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Extended-spectrum antibiotics for community-acquired pneumonia with a low risk for drug-resistant pathogens

Open AccessPublished:September 15, 2022DOI:https://doi.org/10.1016/j.ijid.2022.09.015

      Highlights

      • This study focused on the use of extended-spectrum antibiotics in patients with community-acquired pneumonia with a low risk for drug-resistant pathogens (DRPs).
      • Unnecessary extended-spectrum antibiotics use was defined by the 2019 community-acquired pneumonia guidelines.
      • Extended-spectrum antibiotics use was associated with increased 30-day mortality.
      • Risk assessment of DRPs is essential in determining empirical antibiotic therapy.
      • Extended-spectrum antibiotics use may be harmful in patients with a low risk for DRPs.

      Abstract

      Objectives

      The potential hazards of extended-spectrum antibiotic therapy for patients with community-acquired pneumonia (CAP) with low risk for drug-resistant pathogens (DRPs) remain unclear; however, risk assessment for DRPs is essential to determine the initial antibiotics to be administered. The study objective was to assess the effect of unnecessary extended-spectrum therapy on the mortality of such patients.

      Methods

      A post hoc analysis was conducted after a prospective multicenter observational study for CAP. Multivariable logistic regression analysis was performed to assess the effect of extended-spectrum therapy on 30-day mortality. Three sensitivity analyses, including propensity score analysis to confirm the robustness of findings, were also performed.

      Results

      Among 750 patients with CAP, 416 with CAP with a low risk for DRPs were analyzed; of these, 257 underwent standard therapy and 159 underwent extended-spectrum therapy. The 30-day mortality was 3.9% and 13.8% in the standard and extended-spectrum therapy groups, respectively. Primary analysis revealed that extended-spectrum therapy was associated with increased 30-day mortality compared with standard therapy (adjusted odds ratio 2.82; 95% confidence interval 1.20-6.66). The results of the sensitivity analyses were consistent with those of the primary analysis.

      Conclusion

      Physicians should assess the risk for DRPs when determining the empirical antibiotic therapy and should refrain from administering unnecessary extended-spectrum antibiotics for patients with CAP with a low risk for DRPs.

      Keywords

      Introduction

      Pneumonia is one of the most common and life-threatening diseases worldwide (

      World Health Organization. The top 10 causes of death. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death, 2020 (accessed 13 June 2022).

      ). Previous studies have demonstrated that the administration of inappropriate initial antibiotics can lead to adverse outcomes, including death (
      • Kumar A
      • Ellis P
      • Arabi Y
      • Roberts D
      • Light B
      • Parrillo JE
      • et al.
      Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.
      ;
      • Shindo Y
      • Sato S
      • Maruyama E
      • Ohashi T
      • Ogawa M
      • Hashimoto N
      • et al.
      Health-care-associated pneumonia among hospitalized patients in a Japanese community hospital.
      ;
      • Tumbarello M
      • De Pascale G
      • Trecarichi EM
      • Spanu T
      • Antonicelli F
      • Maviglia R
      • et al.
      Clinical outcomes of Pseudomonas aeruginosa pneumonia in intensive care unit patients.
      ). Nevertheless, physicians often suggest the administration of unnecessary extended-spectrum antibiotics, such as antipseudomonal and antimethicillin-resistant Staphylococcus aureus (MRSA) drugs, for patients with pneumonia to avoid any potential delays in appropriate antibiotics administration (
      • Klompas M.
      Overuse of broad-spectrum antibiotics for pneumonia.
      ). Some studies have revealed that the use of extended-spectrum antibiotics for patients with community-acquired pneumonia (CAP), including healthcare-associated pneumonia (HCAP), was associated with increased mortality (
      • Attridge RT
      • Frei CR
      • Restrepo MI
      • Lawson KA
      • Ryan L
      • Pugh MJ
      • et al.
      Guideline-concordant therapy and outcomes in healthcare-associated pneumonia.
      ;
      • Jones BE
      • Ying J
      • Stevens V
      • Haroldsen C
      • He T
      • Nevers M
      • et al.
      Empirical anti-MRSA vs standard antibiotic therapy and risk of 30-day mortality in patients hospitalized for pneumonia.
      ;
      • Webb BJ
      • Sorensen J
      • Jephson A
      • Mecham I
      • Dean NC.
      Broad-spectrum antibiotic use and poor outcomes in community-onset pneumonia: a cohort study.
      ).
      To accomplish the appropriate initial antibiotic treatment for patients with pneumonia, risk assessment for drug-resistant pathogens (DRPs) is essential (
      • Aliberti S
      • Di Pasquale M
      • Zanaboni AM
      • Cosentini R
      • Brambilla AM
      • Seghezzi S
      • et al.
      Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia.
      ;
      • Aliberti S
      • Dela Cruz CS
      • Amati F
      • Sotgiu G
      • Restrepo MI
      Community-acquired pneumonia.
      ;
      • Kobayashi D
      • Shindo Y
      • Ito R
      • Iwaki M
      • Okumura J
      • Sakakibara T
      • et al.
      Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ;
      • Shorr AF
      • Zilberberg MD
      • Reichley R
      • Kan J
      • Hoban A
      • Hoffman J
      • et al.
      Validation of a clinical score for assessing the risk of resistant pathogens in patients with pneumonia presenting to the emergency department.
      ;
      • Webb BJ
      • Dascomb K
      • Stenehjem E
      • Vikram HR
      • Agrwal N
      • Sakata K
      • et al.
      Derivation and multicenter validation of the drug resistance in pneumonia clinical prediction score.
      ). Recent international guidelines on CAP have highlighted the importance of evaluation for the selection of initial antibiotics (
      • Metlay JP
      • Waterer GW
      • Long AC
      • Anzueto A
      • Brozek J
      • Crothers K
      • 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.
      ). The 2019 American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) CAP guidelines recommend the following strategy to determine the initial antibiotics to administer: an initial assessment of disease severity and evaluation of previous respiratory isolation of DRPs, including Pseudomonas aeruginosa and MRSA, followed by the assessment of the risk factors for DRPs in patients with severe CAP (
      • Metlay JP
      • Waterer GW
      • Long AC
      • Anzueto A
      • Brozek J
      • Crothers K
      • 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.
      ). In terms of DRP risk assessment, differences in regional prevalence should be taken into consideration (
      • Metlay JP
      • Waterer GW
      • Long AC
      • Anzueto A
      • Brozek J
      • Crothers K
      • 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.
      ;
      • Shindo Y
      • Hasegawa Y.
      Regional differences in antibiotic-resistant pathogens in patients with pneumonia: implications for clinicians.
      ). In the last decade, several research groups have proposed different prediction models for DRPs (
      • Aliberti S
      • Di Pasquale M
      • Zanaboni AM
      • Cosentini R
      • Brambilla AM
      • Seghezzi S
      • et al.
      Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia.
      ;
      • Prina E
      • Ranzani OT
      • Polverino E
      • Cillóniz C
      • Ferrer M
      • Fernandez L
      • et al.
      Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ;
      • Shorr AF
      • Zilberberg MD
      • Reichley R
      • Kan J
      • Hoban A
      • Hoffman J
      • et al.
      Validation of a clinical score for assessing the risk of resistant pathogens in patients with pneumonia presenting to the emergency department.
      ;
      • Webb BJ
      • Dascomb K
      • Stenehjem E
      • Vikram HR
      • Agrwal N
      • Sakata K
      • et al.
      Derivation and multicenter validation of the drug resistance in pneumonia clinical prediction score.
      ). However, their prediction of patients at high risk for DRPs may not be sufficient, whereas their predictive performance to identify patients at low risk was high (
      • Kobayashi D
      • Shindo Y
      • Ito R
      • Iwaki M
      • Okumura J
      • Sakakibara T
      • et al.
      Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
      ;
      • Webb BJ
      • Dascomb K
      • Stenehjem E
      • Vikram HR
      • Agrwal N
      • Sakata K
      • et al.
      Derivation and multicenter validation of the drug resistance in pneumonia clinical prediction score.
      ). Although the guidelines suggest the previously mentioned treatment approach, the association between adherence to this strategy and patient outcomes is relatively unclear. Furthermore, to the best of our knowledge, evidence of the detrimental effects of the unnecessary use of extended-spectrum antibiotics in patients with CAP with a low risk for DRPs is scarce and requires further evaluation.
      We hypothesized that the unnecessary use of extended-spectrum antibiotics for patients with CAP with a low risk for DRPs is associated with increased mortality. This study aimed to clarify the effect of extended-spectrum antibiotics use in patients with CAP with a low risk for DRPs according to the treatment strategies of the 2019 ATS/IDSA CAP guidelines.

