonardi D, Aliberti S, et al. Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy. Pulm Pharmacol Ther 2010; 23:200.

56. Pomares X, Montón C, Espasa M, et al. Long-term azithromycin therapy in patients with severe COPD and repeated exacerbations. Int J Chron Obstruct Pulmon Dis 2011; 6:449.

57. Berkhof FF, Doornewaard-ten Hertog NE, Uil SM, et al. Azithromycin and cough-specific health status in patients with chronic obstructive pulmonary disease and chronic cough: a randomised controlled trial. Respir Res 2013; 14:125.

58. Herath SC, Normansell R, Maisey S, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2018; 10:CD009764.

59. Huckle AW, Fairclough LC, Todd I. Prophylactic Antibiotic Use in COPD and the Potential Anti-Inflammatory Activities of Antibiotics. Respir Care 2018; 63:609.

60. Brill SE, Law M, El-Emir E, et al. Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial. Thorax 2015; 70:930.

Topic 7019 Version 67.0

GRAPHICS

Our approach to empiric antibacterial treatment of COPD exacerbations in out

Prompt and appropriate antibiotic use has been associated with improved clinical outcomes in patients with severe COPD exacerbations. Empiric regimens are designed to target the most likely pathogens (Haemophilu Moraxella catarrhalis, and Streptococcus pneumoniae) and should be broadened to target drug-resistant path difficult-to-eradicate pathogens (eg, macrolide-resistant S. pneumoniae, nontypeable strains of H. influenzae) poor outcomes. Coverage for Pseudomonas is indicated in patients with risk factors for infection with this pa patients should be evaluated for clinical response in approximately 72 hours, and sputum Gram stain and cu considered for those who fail to response to empiric treatment. Modifications to this approach may be need with a history of colonization or infection with drug-resistant pathogens (including Pseudomonas) or when a is suspected.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Antiviral therapy for influenza is also indicated for exacerbations triggered by influenza infection.

¶ Suspicion for other cardiopulmonary disorders (heart failure, pneumothorax) and more severe infections ( should be absent for the diagnosis of an acute COPD exacerbation.

Δ Age alone is not a strict risk factor but should be considered as additive to other risk factors.

◊ Selection among antibiotic choices is based on local microbial sensitivity patterns, patient comorbidities, p organisms, potential adverse events and drug interactions, and also provider and patient preferences. In pa modifications to this regimen may be needed for patients with a history of drug-resistant Pseudomonas base illness, degree of suspicion for Pseudomonas, and prior susceptibility profiles of pseudomonal isolates.

§ If recent antibiotic exposure (eg, within the past 3 months), select an antibiotic from a different class than agent used.

¥ Trimethoprim-sulfamethoxazole is a reasonable alternative when macrolides and cephalosporins cannot b allergy, potential adverse effects, or availability.

‡ Some experts add amoxicillin or another agent with better activity against S. pneumoniae to ciprofloxacin f treatment.

† Because fluoroquinolone resistance is prevalent among Pseudomonas aeruginosa strains, we obtain a sput and culture with susceptibility testing for these patients to help guide subsequent management decisions. F outpatients, obtaining a sputum culture is not needed unless the patient fails to respond to empiric treatme

** Levofloxacin has lesser activity against Pseudomonas than ciprofloxacin but has greater activity against S. M. catarrhalis is thus a reasonable alternative to ciprofloxacin for patients who are at increased risk of Pseud but lack microbiologic evidence of Pseudomonas infection or colonization.

References: 1. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: New developments concerning microbiology and pathophysiolog

approaches to risk stratification and therapy. Infect Dis Clin N Am 2004; 18:861. 2. Sethi S, Anzueto A, Miravitlles M, et al. Determinants of bacteriological outcomes in exacerbations of chronic obstructive pulmo

2016; 44:65. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: cha

factors. BMC Pulm Med 2014; 14:103.

