Open access peer-reviewed chapter

Pneumonia: Drug-Related Problems and Hospital Readmissions

Written By

Kien T. Nguyen, Suol T. Pham, Thu P.M. Vo, Chu X. Duong, Dyah A. Perwitasari, Ngoc H.K. Truong, Dung T.H. Quach, Thao N.P. Nguyen, Van T.T. Duong, Phuong M. Nguyen, Thao H. Nguyen, Katja Taxis and Thang Nguyen

Submitted: August 20th, 2021 Reviewed: August 25th, 2021 Published: September 10th, 2021

DOI: 10.5772/intechopen.100127

Chapter metrics overview

239 Chapter Downloads

View Full Metrics

Abstract

Pneumonia is one of the most common infectious diseases and the fourth leading cause of death globally. According to US statistics in 2019, pneumonia is the most common cause of sepsis and septic shock. In the US, inpatient pneumonia hospitalizations account for the top 10 highest medical costs, totaling $9.5 billion for 960,000 hospital stays. The emergence of antibiotic resistance in the treatment of infectious diseases, including the treatment of pneumonia, is a globally alarming problem. Antibiotic resistance increases the risk of death and re-hospitalization, prolongs hospital stays, and increases treatment costs, and is one of the greatest threats in modern medicine. Drug-related problems (DRPs) in pneumonia - such as suboptimal antibiotic indications, prolonged treatment duration, and drug interactions - increase the rate of antibiotic resistance and adverse effects, thereby leading to an increased burden in treatment. In a context in which novel and effective antibiotics are scarce, mitigating DRPs in order to reduce antibiotic resistance is currently a prime concern. A variety of interventions proven useful in reducing DRPs are antibiotic stewardship programs, the use of biomarkers, computerized physician order entries and clinical decision support systems, and community-acquired pneumonia scores.

Keywords

  • Pneumonia
  • drug-related problems
  • re-hospitalization
  • prescriptions
  • interventions

1. Introduction

Pneumonia is an acute lower respiratory tract infection caused by bacteria, viruses, or fungi. Groups of patients at high risk of getting pneumonia include children under 5 years old, people over 65 years old, and people with comorbidities. Pneumonia is the leading cause of death in children, and among the top four causes of death globally [1]. Each year, pneumonia kills more than 800,000 children under the age of 5, equivalent to about 2,200 children every day [2]. In the United States, the annual incidence of community-acquired pneumonia (CAP) was 248 cases per 100,000 persons [3]. A study in central Vietnam reported that the incidence of CAP in subjects aged ≥ 65 years was 4.6 per 1,000 person-years (95% CI, 3.8–5.5) [4]. Hospitalized patients diagnosed with pneumonia accounted for 19.9%, 6.4%, and 1.5% in the Philippines, Malaysia, and Indonesia, respectively. The total estimated costs incurred for pneumonia patients were in Malaysia 4.1 million USD, in Indonesia 2.6 million USD, and in the Philippines 2.6 million USD [5].

Drug-related problems are defined as ‘events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes’ [6]. Causes of DRPs can be related to inappropriate drug selection, inappropriate dosage, duration of use of medication longer or shorter than recommended, incorrect drug use processes, or poor compliance, all resulting in decreased treatment effectiveness and increased morbidity and mortality [7, 8, 9]. In Ethiopia, the proportion of patients hospitalized for infectious diseases, and who also had DRPs, was 71.51% (123/172); of these, the unnecessary broad-spectrum antibiotic option ceftriaxone accounted for 44.77% [10]. Similarly, in a study in Spain, almost half (45.1%) of hospitalized patients suffered from DRPs [11]. Common DRPs associated with pneumonia include inappropriate antibiotic indications, prolonged antibiotic treatment, and overtreatment, which may lead to potential drug–drug interactions [12, 13, 14, 15]. In the context of increasing antibiotic resistance, prescribing doctors, often concerned about possibly missing pathogenic bacteria, tend to prescribe broad-spectrum antibiotics over a longer treatment time to avoid recurrence of the disease. Fear, rather than lack of knowledge, is a major barrier to preventing overtreatment with antibiotics [16]. Therefore, a new method being considered for improving empirical antibiotic selection is the community-acquired pneumonia score. This score can be used in a prediction model of clinical data, enabling more accurate application of empirical antibiotics [17]. In addition, many intervention tools need to be applied, such as antibiotic management programs, biomarkers, and computerized physician order entries (CPOE), to ensure the effectiveness and safety of guideline compliance. The computerized physician order entry (CPOE) and clinical decision support systems (CDSS) are valuable technological tools for use in interventions to prevent adverse drug events (ADEs). However, in the healthcare system, the role of the clinical pharmacist in minimizing DRPs remains crucial [14]. The chapter is, therefore, to summarize an overview of DRPs in pneumonia and recommend some strategies for reducing these DRPs.