      Patients and methods

      Study design and setting

      This study was a post hoc analysis based on a prospective observational study that was performed at four medical institutions in Japan (one 1000-bed university hospital and three major community hospitals with more than 500 beds) from April 1, 2013 to March 31, 2014. This study was approved by the ethics review committee of Nagoya University School of Medicine (number, 2019-0312) and the respective institutional review boards of the participating institutions. The study was registered with the University Hospital Medical Information Network (registration number UMIN000009837). The protocol of this study was in accordance with the Declaration of Helsinki and the Japanese Ethics Guidelines for Epidemiological Studies. Although the need for the participants’ written informed consent was waived, the opt-out method was adapted according to the ethics guidelines. Eligible patients were provided with information about the study through the internet, brochures, and bulletin boards at the participating institutions and were given the opportunity to withdraw from the study if they wished to.

      Participants

      The study methods used in this study were as previously described (
      • Kobayashi D
      • Shindo Y
      • Ito R
      • Iwaki M
      • Okumura J
      • Sakakibara T
      • et al.
      Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ). Briefly, all adult patients who were hospitalized (aged ≥20 years) with newly developed CAP (including HCAP) were enrolled and followed up after 1 month. Patients with a low risk for DRPs according to the 2019 ATS/IDSA CAP guidelines were considered eligible for this study (
      • Metlay JP
      • Waterer GW
      • Long AC
      • Anzueto A
      • Brozek J
      • Crothers K
      • 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.
      ). The following patients were excluded: those with previous isolation for DRPs and those with severe CAP with a high risk for DRPs using locally validated prediction rules in Japan (
      • Kobayashi D
      • Shindo Y
      • Ito R
      • Iwaki M
      • Okumura J
      • Sakakibara T
      • et al.
      Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ).

      Definitions of severity, the prediction rules for DRPs, and classification of antibiotics

      The 2007 IDSA/ATS criteria were followed to assess disease severity (
      • Mandell LA
      • Wunderink RG
      • Anzueto A
      • Bartlett JG
      • Campbell GD
      • Dean NC
      • et al.
      Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
      ). The severe CAP was considered if a patient satisfied one of the two major criteria (requiring mechanical ventilation or experiencing septic shock with the need of vasopressors) or three or more of the minor criteria (respiratory rate >30 breaths/min, arterial oxygen partial pressure to fractional inspired oxygen ≤250, multilobar infiltrates, confusion, blood urea nitrogen level >20 mg/dl, leukopenia resulting from infection, thrombocytopenia, hypothermia, or hypotension requiring aggressive fluid resuscitation) (
      • Mandell LA
      • Wunderink RG
      • Anzueto A
      • Bartlett JG
      • Campbell GD
      • Dean NC
      • et al.
      Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
      ).
      Prediction rules for DRPs that were derived and validated in our previous studies were followed (
      • Kobayashi D
      • Shindo Y
      • Ito R
      • Iwaki M
      • Okumura J
      • Sakakibara T
      • et al.
      Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ). In these studies, CAP-DRPs were defined as identified pathogens that are not susceptible to the antibiotics commonly administered for CAP, including nonantipseudomonal β-lactam (ceftriaxone or ampicillin-sulbactam), macrolides (azithromycin or clarithromycin), and fluoroquinolones (moxifloxacin, levofloxacin, or garenoxacin). The risk factors of CAP-DRPs included the use of antibiotics within the previous 90 days, hospitalization for ≥2 days during the preceding 90 days, immunosuppression, use of gastric acid–suppressive agents, tube feeding, and nonambulatory status. In addition, MRSA-specific risk factors included chronic dialysis during the preceding 30 days, congestive heart failure, and positive MRSA history within the previous 90 days. Patients were defined to be at low risk for DRPs when they presented with no or one risk factor of CAP-DRPs or when they presented with two risk factors of CAP-DRPs and no MRSA-specific risk factors (
      • Kobayashi D
      • Shindo Y
      • Ito R
      • Iwaki M
      • Okumura J
      • Sakakibara T
      • et al.
      Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
      ;
      • Webb BJ
      • Dascomb K
      • Stenehjem E
      • Vikram HR
      • Agrwal N
      • Sakata K
      • et al.
      Derivation and multicenter validation of the drug resistance in pneumonia clinical prediction score.
      ).
      Antibiotics were classified into two categories: standard and extended-spectrum therapy. Standard therapy for patients with nonsevere CAP involved a nonantipseudomonal β-lactam plus a macrolide (or minocycline) or a respiratory fluoroquinolone, whereas that for those with severe CAP involved a nonantipseudomonal β-lactam plus a macrolide or a nonantipseudomonal β-lactam plus a respiratory fluoroquinolone. Extended-spectrum therapy was defined as any antibiotics with antipseudomonal activity, such as piperacillin-tazobactam, ceftazidime, cefepime, cefozopran, cefoperazone-sulbactam, meropenem, imipenem-cilastatin, doripenem, or aztreonam, or with anti-MRSA activity, including vancomycin, teicoplanin, or linezolid (
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Goto Y
      • et al.
      Risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study.
      ). Fluoroquinolones were excluded from extended-spectrum antibiotics because they were recommended as a therapeutic regimen for patients with CAP at low risk for DRPs.