Graphic 66357 Version 14.0

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Our approach to empiric antibacterial treatment of COPD exacerbations in hospitalized patients*

Prompt and appropriate antibiotic use has been associated with improved clinical outcomes in patients hospitalized for COPD exacerbations. Empiric regimens are designed to target the most likely pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae). Pseudomonas should be targeted in those with risk factors for infection with this pathogen. Generally, a sputum Gram stain and culture with susceptibility testing should be obtained for hospitalized patients. Modifications to the empiric regimen may be needed based on sputum Gram stain and culture results, particularly for patients who do not respond to the initial empiric regimen within 48 to 72 hours of starting treatment. Modifications to this approach may be needed for

patients with a history of colonization or infection with drug-resistant pathogens (including Pseudomonas) or when a specific pathogen is suspected.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Antiviral therapy for influenza is also indicated for exacerbations triggered by influenza infection.

¶ Selection among antibiotic choices is based on local microbial sensitivity patterns, patient comorbidities, prior infecting organisms, potential adverse events and drug interactions, and also provider and patient preferences. Modifications to these regimens may be needed for patients with suspicion for specific pathogens and/or history of drug-resistant organisms (eg, drug-resistant Pseudomonas).

Δ For those who cannot tolerate these agents, alternatives include ciprofloxacin, aztreonam, certain carbapenems (eg, meropenem, imipenem), and aminoglycosides. We generally select among them based on local epidemiology, prior susceptibility testing results, drug interactions, and patient comorbidities or intolerances. Two agents are often needed for empiric treatment. Refer to the UpToDate content for detail.

◊ If recent antibiotic exposure (eg, within the past 3 months), select an antibiotic from a different class than the most recent agent used.

References: 1. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: New developments concerning microbiology and

pathophysiology--impact on approaches to risk stratification and therapy. Infect Dis Clin N Am 2004; 18:861. 2. Sethi S, Anzueto A, Miravitlles M, et al. Determinants of bacteriological outcomes in exacerbations of chronic

obstructive pulmonary disease. Infection 2016; 44:65. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary

disease: characterization and risk factors. BMC Pulm Med 2014; 14:103.

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Relative frequency of bacterial pathogens isolated from 14 antibiotic comparison trials in exacerbations of chronic obstructive pulmonary disease*

Pathogen Percentage of bacterial isolates (range)

Haemophilus influenzae 13 to 50

Moraxella catarrhalis 9 to 21

Streptococcus pneumoniae 7 to 26

Pseudomonas aeruginosa 1 to 13

* Enterobacteriaceae have been isolated from the respiratory tract of 3 to 19 percent of patients with chronic obstructive pulmonary disease (COPD) exacerbations and Staphylococcus aureus has been isolated from the respiratory tract of 1 to 20 percent of patients with COPD exacerbations, but their pathogenic significance in this setting has not been defined. Haemophilus parainfluenzae has been isolated from the respiratory tract of 2 to 32 percent of patients with COPD exacerbations, but these organisms are unlikely to cause COPD exacerbations.

Modified with permission from the American Thoracic Society. Copyright © 2004 American Thoracic Society. Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society 2004; 1:109. Official Journal of the American Thoracic Society.

Graphic 70203 Version 9.0

Risk factors for poor outcomes in patients with acute COPD exacerbations

Comorbid conditions (especially heart failure or ischemic heart disease)

Severe underlying COPD (eg, FEV <50%)

Frequent exacerbations of COPD (ie, ≥2 exacerbations per year)

Hospitalization for an exacerbation within the past 3 months

Receipt of continuous supplemental oxygen

Age ≥65 years*

Patients with greater underlying COPD severity are at higher risk for poor outcomes if initial antibiotic therapy is inadequate. We thus use a broader empiric regimen for such patients.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Older age (eg, age ≥65 years) is also associated with poorer outcomes and/or risk of infection with drug-resistant pathogens. While not a strict indication for broadening antibiotic therapy, we consider older age as additive to the risk factors listed above.

References: 1. Balter MS, La Forge J, Low DE, et al. Canadian guidelines for the management of acute exacerbations of chronic

bronchitis. Can Respir J 2003; 10 Suppl B:3B. 2. Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory treatment of acute exacerbations

of chronic bronchitis. DAFNE Study Group. Eur Respir J 2001; 17:928. 3. Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term outcomes of

acute exacerbations of chronic bronchitis. Thorax 2006; 61:337. 4. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation:

a prospective study. Eur Respir J 2009; 34:1072. 5. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012;

7:1129.

