Initial treatment failure in non-ICU community-acquired pneumonia: risk factors and association with length of stay, total hospital charges, and mortality

Figures & data

Table 1. Failure algorithms for the 40 most commonly initial antibiotic regimens in non-ICU CAP.

Initial IV antibiotic regimen	Definition of failure
Ampicillin/sulbactam	Any new antibiotic except ampicillin, penicillin, or penicillin G
Azithromycin	Any new antibiotic except clarithromycin or erythromycin
Azithromycin & Cefepime	Any new antibiotic except ampicillin, first-, second-, or third-generation cephalosporins*, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Cefepime & Ciprofloxacin & Vancomycin	Addition of carbapenems, linezolid, or tigecycline
Azithromycin & Cefotaxime	Any new antibiotic except ampicillin, ceftriaxone, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Ceftriaxone	Any new antibiotic except ampicillin, cefotaxime, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Ceftriaxone & Levofloxacin	Any new antibiotic except ampicillin, cefotaxime, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Ceftriaxone & Moxifloxacin	Any new antibiotic except ampicillin, cefotaxime, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Ceftriaxone & Piperacillin/Tazobactam	Any new antibiotic except ampicillin, ampicillin/sulbactam, cefotaxime, clindamycin, first- or second-generation cephalosporins, fluoroquinolones, macrolides, metronidazole, penicillin, or penicillin G
Azithromycin & Ceftriaxone & Piperacillin/ Tazobactam & Vancomycin	Any new antibiotic except ampicillin, ampicillin/sulbactam, cefotaxime, first- or second-generation cephalosporins, fluoroquinolones, macrolides, methicillin, nafcillin, oxacillin, penicillin, penicillin G, or ticarcillin/clavulanate
Azithromycin & Ceftriaxone & Vancomycin	Any new antibiotic except ampicillin, ampicillin/sulbactam, cefotaxime, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Levofloxacin	Any new antibiotic except ampicillin, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Moxifloxacin	Any new antibiotic except ampicillin, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Moxifloxacin & Vancomycin	Any new antibiotic except ampicillin, daptomycin, first- or second-generation cephalosporins, fluoroquinolones, macrolides, methicillin, nafcillin, oxacillin, penicillin, penicillin G, or SMX-TMP
Azithromycin & Piperacillin/Tazobactam	Any new antibiotic except ampicillin, ampicillin/sulbactam, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Azithromycin & Piperacillin/Tazobactam & Vancomycin	Addition of carbapenems, linezolid, or tigecycline
Cefazolin	Any new antibiotic except first-generation cephalosporins, methicillin, nafcillin, oxacillin, penicillin, or penicillin G
Cefepime	Addition of carbapenems, clindamycin, daptomycin, doxycycline, fluoroquinolones, linezolid, quinupristin/dalfopristin, SMX-TMP, tigecycline, or vancomycin
Cefepime & Levofloxacin	Any new antibiotic except ampicillin, ceftazidime, first-, second- or third-generation cephalosporins*, fluoroquinolones, macrolides, penicillin, or penicillin G
Cefepime & Vancomycin	Addition of carbapenems, daptomycin, fluoroquinolones, linezolid, or tigecycline