      End points

      The primary study end point was the 30-day all-cause mortality, defined as death within 30 days of admission. Patients who were discharged or transferred to other hospitals within 30 days of admission with improvement in pneumonia were considered alive for this analysis (
      • Fine MJ
      • Auble TE
      • Yealy DM
      • Hanusa BH
      • Weissfeld LA
      • Singer DE
      • et al.
      A prediction rule to identify low-risk patients with community-acquired pneumonia.
      ;
      • Kobayashi D
      • Shindo Y
      • Ito R
      • Iwaki M
      • Okumura J
      • Sakakibara T
      • et al.
      Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Goto Y
      • et al.
      Risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study.
      ). The effect of the extended-spectrum therapy on 30-day mortality was also evaluated according to the severity of illness as a subgroup analysis.

      Statistical analyses

      Demographic and clinical characteristics were described. All categorical data were summarized as frequencies and presented as percentages. All tests were two-tailed and considered statistically significant if P-values were <0.05.
      To assess the effect of the extended-spectrum therapy on 30-day mortality, a multivariable logistic regression analysis was performed. Five factors (nonambulatory status, respiratory rate ≥30/min, albumin <3.0 g/dl, pH <7.35, and blood urea nitrogen ≥20 mg/dl) were selected as covariables associated with 30-day mortality in patients with CAP undergoing appropriate initial antibiotic treatment (
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Goto Y
      • et al.
      Risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study.
      ). The odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated by setting standard therapy as the reference.
      To confirm the robustness of the results, three sensitivity analyses using different analytical approaches to covariable adjustment were performed. Initially, a multivariable logistic regression analysis including other covariables as potential confounders (age ≥80 years, nonambulatory status, body temperature <36.0°C, respiratory rate ≥30/min, white blood cell count ≤4,000 cells/μl, hematocrit <30.0%, albumin <3.0 g/dl, and arterial carbon dioxide partial pressure ≥50 Torr) was conducted, which were associated with the 30-day mortality in patients with CAP with a low risk for DRPs (
      • Okumura J
      • Shindo Y
      • Takahashi K
      • Sano M
      • Sugino Y
      • Yagi T
      • et al.
      Mortality in patients with community-onset pneumonia at low risk of drug-resistant pathogens: impact of beta-lactam plus macrolide combination therapy.
      ). A propensity score was then developed for the extended-spectrum therapy using a logistic regression analysis with the following covariables associated with mortality, disease severity, or isolation of DRPs: age, sex, comorbidities, nonambulatory status, residence at a nursing home or long-term care facility, infusion therapy, wound care, tube feeding, gastric acid suppression, physical findings, laboratory findings, arterial blood gas data, radiological findings, and requiring vasopressors or requiring mechanical ventilation (including noninvasive positive-pressure ventilation) at the time of CAP diagnosis (
      • España PP
      • Capelastegui A
      • Gorordo I
      • Esteban C
      • Oribe M
      • Ortega M
      • et al.
      Development and validation of a clinical prediction rule for severe community-acquired pneumonia.
      ;
      • Fine MJ
      • Auble TE
      • Yealy DM
      • Hanusa BH
      • Weissfeld LA
      • Singer DE
      • et al.
      A prediction rule to identify low-risk patients with community-acquired pneumonia.
      ;
      • Mandell LA
      • Wunderink RG
      • Anzueto A
      • Bartlett JG
      • Campbell GD
      • Dean NC
      • et al.
      Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
      ;
      • Okumura J
      • Shindo Y
      • Takahashi K
      • Sano M
      • Sugino Y
      • Yagi T
      • et al.
      Mortality in patients with community-onset pneumonia at low risk of drug-resistant pathogens: impact of beta-lactam plus macrolide combination therapy.
      ;
      • Shindo Y
      • Hasegawa Y.
      Regional differences in antibiotic-resistant pathogens in patients with pneumonia: implications for clinicians.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Goto Y
      • et al.
      Risk factors for 30-day mortality in patients with pneumonia who receive appropriate initial antibiotics: an observational cohort study.
      ). The inverse probability of treatment weighting (IPTW) analysis was then performed to assess the effect of extended-spectrum therapy on the 30-day mortality (
      • Cole SR
      • Hernán MA.
      Constructing inverse probability weights for marginal structural models.
      ). The details of the IPTW analysis have been described in the Supplementary Material. Finally, a stratified analysis was conducted using the composite score on disease severity, and the pneumonia severity index (PSI) classes (class I-III, IV, and V) (
      • Fine MJ
      • Auble TE
      • Yealy DM
      • Hanusa BH
      • Weissfeld LA
      • Singer DE
      • et al.
      A prediction rule to identify low-risk patients with community-acquired pneumonia.
      ). Patients with missing values were excluded. All statistical analyses were performed using the SPSS statistics software (version 28; IBM, Armonk, NY, USA) and R (ver.4.1.1; R Foundation for Statistical Computing, Vienna, Austria).