Graphic 126161 Version 1.0

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1

Risk factors for infection with Pseudomonas aeruginosa in patients with acute COPD exacerbations

Chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum (particularly in the past 12 months)

Very severe COPD (FEV <30% predicted)

Bronchiectasis on chest imaging

Broad-spectrum antibiotic use within the past 3 months

Chronic systemic glucocorticoid use

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

References: 1. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation:

a prospective study. Eur Respir J 2009; 34:1072. 2. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012;

7:1129. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary

disease: characterization and risk factors. BMC Pulm Med 2014; 14:103. 4. Boixeda R, Almagro P, Díez-Manglano J, et al. Bacterial flora in the sputum and comorbidity in patients with acute

exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:2581.

Graphic 126162 Version 1.0

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1

Alternatives to anti-pneumococcal beta-lactams for the empiric treatment of Pseudomonas inpatients with AECOPD

Antibiotic or antibiotic class

Comment

Ciprofloxacin Active against Pseudomonas but does not have strong activity against Streptococcus pneumoniae and Moraxella catarrhalis, which are also common causes of COPD exacerbations One of the few oral agents with anti-pseudomonal activity, thus, use is often reserved for the outpatient setting

Aztreonam Lacks activity against S. pneumoniae and other gram-positive pathogens Resistance to aztreonam among pseudomonal isolates is also common

Anti-pseudomonal carbapenems (eg, meropenem, doripenem)

Active against Pseudomonas and other common COPD pathogens Spectrum of activity often broader than necessary

Aminoglycosides (eg, tobramycin, gentamicin, amikacin, plazomicin)

Active against Pseudomonas aeruginosa but generally not used as single agents because of inadequate clinical efficacy

For patients who cannot tolerate anti-pneumococcal beta-lactams (eg, cefepime, piperacillin- tazobactam), alternatives include ciprofloxacin, aztreonam, certain carbapenems, and aminoglycosides. Each comes with relative disadvantages when compared with the anti- pseudomonal beta-lactams. We generally select among them based on local epidemiology, prior susceptibility testing results, drug interactions, and patient comorbidities or intolerances. For empiric treatment, two agents are often needed. The treatment of Pseudomonas is discussed in detail in the UpToDate text.

AECOPD: acute exacerbation of chronic obstructive pulmonary disease.

Graphic 135124 Version 1.0

Indications for pneumococcal vaccination in adults in the United States

All adults ≥65 years of age

Adults 19 to 64 years of age with any of the following: Predisposing medical conditions:

Alcohol use disorder Chronic heart disease Chronic lung disease Chronic liver disease Diabetes mellitus Sickle cell disease or other hemoglobinopathies Current cigarette smoking

Increased risk of meningitis: Cerebrospinal fluid leak Cochlear implant

Immunocompromising conditions and other conditions associated with altered immunocompetence :

Congenital or acquired immunodeficiency Generalized active malignancy Human immunodeficiency virus infection Iatrogenic immunosuppression Hodgkin disease Leukemia Lymphoma Multiple myeloma Solid organ transplant Chronic kidney disease and nephrotic syndrome Functional or anatomic asplenia

History of invasive pneumococcal disease

Pneumococcal vaccination is indicated for adults with risk factors for acquisition of or severe adverse outcomes from pneumococcal disease. These adults should receive either PCV20 alone or PCV15 followed by PPSV23. When administering the PCV15 and PPSV23 combination, PCV15 should be given first when possible. The recommended intervals between the two vaccines vary based on sequence and indication. Refer to the UpToDate topic on pneumococcal vaccination in adults for additional detail.

ACIP: Advisory Committee on Immunization Practices; HIV: human immunodeficiency virus; PCV20: 20-valent pneumococcal conjugate vaccine; PCV15: 15-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine.

* Including congestive heart failure and cardiomyopathies, excluding hypertension.