Cefotaxime	Any new antibiotic except ampicillin, ceftriaxone, first- or second-generation cephalosporins, penicillin, or penicillin G
Ceftriaxone	Any new antibiotic except ampicillin, cefotaxime, first- or second-generation cephalosporins, penicillin, or penicillin G
Ceftriaxone & Levofloxacin	Any new antibiotic except ampicillin, cefotaxime, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Ceftriaxone & Moxifloxacin	Any new antibiotic except ampicillin, cefotaxime, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Ceftriaxone & Piperacillin/Tazobactam	Any new antibiotic except ampicillin, ampicillin/sulbactam, cefotaxime, first- or second-generation cephalosporins, penicillin, or penicillin G
Ceftriaxone & Vancomycin	Any new antibiotic except ampicillin, cefotaxime, first- or second-generation cephalosporins, methicillin, nafcillin, oxacillin, penicillin, or penicillin G
Clindamycin & Levofloxacin	Any new antibiotic except ampicillin, ampicillin/sulbactam, first- or second-generation cephalosporins, fluoroquinolones, macrolides, metronidazole, penicillin, or penicillin G
Doripenem & Levofloxacin	Addition of daptomycin, linezolid, SMX-TMP, tigecycline, or vancomycin
Imipenem-Cilastatin	Addition of clindamycin, daptomycin, doripenem, doxycycline, fluoroquinolones, linezolid, meropenem, piperacillin/tazobactam, quinupristin/dalfopristin, SMX-TMP, ticarcillin/clavulanate, tigecycline, or vancomycin
Levofloxacin	Any new antibiotic except ampicillin, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Levofloxacin & Linezolid	Addition of carbapenems, piperacillin/tazobactam, third- or fourth-generation cephalosporins, ticarcillin/clavulanate, or tigecycline
Levofloxacin & Linezolid & Piperacillin/Tazobactam	Addition of carbapenems or tigecycline
Levofloxacin & Piperacillin/Tazobactam	Addition of carbapenems, linezolid, tigecycline, or vancomycin
Levofloxacin & Piperacillin/Tazobactam & Vancomycin	Any new antibiotic except ampicillin, ampicillin/sulbactam, first- or second-generation cephalosporins, fluoroquinolones, macrolides, methicillin, nafcillin, oxacillin, penicillin, penicillin G, piperacillin/tazobactam, or ticarcillin/clavulanate
Levofloxacin & Vancomycin	Any new antibiotic except first- or second-generation cephalosporins, fluoroquinolones, macrolides, methicillin, nafcillin, oxacillin, penicillin, or penicillin G
Moxifloxacin	Any new antibiotic except ampicillin, first- or second-generation cephalosporins, fluoroquinolones, macrolides, penicillin, or penicillin G
Moxifloxacin & Vancomycin	Any new antibiotic except first- or second-generation cephalosporins, fluoroquinolones, macrolides, methicillin, nafcillin, oxacillin, penicillin, or penicillin G
Piperacillin/Tazobactam	Any new antibiotic except ampicillin, ampicillin/sulbactam, first- or second-generation cephalosporins, penicillin, penicillin G, or ticarcillin/clavulanate
Piperacillin/Tazobactam & Vancomycin	Any new antibiotic except ampicillin, ampicillin/sulbactam, first- or second-generation cephalosporins, methicillin, nafcillin, oxacillin, penicillin, penicillin G, or ticarcillin/clavulanate
Vancomycin	Any new antibiotic except methicillin, nafcillin, oxacillin, penicillin, or penicillin G