      Results

      Participants and baseline characteristics

      A total of 750 patients with CAP were evaluated, and 721 patients were eligible to be included in the current study. Of the 627 patients with a low risk for DRPs, 257 underwent standard therapy, and 159 underwent extended-spectrum therapy (Figure 1). The baseline characteristics of the patients undergoing both therapies are presented in Table 1. Frequencies of patients with chronic lung diseases, central nervous system disorders, immunosuppression, nonambulatory status, abnormal vital signs, platelet count <100,000/cells/μl, albumin <3.0 g/dl, blood urea nitrogen ≥20 mg/dl, pH <7.35, the ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤250, arterial carbon dioxide partial pressure ≥50 Torr, bilateral lung involvement, and severe pneumonia were higher in the extended-spectrum therapy group than in the standard therapy group.
      Figure 1
      Figure 1Patient flow.
      Abbreviations: DRP, drug-resistant pathogen; CAP, community-acquired pneumonia.
      CAP-DRPs were defined as pathogens not susceptible to antibiotics commonly administered in patients with CAP, including nonantipseudomonal β-lactam (ceftriaxone or ampicillin-sulbactam), macrolides (azithromycin or clarithromycin), and fluoroquinolones (moxifloxacin, levofloxacin or garenoxacin).
      aIdentified DRPs were as follows: 10, Pseudomonas aeruginosa; 18, methicillin-resistant Staphylococcus aureus; and 3, Stenotrophomonas maltophilia in patients with nonsevere CAP; 4, P. aeruginosa and 2, methicillin-resistant S. aureus in patients with severe CAP. P. aeruginosa and methicillin-resistant S. aureus were detected simultaneously in four patients, two nonsevere and two severe.
      bPatients at low risk of CAP-DRPs were defined as those without prior isolation of DRPs and those with severe CAP and not at a high risk of CAP-DRPs using locally validated prediction rules in Japan.
      cStandard therapy involved a nonantipseudomonal β-lactam plus a macrolide (or minocycline) or a respiratory fluoroquinolone for patients with nonsevere CAP and a nonantipseudomonal β-lactam plus a macrolide or a nonantipseudomonal β-lactam plus a respiratory fluoroquinolone for patients with severe CAP. Extended-spectrum therapy was defined as any antibiotics against P. aeruginosa or methicillin-resistant S. aureus.
      Table 1Patient characteristics.
      VariablesStandard therapy (n = 257)Extended-spectrum therapy (n = 159)
      Age ≥80 years77 (30.0)61 (38.4)
      Sex, male169 (65.8)118 (74.2)
      Comorbidities
       Neoplastic diseases36 (14.0)30 (18.9)
       Chronic lung diseases89 (34.6)71 (44.7)
       Congestive heart failure33 (12.8)27 (17.0)
       Chronic renal diseases24 (9.3)12 (7.5)
       Chronic dialysis4 (1.6)3 (1.9)
       Chronic liver diseases6 (2.3)5 (3.1)
       Central nervous system disorders25 (9.7)28 (17.6)
       Diabetes mellitus45 (17.5)24 (15.1)
       Immunosuppression
      Immunosuppression included any immunosuppressive disease, such as congenital or acquired immunodeficiency, hematologic diseases, and neutropenia (1000 cells/μl), treatment with immunosuppressive drugs within the previous 30 days, or corticosteroids at a daily dose of at least 10 mg/day of a prednisone equivalent for more than 2 weeks.
      11 (4.3)19 (11.9)
       Nonambulatory status
      Non-ambulatory status was defined as being bedridden or using a wheelchair due to difficulty in walking.
      20 (7.8)30 (18.9)
      Pneumonia type
       Community-acquired pneumonia208 (80.9)102 (64.2)
       Healthcare-associated pneumonia49 (19.1)57 (35.8)
      Physical findings
       Orientation disturbance, confusion36 (14.0)41 (25.8)
       Systolic blood pressure <90 mmHg7 (2.7)15 (9.4)
       Pulse rate ≥125 beats/min20 (7.8)26 (16.4)
       Respiratory rate ≥30 breaths/min41 (16.0)47 (29.6)
       Body temperature <36°C1 (0.4)5 (3.1)
      Laboratory findings
       White blood cell count <4000 cells/μl5 (1.9)8 (5.0)
       Hematocrit <30.0%21 (8.2)20 (12.6)
       Platelet count <100,000 cells/μl1 (0.4)13 (8.2)
       Albumin <3.0 g/dl48 (18.7)67 (42.1)
       Total bilirubin ≥1.2 mg/dl
      The number of patients in which total bilirubin was assessed was 255 and 158 in the standard therapy and the extended-spectrum therapy groups, respectively.
      40 (15.7)29 (18.4)
       Glucose <60 mg/dl or ≥250 mg/dl
      The number of patients in which glucose was assessed was 256 and 157 in the standard therapy and the extended-spectrum therapy groups, respectively.
      12 (4.7)12 (7.6)
       Blood urea nitrogen ≥20 mg/dl98 (38.1)83 (52.2)
       Creatinine ≥1.2 mg/dl52 (20.2)37 (23.3)
       Sodium concentration <130 mmol/l or ≥150 mmol/l18 (7.0)19 (11.9)
       Potassium concentration <3.0 mmol/l or ≥6.0 mmol/l8 (3.1)7 (4.4)
       C-reactive protein ≥20 mg/dl66 (25.7)48 (30.2)
       pH <7.35
      Arterial blood gas analysis was performed in 248 and 143 in the standard therapy and the extended-spectrum therapy groups, respectively. For patients in whom arterial blood gas analyses were not performed, PaO2 was estimated from SpO2.
      14 (5.6)24 (16.8)
       PaO2/FIO2 ratio ≤ 250
      Arterial blood gas analysis was performed in 248 and 143 in the standard therapy and the extended-spectrum therapy groups, respectively. For patients in whom arterial blood gas analyses were not performed, PaO2 was estimated from SpO2.
      61 (23.7)69 (43.4)
       PaCO2 ≥50 Torr
      Arterial blood gas analysis was performed in 248 and 143 in the standard therapy and the extended-spectrum therapy groups, respectively. For patients in whom arterial blood gas analyses were not performed, PaO2 was estimated from SpO2.
      13 (5.2)20 (14.0)
      Radiological findings
       Bilateral lung involvement106 (41.2)96 (60.4)
       Pleural effusion40 (15.6)35 (22.0)
      Pneumonia severity index class
      The pneumonia severity index was assessed in 252 receiving standard therapy and 144 receiving extended-spectrum therapy.
       I-III (mild)114 (45.2)33 (22.9)
       IV (moderate)106 (42.1)60 (41.7)
       V (severe)32 (12.7)51 (35.4)
      Abbreviation: PaO2, partial pressure of oxygen; FIO2, fraction of inspiration oxygen; PaCO2, partial pressure of carbon dioxide.
      Data are presented as no (%).
      a Immunosuppression included any immunosuppressive disease, such as congenital or acquired immunodeficiency, hematologic diseases, and neutropenia (1000 cells/μl), treatment with immunosuppressive drugs within the previous 30 days, or corticosteroids at a daily dose of at least 10 mg/day of a prednisone equivalent for more than 2 weeks.
      b Non-ambulatory status was defined as being bedridden or using a wheelchair due to difficulty in walking.
      c The number of patients in which total bilirubin was assessed was 255 and 158 in the standard therapy and the extended-spectrum therapy groups, respectively.
      d The number of patients in which glucose was assessed was 256 and 157 in the standard therapy and the extended-spectrum therapy groups, respectively.
      e Arterial blood gas analysis was performed in 248 and 143 in the standard therapy and the extended-spectrum therapy groups, respectively. For patients in whom arterial blood gas analyses were not performed, PaO2 was estimated from SpO2.
      f The pneumonia severity index was assessed in 252 receiving standard therapy and 144 receiving extended-spectrum therapy.

      Identified pathogens

      The proportion of the identified pathogens was 51.4% (132/257) and 52.2% (83/159) in the standard therapy and extended-spectrum therapy groups, respectively. The distribution of identified pathogens is presented in Supplementary Table 1. Non-CAP-DRPs, such as Streptococcus pneumoniae, MRSA, Haemophilus influenzae, and antibiotic-sensitive enteric gram-negative bacilli, were identified in 46.7% (120/257) of the patients in the standard therapy group and 42.8% (68/159) of the extended-spectrum therapy group. CAP-DRPs were identified in 12 patients (4.7%) undergoing standard therapy and in 15 patients (9.4%) undergoing extended-spectrum therapy.