*

¶

Δ

◊

§

¥

‡

†

¶ Including chronic obstructive pulmonary disease, emphysema, and asthma.

Δ Some UpToDate authors differ from ACIP guidance on vaccine selection for immunocompromised individuals. Refer to the UpToDate topic on pneumococcal vaccination in adults for additional information.

◊ Includes B (humoral) or T lymphocyte deficiency, complement deficiencies (particularly C1, C2, C3, and C4 deficiencies), and phagocytic disorders (excluding chronic granulomatous disease).

§ HIV infection is an indication for pneumococcal vaccination, regardless of CD4 cell count.

¥ Treatment with any immunosuppressive drugs (including long-term glucocorticoids, tumor necrosis factor alpha inhibitors, cancer chemotherapy, and other cytokine inhibitors) or radiation therapy.

‡ Chronic kidney disease is defined as glomerular filtration rate <60 mL/min/1.73 m for ≥3 months.

† The United States Centers for Disease Control and Prevention ACIP does not mention individuals with a prior history of invasive pneumococcal disease in their recommendations on pneumococcal vaccinations. We suggest pneumococcal vaccination in this population due to their increased risk for recurrent pneumococcal disease. Refer to the UpToDate topic on pneumococcal vaccination in adults for additional detail.

Graphic 86782 Version 32.0

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Recommended adult immunization schedule by medical condition and other in

Administer recommended vaccines if vaccination history is incomplete or unknown. Do not restart or add do use of trade names is for identification purposes only and does not imply endorsement by the ACIP or CDC.

Polio vaccination Routine vaccination:

Routine poliovirus vaccination of adults residing in the United States is not necessary. Special situations:

Adults at increased risk of exposure to poliovirus with: No evidence of a complete polio vaccination series (ie, at least 3 doses): Administer remain Evidence of completed polio vaccination series (ie, at least 3 doses): May administer one life

For detailed information, refer to www.cdc.gov/vaccines/vpd/polio/hcp/recommendations.html.

HSCT: hematopoietic stem cell transplant.

* Precaution for LAIV4 does not apply to alcoholism.

¶ COVID-19 vaccination Routine vaccination:

Primary series: 2-dose series at 0, 4 to 8 weeks (Moderna) or 2-dose series at 0, 3 to 8 weeks (Nov Booster dose: Refer to www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerati

Special situations: Persons who are moderately or severely immunocompromised.

Primary series: 3-dose series at 0, 4, 8 weeks (Moderna) or 3-dose series at 0, 3, 7 weeks (Pfizer-BioNTech). 2-dose series at 0, 3 weeks (Novavax).

Booster dose: Refer to www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-conside Pre-exposure prophylaxis (eg, monoclonal antibodies) may be considered to complement C considerations/interim-considerations-us.html#immunocompromised.

For Janssen COVID-19 Vaccine recipients refer to COVID-19 schedule at www.cdc.gov/vaccines/c NOTE: Current COVID-19 schedule available at www.cdc.gov/vaccines/covid-19/downloads/COVID- information on Emergency Use Authorization (EUA) indications for COVID-19 vaccines, please visit disease-2019-covid-19/covid-19-vaccines.

Contraindications and precautions: Refer to contraindications and precautions to COVID-19 vaccination.

Δ Influenza vaccination Routine vaccination:

Age 19 years or older: 1 dose any influenza vaccine appropriate for age and health status annual Age 65 years or older: Any one of quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), adjuvanted inactivated influenza vaccine (aIIV4) is preferred. If none of these three vaccines is ava For the 2022–2023 season, refer to www.cdc.gov/mmwr/volumes/71/rr/rr7101a1.htm. For the 2023–2024 season, refer to the 2023–2024 ACIP influenza vaccine recommendations.