*Including ceftazidime, which provides coverage for Pseudomonas spp

Figure 1. Sample selection. *Or at least 1 dose of such therapy, for those who died within 48 hours of admission. NOTE: ICD-9-CM diagnosis codes 481, 482.XX, 483.X, 484.3, 484.5, 485, 486, and 487.0 used to define pneumonia. ICU: Intensive care unit.

Table 2. Demographic and clinical characteristics of non-ICU patients admitted for CAP: 2000–2009 (n = 32,234).*†

Characteristic
Mean (SD) age, years	69.5 (16.9)
Gender
Male	15,429 (47.9)
Female	16,804 (52.1)
Unknown/missing	1 (0.0)
Race
Caucasian	25,783 (80.0)
African American	3728 (11.6)
Hispanic	589 (1.8)
Other	472 (1.5)
Unknown/missing	1662 (5.2)
Principal payer
Medicare	8873 (27.5)
HMO/Managed Care	2698 (8.4)
Other	2265 (7.0)
Unknown/missing	18,398 (57.1)
Comorbidities
Congestive heart failure	8668 (26.9)
Coronary heart disease	7665 (23.8)
Cerebrovascular disease	1395 (4.3)
Type 2 diabetes	7244 (22.5)
Asthma	4048 (12.6)
COPD	8016 (24.9)
Other respiratory diseases	11,007 (34.1)
Evidence of an immunocompromising condition‡	10,617 (32.9)
Lupus	59 (0.2)
Liver disease	661 (2.1)
Renal failure	4092 (12.7)
PVD	916 (2.8)
Hypoalbuminemia	161 (0.5)
Alcohol/drug abuse	3751 (11.6)
Septicemia/bacteremia	2000 (6.2)
SIRS	1375 (4.3)
Empyema	186 (0.6)
Pleural effusion	2253 (7.0)
Malnutrition	910 (2.8)
Clinical characteristics noted at admission§
Leukopenia	460 (1.9)
Thrombocytopenia	382 (2.1)
Hyperglycemia	1437 (5.7)
Hyponatremia	1079 (4.2)
Acidosis	390 (9.9)
Uremia	6117 (23.0)
Anemia	2171 (8.2)
Hypoxemia	1071 (23.1)
Receipt during first 48 h of
Vasoactive medications	359 (1.1)
Swan-Ganz catheterization	12 (0.0)
Parenteral nutrition	25 (0.1)
Endotracheal intubation/mechanical ventilation	317 (1.0)
Prior pneumonia admission in previous 12 months	1431 (4.4)
Hospital characteristics
Teaching facility	17,508 (54.3)
Urban setting	32,087 (99.5)
Geographic region
New England	2975 (9.2)
Mid-Atlantic	11,733 (36.4)
West North Central	106 (0.3)
East North Central	8582 (26.6)
East South Central	898 (2.8)
South Atlantic	3232 (10.0)
West South Central	2711 (8.4)
Mountain	130 (0.4)
Pacific	1867 (5.8)
Bed size
<100	2833 (8.8)
100–199	6378 (19.8)
200–299	9516 (29.5)
300–499	7375 (22.9)
≥500	6132 (19.0)

*Unless otherwise indicated, all values are number of patients (%).

†January 1, 2000–June 30, 2009.

‡Defined as cancer, HIV/AIDS, other primary or secondary immunodeficiency, or receipt within first 48 h of admission of oral/IV corticosteroids, anti-TNFs, and/or drotrecogin alfa.

§Based on first recorded value of all relevant labs ordered within first 24 h in hospital.

AIDS, Acquired Immune Deficiency Syndrome; CAP, Community-acquired pneumonia; COPD, Chronic obstructive pulmonary disease; HIV, Human immunodeficiency virus; HMO, Health-maintenance organization; ICU, Intensive-care unit; PVD, Peripheral vascular disease; SIRS, Systemic inflammatory response syndrome; TNF, Tumor-necrosis factor.

Table 3. Frequency distribution of initial antibiotic regimens among non-ICU patients admitted for CAP: 2000–2009 (n = 32,234).*

Regimen	Patients (%)
Levofloxacin	8615 (26.7)
Azithromycin & ceftriaxone	6492 (20.1)
Ceftriaxone	4303 (13.3)
Azithromycin & cefotaxime	1709 (5.3)
Moxifloxacin	1533 (4.8)
Piperacillin/tazobactam	1307 (4.1)
Azithromycin	996 (3.1)
Cefotaxime	921 (2.9)
Ceftriaxone & levofloxacin	750 (2.3)
Azithromycin & levofloxacin	441 (1.4)
All others	5167 (16.0)
Total	32,234 (100.0)

*January 1, 2000–June 30, 2009.

CAP, Community-acquired pneumonia; ICU, Intensive-care unit.

Table 4. Multivariate logistic regression of factors associated with failure of initial antibiotic therapy in non-ICU CAP.