      Administered initial antibiotics

      The administered initial antibiotics are listed in Table 2. In the standard therapy group, most patients received a nonantipseudomonal β-lactam plus a macrolide, regardless of disease severity, and all patients in this group received azithromycin. The most commonly used antibiotic therapy for the patients in the extended-spectrum therapy group was piperacillin-tazobactam monotherapy, followed by piperacillin-tazobactam plus macrolides and carbapenems plus azithromycin therapy in patients with nonsevere CAP, whereas the most frequently administered antibiotic therapy was carbapenems plus azithromycin therapy, followed by carbapenems and piperacillin-tazobactam monotherapy in patients with severe CAP. In the extended-spectrum therapy group, combination therapy was administered to more than 60% of patients with nonsevere as well as severe CAP. The administered initial antibiotics in patients who were not classified into the standard therapy or the extended-spectrum therapy groups are also described in Supplementary Table 2.
      Table 2Administered initial antibiotics.
      AntibioticsStandard therapy (n = 257)Extended-spectrum therapy (n = 159)
      Nonsevere (n = 215)Severe (n = 42)Nonsevere (n = 93)Severe (n = 66)
      Monotherapy
       Quinolones
      Moxifloxacin, levofloxacin or garenoxacin were defined as quinolones.
      16 (7.4)0 (0)--
       Piperacillin-tazobactam--23 (24.7)11 (16.7)
       Antipseudomonal cephalosporins
      Ceftazidime, cefepime, cefozopran or cefoperazone-sulbactam were defined as antipseudomonal cephalosporins.
      --9 (9.7)1 (1.5)
       Carbapenems
      Meropenem, imipenem-cilastatin or doripenem were defined as carbapenems.
      --4 (4.3)12 (18.2)
      Combination therapy
       Ampicillin-sulbactam + azithromycin87 (40.5)22 (52.4)--
       Ceftriaxone + azithromycin112 (52.1)17 (40.5)--
       Ampicillin-sulbactam + levofloxacin0 (0)2 (4.8)--
       Ceftriaxone + levofloxacin0 (0)1 (2.4)--
       Piperacillin-tazobactam + macrolides
      Azithromycin or clarithromycin was defined as macrolides.
      --20 (21.5)7 (10.6)
       Piperacillin-tazobactam + levofloxacin--4 (4.3)3 (4.5)
       Antipseudomonal cephalosporins
      Ceftazidime, cefepime, cefozopran or cefoperazone-sulbactam were defined as antipseudomonal cephalosporins.
       + azithromycin
      --7 (7.5)4 (6.1)
       Carbapenems
      Meropenem, imipenem-cilastatin or doripenem were defined as carbapenems.
       + azithromycin
      --13 (14.0)13 (19.7)
       Carbapenems
      Meropenem, imipenem-cilastatin or doripenem were defined as carbapenems.
       + levofloxacin
      --10 (10.8)8 (12.1)
       Piperacillin-tazobactam + anti-MRSA antibiotics
      Vancomycin, teicoplanin or linezolid were defined as anti-MRSA antibiotics.
      --0 (0)2 (3.0)
       Piperacillin-tazobactam + azithromycin + anti-MRSA antibiotics
      Vancomycin, teicoplanin or linezolid were defined as anti-MRSA antibiotics.
      --1 (1.1)1 (1.5)
       Meropenem + anti-MRSA antibiotics
      Vancomycin, teicoplanin or linezolid were defined as anti-MRSA antibiotics.
      --1 (1.1)1 (1.5)
       Meropenem + azithromycin + vancomycin--0 (0)1 (1.5)
       Meropenem + levofloxacin + vancomycin--0 (0)1 (1.5)
       Ceftriaxone + teicoplanin--0 (0)1 (1.5)
       Levofloxacin + linezolid--1 (1.1)0 (0)
      Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus.
      Data are presented as no (%).
      a Moxifloxacin, levofloxacin or garenoxacin were defined as quinolones.
      b Ceftazidime, cefepime, cefozopran or cefoperazone-sulbactam were defined as antipseudomonal cephalosporins.
      c Meropenem, imipenem-cilastatin or doripenem were defined as carbapenems.
      d Azithromycin or clarithromycin was defined as macrolides.
      e Vancomycin, teicoplanin or linezolid were defined as anti-MRSA antibiotics.