Special situations: Egg allergy, hives only: Any influenza vaccine appropriate for age and health status annually. Egg allergy–any symptom other than hives (eg, angioedema, respiratory distress, or required e vaccine appropriate for age and health status may be administered. If using egg-based IIV4 or LAI provider who can recognize and manage severe allergic reactions. Close contacts (eg, caregivers, health care workers) of severely immunosuppressed persons receive LAIV4. If LAIV4 is given, they should avoid contact with/caring for such immunosuppressed Severe allergic reaction (eg, anaphylaxis) to a vaccine component or a previous dose of any i precautions. History of Guillain-Barré syndrome within 6 weeks after previous dose of influenza vaccine: risks for those at higher risk for severe complications from influenza.

Contraindications and precautions: For contraindications and precautions to influenza vaccination, refer to IIV4 Appendix, LAIV4 Appe

◊ Tetanus, diphtheria, and pertussis (Tdap) vaccination Routine vaccination:

Previously did not receive Tdap at or after age 11 years: 1 dose Tdap, then Td or Tdap every 10 Special situations:

Previously did not receive primary vaccination series for tetanus, diphtheria, or pertussis: 1 dose of Td or Tdap 6 to 12 months later (Tdap can be substituted for any Td dose, but preferred as Pregnancy: 1 dose Tdap during each pregnancy, preferably in early part of gestational weeks 27 t Wound management: Persons with 3 or more doses of tetanus-toxoid-containing vaccine: For cle last dose of tetanus-toxoid-containing vaccine; for all other wounds, administer Tdap or Td if more preferred for persons who have not previously received Tdap or whose Tdap history is unknown. I use Tdap. For detailed information, refer to www.cdc.gov/mmwr/volumes/69/wr/mm6903a5.htm.

Contraindications and precautions: For contraindications and precautions to tetanus, diphtheria, and acellular pertussis (Tdap), refer t

§ Measles, mumps, and rubella vaccination Routine vaccination:

No evidence of immunity to measles, mumps, or rubella: 1 dose. Evidence of immunity: Born before 1957 (health care personnel, refer below), documentation (diagnosis of disease without laboratory confirmation is not evidence of immunity).

Special situations: Pregnancy with no evidence of immunity to rubella: MMR contraindicated during pregnancy; a Nonpregnant women of childbearing age with no evidence of immunity to rubella: 1 dose. HIV infection with CD4 percentages ≥15% and CD4 count ≥200 cells/mm for at least 6 mon dose series at least 4 weeks apart; MMR contraindicated for HIV infection with CD4 percentage <1 Severe immunocompromising conditions: MMR contraindicated. Students in postsecondary educational institutions, international travelers, and household o evidence of immunity to measles, mumps, or rubella: 2-dose series at least 4 weeks apart if pre 1 dose MMR. In mumps outbreak settings, for information about additional doses of MMR (including 3rd dose Health care personnel:

Born before 1957 with no evidence of immunity to measles, mumps, or rubella: Consider rubella. Born in 1957 or later with no evidence of immunity to measles, mumps, or rubella: 2-dose rubella.

Contraindications and precautions: For contraindications and precautions to measles, mumps, rubella (MMR), refer to MMR Appendix

¥ Varicella vaccination Routine vaccination:

No evidence of immunity to varicella: 2-dose series 4 to 8 weeks apart if previously did not rece varicella vaccine] for children); if previously received 1 dose varicella-containing vaccine, 1 dose at

Evidence of immunity: US-born before 1980 (except for pregnant women and health care per vaccine at least 4 weeks apart, diagnosis or verification of history of varicella or herpes zoster

Special situations: Pregnancy with no evidence of immunity to varicella: VAR contraindicated during pregnancy; a previously received 1 dose varicella-containing vaccine or dose 1 of 2-dose series (dose 2: 4 to 8 w regardless of whether US-born before 1980.

3

Health care personnel with no evidence of immunity to varicella: 1 dose if previously received previously did not receive any varicella-containing vaccine, regardless of whether US-born before HIV infection with CD4 percentages ≥15% and CD4 count ≥200 cells/mm with no evidence VAR contraindicated for HIV infection with CD4 percentage <15% or CD4 count <200 cells/mm . Severe immunocompromising conditions: VAR contraindicated.

Contraindications and precautions: For contraindications and precautions to varicella (VAR), refer to VAR Appendix.