Risk factors	OR	95% CI	p-value
Age (vs <65 years)
<65 years	1.00	–	–
65–74 years	0.93	(0.84, 1.02)	0.13
≥75 years	0.96	(0.89, 1.04)	0.34
Time to first dose of IV antibiotic therapy (vs ≤4 h)
<4 h	1.00	–	–
5–8 h	1.07	(0.96, 1.19)	0.23
>8 h	1.22	(1.14, 1.30)	<0.01
Gender (male vs female)	1.05	(0.98, 1.12)	0.15
Race (vs Caucasian)
Caucasian	1.00	–	–
All others	1.10	(1.01, 1.19)	0.03
Comorbidities (yes vs no)
Congestive heart failure	1.10	(1.02, 1.19)	0.01
Coronary heart disease	0.87	(0.80, 0.94)	<0.01
Cerebrovascular disease	1.38	(1.20, 1.60)	<0.01
Type II diabetes	0.86	(0.79, 0.93)	<0.01
Chronic obstructive pulmonary disease	1.08	(1.00, 1.17)	0.04
Any other comorbid respiratory disease	1.53	(1.42, 1.65)	<0.01
Immunocompromising conditions	1.43	(1.32, 1.56)	<0.01
Liver disease	1.28	(1.04, 1.57)	0.02
Renal failure	1.45	(1.32, 1.59)	<0.01
Peripheral vascular disease	1.02	(0.84, 1.24)	0.83
Alcohol/drug abuse	0.77	(0.69, 0.87)	<0.01
Pleural effusion	1.40	(1.25, 1.57)	<0.01
Malnutrition	1.87	(1.60, 2.18)	<0.01
Clinical characteristics noted at admission (vs no)
Leukopenia	1.34	(1.04, 1.73)	0.02
Thrombocytopenia	1.70	(1.32, 2.20)	<0.01
Hyperglycemia	1.41	(1.20, 1.65)	<0.01
Hyponatremia	1.38	(1.16, 1.65)	<0.01
Acidosis	1.77	(1.38, 2.27)	<0.01
Uremia	1.45	(1.33, 1.58)	<0.01
Anemia	1.58	(1.40, 1.78)	<0.01
Hypoxemia	1.31	(1.11, 1.56)	<0.01
Receipt during first 24 h of (yes vs no)
Vasoactive medications	1.51	(1.17, 1.94)	<0.01
Parenteral nutrition	0.77	(0.28, 2.12)	0.61
Endotracheal intubation, mechanical ventilation, and/or central venous catheterization	2.43	(1.90, 3.12)	<0.01
Pneumonia admission in previous 12 months (yes vs no)	1.19	(1.03, 1.37)	0.02
Hospital characteristics
Teaching vs non-teaching	0.82	(0.76, 0.88)	<0.01
Bed size (<300 vs ≥300)	1.02	(0.95, 1.10)	0.63

CAP, Community-acquired pneumonia; ICU, Intensive-care unit.

Definitions for comorbidities of interest.

Comorbidity	ICD-9-CM Diagnoses
Congestive heart failure	398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 428.0X
Coronary heart disease	410.XX–414.XX
Cerebrovascular disease	430–437.1, 437.3–437.5, 437.8, 437.9, 438.XX
Type II diabetes	250.XX
Chronic obstructive pulmonary disease	491.XX, 492.XX, 496.XX
Any other comorbid respiratory disease	460–479.XX, 493.X–495.X, 500–519.X
Immunocompromising conditions*	140.XX–209.XX, 230.XX–238.XX (cancer), 042, 079.53, V08.XX (human immunodeficiency virus/ acquired immune deficiency syndrome), 279.X (primary or secondary immunodeficiency)
Liver disease	006.3, 070.22, 070.32, 070.33, 070.44, 070.54, 456.0–456.21, 571.XX, 572.0, 572.2–572.8, 573.X, 996.82, V42.7
Renal failure	584.XX–586.XX
Peripheral vascular disease	440.2X, 440.3X, 443.9X, 444.22
Alcohol/drug abuse	265.2, 291.0, 291.1, 291.2, 291.3, 291.4, 291.5, 291.81, 291.89, 291.9, 303.XX–305.XX, 648.4, 980.9, V11.3
Pleural effusion	511.X
Malnutrition	261–263.X, 648.9, 995.52, 995.84

*Also included receipt within the first 24 h of admission of oral or intravenous corticosteroids, etanercept, infliximab, adalimumab, abatacept, cerolizumab, and/or drotrecogin alfa.