      Primary study end point

      Figure 2 presents the 30-day mortality proportions of the standard therapy and extended-spectrum therapy groups. The 30-day mortality of the standard therapy group was 3.9% (10/257), whereas that of the extended-spectrum therapy group was 13.8% (22/159) (Figure 2a). On categorizing disease severity into two groups according to the 2007 IDSA/ATS criteria (
      • Mandell LA
      • Wunderink RG
      • Anzueto A
      • Bartlett JG
      • Campbell GD
      • Dean NC
      • et al.
      Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
      ), the 30-day mortality of the standard therapy and extended-spectrum therapy groups in patients with nonsevere CAP was 2.8% (6/215) and 9.7% (9/93), respectively (Figure 2b), whereas in patients with severe CAP, it was 9.5% (4/42) and 19.7% (13/66), respectively (Figure 2c).
      Figure 2
      Figure 230-day mortality in the treatment groups based on severity.
      Abbreviation: CAP, community-acquired pneumonia.
      Standard therapy involved a nonantipseudomonal β-lactam plus a macrolide (or minocycline) or a respiratory fluoroquinolone for patients with nonsevere CAP and a nonantipseudomonal β-lactam plus a macrolide or a nonantipseudomonal β-lactam plus a respiratory fluoroquinolone for patients with severe CAP. Extended-spectrum therapy was defined as any antibiotics against Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus.
      Proportions of 30-day mortality for the standard therapy and extended-spectrum therapy groups were compared for all patients (a), those with nonsevere CAP (b), and those with severe CAP (c).
      Table 3 presents the effect of extended-spectrum therapy on 30-day mortality. In the crude analysis, extended-spectrum therapy appeared to increase the 30-day mortality compared with standard therapy (OR 3.97; 95% CI 1.83-8.62; P <0.001). In the primary multivariable logistic regression analysis, the extended-spectrum therapy was significantly associated with higher 30-day mortality than standard therapy (adjusted OR [aOR] 2.82; 95% CI 1.20-6.65).
      Table 3Associations of antibiotics with 30-day mortalities in the crude, multivariable, propensity score and stratified analyses.
      30-day all-cause mortality
      Analysis
      No. of events/ no. of patients at risk (%)
      Overall, 27 patients in the standard therapy group and 10 patients in the extended-spectrum therapy were lost to 30-day follow-up; however, they were all discharged from the hospital with improvement in pneumonia.
      Standard therapy10/257 (3.9%)
      Extended-spectrum therapy22/159 (13.8%)
      Crude analysis-OR (95% CI)3.97 (1.83-8.62)
      Multivariable analysis-OR (95% CI)
      OR from the multivariable logistic regression analysis. Covariables include nonambulatory status, respiratory rate ≥30/min, albumin <3.0 g/dl, pH <7.35, blood urea nitrogen ≥20 mg/dl. The analysis comprised 391 patients (248 who underwent standard therapy and 143 who underwent extended-spectrum therapy). 25 patients were excluded due to missing values.
      2.82 (1.20-6.65)
      Sensitivity analyses
      Multivariable analysis-OR (95% CI)
      OR from the multivariable logistic regression analysis. Covariables include age ≥80 years, nonambulatory status, body temperature <36.0°C, respiratory rate ≥30/min, white blood cell count ≤4,000 cells/μl, hematocrit <30.0%, albumin <3.0 g/dl, arterial carbon dioxide partial pressure ≥50 Torr. The analysis comprised 391 patients (248 who underwent standard therapy and 143 who underwent extended-spectrum therapy). 25 patients were excluded due to missing values.
      2.88 (1.22-6.83)
      Propensity score analysis with inverse-probability of treatment weighting analysis
      OR from the inverse probability of treatment weighting analysis according to the propensity score for antibiotics. The analysis comprised 389 patients (247 who underwent standard therapy and 142 who underwent extended-spectrum therapy). 27 patients were excluded due to missing values.
      2.82 (1.11-7.16)
      Stratified analysis by pneumonia severity index
      OR from the stratified analysis by pneumonia severity index classes. The analysis comprised 396 patients (252 who underwent standard therapy and 144 who underwent extended-spectrum therapy). 20 patients were excluded due to missing values.
      3.25 (1.41-7.50)
      Abbreviation: OR, odds ratio.
      a Overall, 27 patients in the standard therapy group and 10 patients in the extended-spectrum therapy were lost to 30-day follow-up; however, they were all discharged from the hospital with improvement in pneumonia.
      b OR from the multivariable logistic regression analysis. Covariables include nonambulatory status, respiratory rate ≥30/min, albumin <3.0 g/dl, pH <7.35, blood urea nitrogen ≥20 mg/dl. The analysis comprised 391 patients (248 who underwent standard therapy and 143 who underwent extended-spectrum therapy). 25 patients were excluded due to missing values.
      c OR from the multivariable logistic regression analysis. Covariables include age ≥80 years, nonambulatory status, body temperature <36.0°C, respiratory rate ≥30/min, white blood cell count ≤4,000 cells/μl, hematocrit <30.0%, albumin <3.0 g/dl, arterial carbon dioxide partial pressure ≥50 Torr. The analysis comprised 391 patients (248 who underwent standard therapy and 143 who underwent extended-spectrum therapy). 25 patients were excluded due to missing values.
      d OR from the inverse probability of treatment weighting analysis according to the propensity score for antibiotics. The analysis comprised 389 patients (247 who underwent standard therapy and 142 who underwent extended-spectrum therapy). 27 patients were excluded due to missing values.
      e OR from the stratified analysis by pneumonia severity index classes. The analysis comprised 396 patients (252 who underwent standard therapy and 144 who underwent extended-spectrum therapy). 20 patients were excluded due to missing values.
      Sensitivity analysis results are presented in Table 3. These trends are in accordance with the findings of the primary analysis. Multivariable logistic regression analysis including other covariables as potential confounders revealed that extended-spectrum therapy significantly increased the 30-day mortality compared with standard therapy (aOR 2.88; 95% CI 1.22-6.83). In the IPTW analysis, according to the propensity score, the extended-spectrum therapy also increased the 30-day mortality (aOR 2.82; 95% CI 1.11-7.16). Results associated with the validity of the IPTW propensity score analysis are provided in the Supplementary Material. The results of the stratified analysis of PSI classes also demonstrated the same trend (aOR 3.25; 95% CI 1.41-7.50) (Table 3). The 30-day mortality of the standard therapy and extended-spectrum therapy groups in each severity class (PSI class I-III [mild], IV [moderate], and V [severe]) is presented in Supplementary Table 3.

      Subgroup analysis

      Primary multivariable logistic regression analysis was also performed to assess the effect of extended-spectrum therapy on the 30-day mortality in each severity class as per the 2007 IDSA/ATS criteria (Supplementary Table 4). Although extended-spectrum therapy did not increase the 30-day mortality in patients with severe CAP (aOR 1.71; 95% CI 0.48-6.11), it was significantly associated with increased 30-day mortality in patients with nonsevere CAP compared with standard therapy (aOR 4.47; 95% CI 1.30-15.36).

      Discussion

      To the best of our knowledge, this is the first post hoc analysis based on a multicenter prospective observational study to assess the effect of extended-spectrum antibiotic therapy on the 30-day mortality in patients with CAP with a low risk for DRPs undergoing treatment as per the 2019 ATS/IDSA CAP guidelines. The results of the primary analysis as well as those of three sensitivity analyses demonstrated that extended-spectrum therapy is constantly associated with increased 30-day mortality compared with standard therapy. In addition, subgroup analyses indicated that the increase in the 30-day mortality because of extended-spectrum therapy was distinct in patients with nonsevere CAP rather than in those with severe CAP. These results suggest that the administration of extended-spectrum antibiotics is harmful in patients with CAP with a low risk for DRPs.
      The increased prevalence of DRPs is an escalating health problem worldwide (

      World Health Organization. Antimicrobial resistance. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance, 2021 (accessed 13 June 2022).