‡ Zoster vaccination Routine vaccination:

Age 50 years or older (NOTE: Serologic evidence of prior varicella is not necessary for zoster vacc available, providers should follow ACIP guidelines for varicella vaccination first. RZV is not indicate RZV in persons without a history of varicella or varicella vaccination): 2-dose series recombinant zo weeks; repeat dose if administered too soon), regardless of previous herpes zoster or history of zo

Special situations: Pregnancy: There is currently no ACIP recommendation for RZV use in pregnancy. Consider delay Immunocompromising conditions (including persons with HIV regardless of CD4 count; NOTE: I herpes zoster, providers should refer to the clinical considerations for use of RZV in immunocomp recommendations for further guidance: www.cdc.gov/mmwr/volumes/71/wr/mm7103a2.htm): 2-d (minimum interval: 4 weeks; repeat dose if administered too soon). For detailed information, refer

Contraindications and precautions: For contraindications and precautions to zoster recombinant vaccine (RZV), refer to RZV Appendix

† Human papillomavirus vaccination Routine vaccination:

HPV vaccination recommended for all persons through age 26 years: 2- or 3-dose series depen Age 15 years or older at initial vaccination: 3-dose series at 0, 1 to 2 months, 6 months (min dose 1 to dose 3: 5 months; repeat dose if administered too soon). Age 9 to 14 years at initial vaccination and received 1 dose or 2 doses less than 5 months Age 9 to 14 years at initial vaccination and received 2 doses at least 5 months apart: HPV

Interrupted schedules: If vaccination schedule is interrupted, the series does not need to be rest No additional dose recommended when any HPV vaccine series has been completed using th

Shared clinical decision-making: Some adults age 27 to 45 years: Based on shared clinical decision-making, 2- or 3-dose series as

Special situations: Age ranges recommended above for routine and catch-up vaccination or shared clinical deci

Immunocompromising conditions, including HIV infection: 3-dose series, even for those w Pregnancy: Pregnancy testing is not needed before vaccination; HPV vaccination is not recom vaccinated while pregnant.

Contraindications and precautions: For contraindications and precautions to human papillomavirus (HPV) vaccination, refer to HPV Ap

** Pneumococcal vaccination Routine vaccination:

Age 65 years or older who have: Not previously received a dose of PCV13, PCV15, or PCV20 or whose previous vaccination this should be followed by a dose of PPSV23 given at least 1 year after the PCV15 dose. A min for adults with an immunocompromising condition (NOTE: Immunocompromising conditions

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iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Ho transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies invasive pneumococcal disease caused by serotypes unique to PPSV23 in these vulnerable gro Previously received only PCV7: Follow the recommendation above. Previously received only PCV13: 1 dose PCV20 at least 1 year after the PCV13 dose OR comp www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo-vaccine-timing.pdf. Previously received only PPSV23: 1 dose PCV15 OR 1 dose PCV20 at least 1 year after the PP PPSV23. Previously received both PCV13 and PPSV23 but NO PPSV23 was received at age 65 years vaccine dose OR complete the recommended PPSV23 series as described here: www.cdc.gov/ Previously received both PCV13 and PPSV23, AND PPSV23 was received at age 65 years o least 5 years after the last pneumococcal vaccine dose. For guidance on determining which pneumococcal vaccines a patient needs and when, pleas www.cdc.gov/vaccines/vpd/pneumo/hcp/pneumoapp.html.

Special situations: Age 19 to 64 years with certain underlying medical conditions or other risk factors who hav alcoholism, chronic heart/liver/lung disease, chronic renal failure, cigarette smoking, cochlear im generalized malignancy, HIV, Hodgkin disease, immunodeficiency, iatrogenic immunosuppressio organ transplants, or sickle cell disease, or other hemoglobinopathies):

Not previously received a PCV13, PCV15, or PCV20 or whose previous vaccination history should be followed by a dose of PPSV23 given at least 1 year after the PCV15 dose. A minimum adults with an immunocompromising condition(NOTE: Immunocompromising conditions inc iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Ho transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies Previously received only PCV7: Follow the recommendation above. Previously received only PCV13: 1 dose PCV20 at least 1 year after the PCV13 dose OR comp www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo-vaccine-timing.pdf. Previously received only PPSV23: 1 dose PCV15 OR 1 dose PCV20 at least 1 year after the PP PPSV23. Previously received both PCV13 and PPSV23 but have not completed the recommended dose OR complete the recommended PPSV23 series as described here: www.cdc.gov/vaccines

For guidance on determining which pneumococcal vaccines a patient needs and when, please re www.cdc.gov/vaccines/vpd/pneumo/hcp/pneumoapp.html.