Advertisement

2. Drug-related problems in pneumonia

2.1 Improper drug selection and dose selection

Prescribing inappropriate antibiotics leads to increased mortality, the development of antimicrobial resistance, and added treatment costs [18, 19]. Meta-analysis of 7401 patients with ventilator-associated pneumonia (VAP), using unadjusted data, revealed that inappropriate antibiotic therapy significantly increased the mortality of patients (odds ratio [OR], 2.34; 95% CI, 1.51–3.63; P = 0.0001, I2 = 28.5%) [8]. A retrospective cohort study of bacteremic pneumonia, conducted in Barnes-Jewish Hospital in Missouri, USA (2008–2015) using multivariable logistic regression analysis for hospital mortality, indicated that inappropriate initial antibiotic treatment had the greatest odds ratio with mortality (OR 2.2, 95% CI 1.5–3.2, P < 0.001). The rate of inappropriate antibiotic initiation was significantly higher in patients with ceftriaxone-resistant pathogens than with ceftriaxone-susceptible pathogens (27.9% vs. 7.1%, P < 0.001), and the associated hospital mortality rates were respectively 41.5% vs. 32.0% (P = 0.001) [9].

Inappropriate antibiotic selection is one of the most common DRPs in patients with pneumonia, and particularly community-acquired pneumonia (CAP). Antibiotic prescriptions collected from 22 pharmacies in Mongolia indicated that inappropriate drug selection affected both adults (57.7%) and children (56.6%) [20]. A study among 518 outpatients with CAP in the Veterans Affairs Western New York Healthcare System indicated that 69% of patients received an inappropriate antibiotic; for 76.7% of them an incorrect drug had been prescribed, based on the patient’s comorbidities [21]. In Thailand, a prospective observational study of severe CAP in general medical wards showed that 52% of patients received initial antibiotic regimens that were discordant with IDSA/ATS guidelines [22].

The increase in resistance rates of bacteria to antibiotics leads to inappropriate selection of initial antibiotics. Due to an “encirclement” mentality, doctors often tend to choose empiric broad-spectrum antibiotics; this invisible cause increases antibiotic resistance, resulting in a “vicious circle” that increasingly burdens patients and society [23, 24, 25]. In particular, prescribing broad-spectrum antibiotics for a low-risk group increases the risk of unwanted effects rather than making treatment beneficial. According to current guidelines for the treatment of community-acquired pneumonia, an outpatient should receive beta-lactam or a macrolide or doxycycline [26, 27]. A retrospective chart review at a large hospital indicated that fluoroquinolones were antibiotics overprescribed for 71% of patients in the low-risk group [28]. Another retrospective chart review among 156 adult patients with a diagnosis of CAP, admitted to a community hospital emergency department in Canada, found that physicians overprescribed fluoroquinolones for 80.8% of patients who did not need them [29]. Over-prescribing of fluoroquinolones for outpatients with pneumonia increases the risk of side effects: tendon rupture, tendonitis, feeling shaky, unusual hunger, serious events of aortic ruptures or tears, and development of antibiotic resistance [30, 31, 32].