      ). The selection of appropriate target patients for the use of extended-spectrum antibiotics has been previously investigated in some studies (
      • Gleason PP
      • Meehan TP
      • Fine JM
      • Galusha DH
      • Fine MJ.
      Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia.
      ;
      • Menéndez R
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      • Borderías L
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      Guidelines for the treatment of community-acquired pneumonia: predictors of adherence and outcome.
      ). Regarding patients with pneumonia, the HCAP concept was considered to resolve this issue and effectively identify patients at risk of DRPs (
      • American Thoracic Society
      Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.
      ;
      • Kollef MH
      • Morrow LE
      • Baughman RP
      • Craven DE
      • McGowan JE
      • Jr Micek ST
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      Health care-associated pneumonia (HCAP): a critical appraisal to improve identification, management, and outcomes–proceedings of the HCAP summit.
      ). However, several researchers have raised doubts on the HCAP concept, suggesting that it could increase the unnecessary use of extended-spectrum antibiotics (
      • Aliberti S
      • Dela Cruz CS
      • Amati F
      • Sotgiu G
      • Restrepo MI
      Community-acquired pneumonia.
      ;
      • Ewig S
      • Kolditz M
      • Pletz MW
      • Chalmers J.
      Healthcare-associated pneumonia: is there any reason to continue to utilize this label in 2019?.
      ;
      • Webb BJ
      • Dascomb K
      • Stenehjem E
      • Vikram HR
      • Agrwal N
      • Sakata K
      • et al.
      Derivation and multicenter validation of the drug resistance in pneumonia clinical prediction score.
      ). Indeed, several studies have revealed an association between the use of extended-spectrum antibiotics and increased mortality in patients with CAP, including HCAP (
      • Attridge RT
      • Frei CR
      • Restrepo MI
      • Lawson KA
      • Ryan L
      • Pugh MJ
      • et al.
      Guideline-concordant therapy and outcomes in healthcare-associated pneumonia.
      ;
      • Jones BE
      • Ying J
      • Stevens V
      • Haroldsen C
      • He T
      • Nevers M
      • et al.
      Empirical anti-MRSA vs standard antibiotic therapy and risk of 30-day mortality in patients hospitalized for pneumonia.
      ;
      • Webb BJ
      • Sorensen J
      • Jephson A
      • Mecham I
      • Dean NC.
      Broad-spectrum antibiotic use and poor outcomes in community-onset pneumonia: a cohort study.
      ). In the last decade, several research groups in different regions have reassessed the essential risk factors of DRPs to be considered when determining the initial antibiotics to be administered after pneumonia diagnosis (
      • Aliberti S
      • Di Pasquale M
      • Zanaboni AM
      • Cosentini R
      • Brambilla AM
      • Seghezzi S
      • et al.
      Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia.
      ;
      • Prina E
      • Ranzani OT
      • Polverino E
      • Cillóniz C
      • Ferrer M
      • Fernandez L
      • et al.
      Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ;
      • Shorr AF
      • Zilberberg MD
      • Reichley R
      • Kan J
      • Hoban A
      • Hoffman J
      • et al.
      Validation of a clinical score for assessing the risk of resistant pathogens in patients with pneumonia presenting to the emergency department.
      ;
      • Webb BJ
      • Dascomb K
      • Stenehjem E
      • Vikram HR
      • Agrwal N
      • Sakata K
      • et al.
      Derivation and multicenter validation of the drug resistance in pneumonia clinical prediction score.
      ). The current international trend in determining the initial antibiotics to be administered for patients with CAP is to assess the history of DRP isolation and risk factors of DRPs (
      • Metlay JP
      • Waterer GW
      • Long AC
      • Anzueto A
      • Brozek J
      • Crothers K
      • 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.
      ;
      • Pletz MW
      • Blasi F
      • Chalmers JD
      • Dela Cruz CS
      • Feldman C
      • Luna CM
      • et al.
      International perspective on the new 2019 American Thoracic Society/Infectious Diseases Society of America community-acquired pneumonia guideline: a critical appraisal by a global expert panel.
      ). The use of extended-spectrum antibiotics, including those exhibiting antipseudomonal activity and anti-MRSA activity, is acceptable for patients with a history of DRP isolation or those at a high risk for DRPs. Therefore, the benefits and drawbacks of extended-spectrum antibiotics use should be carefully considered for patients without a history of DRP isolation and at a low risk for DRPs. The current study evaluated the effect of the extended-spectrum therapy in such patients.
      The results of this study revealed that the extended-spectrum therapy was significantly associated with increased 30-day mortality in patients with a low risk for DRPs. This finding is consistent with those of previous studies.(
      • Attridge RT
      • Frei CR
      • Restrepo MI
      • Lawson KA
      • Ryan L
      • Pugh MJ
      • et al.
      Guideline-concordant therapy and outcomes in healthcare-associated pneumonia.
      ;
      • Jones BE
      • Ying J
      • Stevens V
      • Haroldsen C
      • He T
      • Nevers M
      • et al.
      Empirical anti-MRSA vs standard antibiotic therapy and risk of 30-day mortality in patients hospitalized for pneumonia.
      ;
      • Webb BJ
      • Sorensen J
      • Jephson A
      • Mecham I
      • Dean NC.
      Broad-spectrum antibiotic use and poor outcomes in community-onset pneumonia: a cohort study.
      ) The strategy for identifying patients with a low risk for DRPs in the current study complies with the 2019 ATS/IDSA CAP guidelines (
      • Metlay JP
      • Waterer GW
      • Long AC
      • Anzueto A
      • Brozek J
      • Crothers K
      • 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.
      ). The results suggest that the algorithm used for the selection of nonextended-spectrum antibiotics in CAP is appropriate and can improve patient outcomes. Furthermore, the current study revealed that adverse effects of the extended-spectrum therapy were more prominent in patients with nonsevere CAP than in those with severe CAP, indicating that physicians should refrain from administering extended-spectrum antibiotics to patients who are at a low risk for DRPs with nonsevere CAP. Moreover, no statistically different adverse effects were observed in patients with severe CAP undergoing extended-spectrum therapy compared with those with nonsevere CAP in the current study, implying that multidimensional management strategies, including appropriate respiratory care and adjunctive therapy, and the appropriate use of antibiotics are crucial for improving outcomes of patients with severe CAP (
      • Aliberti S
      • Dela Cruz CS
      • Amati F
      • Sotgiu G
      • Restrepo MI
      Community-acquired pneumonia.
      ;
      • Torres A
      • Cilloniz C
      • Niederman MS
      • Menéndez R
      • Chalmers JD
      • Wunderink RG
      • et al.
      Pneumonia.
      ;
      • Wunderink RG
      • Waterer G.
      Advances in the causes and management of community acquired pneumonia in adults.
      ). Further prospective studies are warranted to validate the guidelines recommendations.
      The possible explanation for the association of extended-spectrum antibiotics with increased mortality includes multiple mechanisms triggered by the antibiotics. The changes in the composition of microbiota after the administration of extended-spectrum antibiotics may be one of the key mechanisms (
      • Thibeault C
      • Suttorp N
      • Opitz B.
      The microbiota in pneumonia: from protection to predisposition.
      ). A review of the microbiota associated with pneumonia revealed that extended-spectrum antibiotics compromise microbiota-dependent colonization resistance mechanisms. As a result, the use of extended-spectrum antibiotics may contribute to the increased risk for hospital-acquired and ventilator-associated pneumonia associated with increased mortality (
      • Thibeault C
      • Suttorp N
      • Opitz B.
      The microbiota in pneumonia: from protection to predisposition.
      ). There may be other possible explanations, such as several extended-spectrum antibiotics can cause acute kidney injury; in particular, the combination of vancomycin with piperacillin-tazobactam, which is often prescribed for pneumonia, is associated with increased acute kidney injury (
      • Bellos I
      • Karageorgiou V
      • Pergialiotis V
      • Perrea DN.
      Acute kidney injury following the concurrent administration of antipseudomonal beta-lactams and vancomycin: a network meta-analysis.
      ;
      • Lee JD
      • Heintz BH
      • Mosher HJ
      • Livorsi DJ
      • Egge JA
      • Lund BC.
      Risk of acute kidney injury and clostridioides difficile infection with piperacillin/tazobactam, cefepime, and meropenem with or without vancomycin.
      ;
      • Luther MK
      • Timbrook TT
      • Caffrey AR
      • Dosa D
      • Lodise TP
      • LaPlante KL.
      Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis.
      ). Moreover, Clostridioides difficile is the causative pathogen of antibiotic-associated colitis (
      • McDonald LC
      • Gerding DN
      • Johnson S
      • Bakken JS
      • Carroll KC
      • Coffin SE
      • et al.
      Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ). A systematic review and meta-analysis revealed that carbapenems and cephalosporins induced C. difficile infection to a larger extent than penicillins or fluoroquinolones (
      • Vardakas KZ
      • Trigkidis KK
      • Boukouvala E
      • Falagas ME.
      Clostridium difficile infection following systemic antibiotic administration in randomised controlled trials: a systematic review and meta-analysis.
      ). In addition, previous studies have demonstrated that extended-spectrum antibiotics predisposed patients to nosocomial lung infections (
      • Metersky ML
      • Frei CR
      • Mortensen EM.
      Predictors of Pseudomonas and methicillin-resistant Staphylococcus aureus in hospitalized patients with healthcare-associated pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ;
      • Thibeault C
      • Suttorp N
      • Opitz B.
      The microbiota in pneumonia: from protection to predisposition.
      ;
      • Venier AG
      • Gruson D
      • Lavigne T
      • Jarno P
      • L'hériteau F
      • Coignard B
      • et al.
      Identifying new risk factors for Pseudomonas aeruginosa pneumonia in intensive care units: experience of the French national surveillance, rea-RAISIN.
      ). Furthermore, acute kidney injury and nosocomial infections, including C. difficile infection, are associated with increased mortality in pneumonia (
      • Becerra MB
      • Becerra BJ
      • Banta JE
      • Safdar N.
      Impact of Clostridium difficile infection among pneumonia and urinary tract infection hospitalizations: an analysis of the Nationwide inpatient sample.
      ;
      • Chawla LS
      • Amdur RL
      • Faselis C
      • Li P
      • Kimmel PL
      • Palant CE.
      Impact of acute kidney injury in patients hospitalized with pneumonia.
      ;
      • Shindo Y
      • Ito R
      • Kobayashi D
      • Ando M
      • Ichikawa M
      • Shiraki A
      • et al.
      Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
      ). Thus, multiple events induced by extended-spectrum antibiotics use may result in adverse outcomes in patients. Although acute kidney injury and C. difficile infection were not assessed in this study, we plan to evaluate them in an ongoing multicenter observational study.
      This study has several limitations. There may be a potential bias because of the post hoc analysis based on a prospective observational study. Moreover, there might be unidentified confounding factors for the end point, and the number of events was relatively small. Accordingly, a primary multivariable logistic regression analysis and three sensitivity analyses were conducted. Moreover, the data used in this study were obtained before the COVID-19 pandemic. The results of this study may be applied to patients with CAP but not to those with COVID-19 pneumonia; we aim to investigate the effect of extended-spectrum therapy on mortality in patients with CAP, including COVID-19 pneumonia, in another multicenter observational study. Despite these limitations, the results of this study provided valuable information regarding the selection of appropriate initial antibiotics for patients with CAP with a low risk for DRPs.