Contraindications and precautions: For contraindications and precautions to Pneumococcal conjugate (PCV15 and PCV20), refer to PC PPSV23 Appendix.

¶¶ Hepatitis A vaccination Routine vaccination:

Not at risk but want protection from hepatitis A (identification of risk factor not required): apart [minimum interval: 6 months]) or 3-dose series HepA-HepB (Twinrix at 0, 1, 6 months [mini

Special situations: At risk for hepatitis A virus infection: 2-dose series HepA or 3-dose series HepA-HepB as above

Chronic liver disease (eg, persons with hepatitis B, hepatitis C, cirrhosis, fatty liver disease, a [ALT] or aspartate aminotransferase [AST] level greater than twice the upper limit of normal). HIV infection. Men who have sex with men.

Injection or noninjection drug use. Persons experiencing homelessness. Work with hepatitis A virus in research laboratory or with nonhuman primates with hepatit Travel in countries with high or intermediate endemic hepatitis A (HepA-HepB [Twinrix] m to 30 days, followed by a booster dose at 12 months). Close, personal contact with international adoptee (eg, household or regular babysitting) endemic hepatitis A (administer dose 1 as soon as adoption is planned, at least 2 weeks befor Pregnancy if at risk for infection or severe outcome from infection during pregnancy. Settings for exposure, including health care settings targeting services to injection or noninj for developmentally disabled persons (individual risk factor screening not required).

Contraindications and precautions: For contraindications and precautions to hepatitis A (HepA) vaccination, refer to HepA Appendix.

ΔΔ Hepatitis B vaccination Routine vaccination:

Age 19 through 59 years: Complete a 2- or 3-, or 4-dose series. 2-dose series only applies when 2 doses of Heplisav-B (NOTE: Heplisav-B and PreHevbrio are persons) are used at least 4 weeks apart. 3-dose series Engerix-B, PreHevbrio (NOTE: Heplisav-B and PreHevbrio are not recommended Recombivax HB at 0, 1, 6 months [minimum intervals: dose 1 to dose 2: 4 weeks / dose 2 to d 3-dose series HepA-HepB (Twinrix at 0, 1, 6 months [minimum intervals: dose 1 to dose 2: 4 w 4-dose series HepA-HepB (Twinrix) accelerated schedule of 3 doses at 0, 7, and 21 to 30 days,

Age 60 years or older with known risk factors for hepatitis B virus infection should complete a H Age 60 years or older without known risk factors for hepatitis B virus infection may complete a

Risk factors for hepatitis B virus infection include: Chronic liver disease (eg, persons with hepatitis C, cirrhosis, fatty liver disease, alcoholic aspartate aminotransferase [AST] level greater than twice upper limit of normal). HIV infection. Sexual exposure risk (eg, sex partners of hepatitis B surface antigen [HBsAg]-positive pe persons seeking evaluation or treatment for a sexually transmitted infection; men who ha Current or recent injection drug use. Percutaneous or mucosal risk for exposure to blood (eg, household contacts of HBsAg disabled persons; health care and public safety personnel with reasonably anticipated risk maintenance dialysis, including in-center or home hemodialysis and peritoneal dialysis, a Incarceration. Travel in countries with high or intermediate endemic hepatitis B.

Special situations: Patients on dialysis: complete a 3- or 4-dose series.