      Conclusion

      The current study was focused on patients with CAP with a low risk for DRPs, and the results revealed that the use of extended-spectrum antibiotics is associated with increased mortality. Physicians should therefore acknowledge the significance of DRPs risk assessment when determining the empirical antibiotic therapy and should refrain from administering extended-spectrum antibiotics to patients with a low risk for DRPs.

      Author contributions

      All authors meet the International Committee of Medical Journal Editors authorship criteria. HK and YS designed this study. DK, YS, HK, TS, YM, TY, and HS participated in data acquisition. HK, YS, and SM created the statistical analysis plan, which was reviewed by all authors. HK, YS, TS, YM, MY, AM, KS, KM, RE, and SM contributed to data interpretation. HS and YH contributed to study supervision. HK and YS wrote the initial draft of the manuscript. TS, YM, MY, AM, TY, and SM contributed to the critical revision of the manuscript for important intellectual content. All authors approved the final draft.

      Funding

      This work was partially supported by the Japan Society for the Promotion of Science KAKENHI (grant number 20K08517 ). This study was also supported by the Central Japan Lung Study Group, a nonprofit organization supported by unrestricted donations from the following pharmaceutical companies: Chugai Pharmaceutical Co., Ltd.; Shionogi & Co., Ltd.; Daiichi Sankyo Co., Ltd.; Dainippon Sumitomo Pharma Co., Ltd.; Janssen Pharmaceutical K.K.; Eli Lilly Japan K.K.; Taisho Toyama Pharmaceutical Co., Ltd.; Meiji Seika Pharma Co., Ltd.; MSD K.K.; Bayer Holding Ltd.; Astellas Pharma Inc.; and Nippon Boehringer Ingelheim Co., Ltd. The founders of the Central Japan Lung Study Group had no role in the design and conduct of the study; gathering, management, analysis, and interpretation of data; and preparation of the manuscript.

      Declaration of Competing Interest

      All of the following information provides relevant financial activities outside of the submitted work. YS reports personal fees (payment for lectures, including service on speaker bureaus) from KYORIN Pharmaceutical Co., Ltd.; AstraZeneca K.K.; Daiichi Sankyo Company, Limited; Nippon Boehringer Ingelheim Co., Ltd.; GlaxoSmithKline plc; and Gilead Sciences Inc. and participates as a member of the case adjudication committee of GlaxoSmithKline Biologicals SA. TY reports grants and personal fees (payment for lectures, including service on speakers bureaus) from Shionogi & Co., Ltd.; Dainippon Sumitomo Pharma Co., Ltd.; and MSD K.K. SM reports personal fees (payment for consultations in other studies) from Takeda Pharmaceutical Co., Ltd. YH reports grants and personal fees (payment for lectures, including service on speakers bureaus) from Chugai Pharmaceutical Co., Ltd.; MSD K.K.; GlaxoSmithKline plc; KYORIN Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Meiji Seika Pharma Co, Ltd.; Sanofi K.K.; and Daiichi Sankyo Inc. All other authors have no competing interests to declare.

      Acknowledgments

      The authors would like to thank Drs. Ryota Ito, Mai Iwaki, Yuka Tomita, Mitsutaka Iguchi, Tomohiko Ogasawara, Yasuteru Sugino, and Hiroyuki Taniguchi for the acquisition of data; Drs. Yosuke Goto, Kunihiko Takahashi, and Nancy Thabet for their comments on the manuscript. The authors are grateful to the clinical research coordinators (Kyoko Kazeto and Sumiyo Tanaka), laboratory staff (Ikuo Yamaguchi, Mariko Mochizuki, Miho Saito, Yoshiko Sugaki, Yusuke Nishida, and Sachie Asai), and all healthcare professionals who participated in the data collection. We would like to thank Enago (www.enago.jp) for the English language review.

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