3-dose series Recombivax HB at 0, 1, 6 months (NOTE: use Dialysis Formulation 1 mL = 40 mc 4-dose series Engerix-B at 0, 1, 2, and 6 months (NOTE: use 2 mL dose instead of the normal a

Contraindications and precautions: For contraindications and precautions to hepatitis B (HepB) vaccination, refer to HepB Appendix.

◊◊ Meningococcal vaccination Special situations for MenACWY:

Anatomical or functional asplenia (including sickle cell disease), HIV infection, persistent co eculizumab, ravulizumab) use: 2-dose series MenACWY-D (Menactra, Menveo, or MenQuadfi) a

Travel in countries with hyperendemic or epidemic meningococcal disease, or microbiologi (Menactra, Menveo, or MenQuadfi) and revaccinate every 5 years if risk remains. First-year college students who live in residential housing (if not previously vaccinated at a Menveo, or MenQuadfi). For MenACWY booster dose recommendations for groups listed under "Special situations" and among men who have sex with men) and additional meningococcal vaccination information, refe

Shared clinical decision-making for MenB: Adolescents and young adults age 16 to 23 years (age 16 to 18 years preferred) not at increa making, 2-dose series MenB-4C (Bexsero) at least 1 month apart or 2-dose series MenB-FHbp (Tru after dose 1, administer dose 3 at least 4 months after dose 2); MenB-4C and MenB-FHbp are not

Special situations for MenB: Anatomical or functional asplenia (including sickle cell disease), persistent complement co ravulizumab) use, or microbiologists routinely exposed to Neisseria meningitidis (NOTE: Men if indicated, but at a different anatomic site, if feasible): 2-dose primary series MenB-4C (Bexsero) at 0, 1 to 2, 6 months (if dose 2 was administered at least 6 months after dose 1, dose 3 not need dose should be administered at least 4 months after dose 3); MenB-4C and MenB-FHbp are not in booster 1 year after primary series and revaccinate every 2 to 3 years if risk remains. Pregnancy: Delay MenB until after pregnancy unless at increased risk and vaccination benefits o For MenB booster dose recommendations for groups listed under "Special situations" and in an among men who have sex with men) and additional meningococcal vaccination information, refe

Contraindications and precautions: For contraindications and precautions to meningococcal ACWY (MenACWY) [MenACWY-CRM (Men MenACWY Appendix. For contraindications and precautions to meningococcal B (MenB) [MenB-4C (Bexsero); MenB-FH

§§ Haemophilus influenzae type b vaccination Special situations:

Anatomical or functional asplenia (including sickle cell disease): 1 dose if previously did not r before splenectomy. Hematopoietic stem cell transplant (HSCT): 3-dose series 4 weeks apart starting 6 to 12 month

Contraindications and precautions: For contraindications and precautions to Haemophilus influenzae type b (Hib) vaccination, refer to

¥¥ Vaccinate after pregnancy.

Reproduced from: Advisory Committee on Immunization Practices. Recommended Adult Immunization Schedule for ages 19 years or https://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions.html (Accessed on February 15, 2023).

Contributor Disclosures

Sanjay Sethi, MD Grant/Research/Clinical Trial Support: Astra Zeneca [COPD]; Regeneron [COPD]; Theravance [COPD]. Consultant/Advisory Boards: Astra Zeneca [COPD]; BI [COPD]; Chiesi [COPD]; GSK [Asthma, COPD]; Nuvaira [COPD]; Pulmonx [COPD]. Speaker's Bureau: AstraZeneca [COPD]; BI [COPD]; GSK [COPD]. All of the relevant financial relationships listed have been mitigated. Timothy F Murphy, MD No relevant financial relationship(s) with ineligible companies to disclose. Julio A Ramirez, MD, FACP Grant/Research/Clinical Trial Support: Eli Lilly [Monoclonal antibodies]; Janssen [Vaccines]; Pfizer [Vaccines]. Consultant/Advisory Boards: Dompe [Infectious diseases]; Nabriva [Respiratory infections]; Paratek [Respiratory infections]; Pfizer [Vaccines]. All of the relevant financial relationships listed have been mitigated. Sheila Bond, MD No relevant financial relationship(s) with ineligible companies to disclose. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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