For this reason, antibiotic stewardship programs (ASPs) and clinical pharmacists play an important role in promoting the appropriate prescribing of empiric antibiotics. A retrospective cohort study of patients with CAP indicated a significant reduction in fluoroquinolone prescribing over time following intervention involving ASPs and clinical pharmacists [33]. An additional new method for improving empirical antibiotic selection is the community-acquired pneumonia score. This score provides a model of clinical data, thereby enabling the proper use of empirical antibiotics [17]. Implementation of an empiric therapy guide is important to minimize DRPs in the initial selection of antibiotics for pneumonia, as the causative organism and the patient’s susceptibility to it are often unknown at the time of prescription. Galanter KM et al. demonstrated that after intervention in accordance with the empiric therapy guide, the rate of broad-spectrum antibiotic indication for CAP decreased significantly, by 17.0% [34].

In Canada, a study on pneumonia showed that prescribed antibiotic doses tended to be higher than recommended [29]. In contrast, a prospective multinational study involving 68 ICUs across 10 countries confirmed that 20% of patients received less than the most conservative PK/PD target (50% f T > MIC), and fewer than 50% of patients received a preferred PK/PD target (100% f T > MIC) [13]. Such insufficient antibiotic exposure can also facilitate antibiotic resistance. For the treatment of CAP, especially critical patients require individualized dosing based on the severity of disease, local documented pathogen susceptibilities, and causal bacteria. Patient characteristics also play an important role in reducing mortality.

2.2 Drug interactions

Pneumonia patients often have not just one diagnosis but suffer from comorbid conditions. Frequent comorbidities are diabetes mellitus, cerebrovascular disease, chronic lung disease, chronic kidney disease, and dementia [15, 35, 36]. Common medication classes used for the management of comorbid conditions are cardiovascular agents, alimentary tract and metabolism agents, nervous system agents, respiratory agents, blood-forming agents, and general anti-infective agents for systemic use. The potential of drug–drug interactions in cases of pneumonia is more prevalent in older patients, possibly leading to chronic diseases and polypharmacy; some drugs even increase the risks of pneumonia [37]. In pneumonia patients, comorbidities have been strongly associated with long-term mortality [36], and concurrent use of multiple drugs can lead to an increased risk of drug–drug interactions (DDIs) [15, 35, 38]. Results of a study in a population, most of whom were concurrently using >10 drugs, revealed that 73.1% of these patients faced potential DDIs. Indeed, more than half of the patients presented with major potential DDIs [15]. Furthermore, nearly 75% of patients with community-acquired pneumonia (CAP) were subjected to polypharmacy [35].

Some clinical consequences of DDIs included increased or decreased therapeutic effectiveness, adverse drug reactions (ADRs), and toxicity (nephrotoxicity, hepatotoxicity) [15, 38]. DDIs can take place between different antibiotics, and between antibiotics and other medications. For treating pneumonia many guidelines recommend using β-lactams, macrolides, and fluoroquinolones. This may cause a prolonged QT interval (when fluoroquinolones or macrolides are administered) or a prolonged Prothrombin Time and International Normalized Ratio (INR) (if fluoroquinolones and warfarin are administered concurrently) [37]. Therefore, to prevent the negative effects of polypharmacy, consultations should be held to identify potential DDIs and alert physicians. Moreover, medical staff should refer to more than one drug interaction checker tool -- like Lexi-Interact, Micromedex, Medscape, Drugs.com. -- as well as adhere to guidelines for optimizing the use of prescribed drugs and discontinuing the use of unnecessary drugs.

2.3 Initiation and duration of administration antibiotic treatment

Patients whose initial appropriate antibiotics therapy is delayed may have increased morbidity rates compared to those receiving appropriately prescribed therapy on time. A systematic review in patients hospitalized with infections due to Klebsiella pneumoniaeor Escherichia colifound that a delay in appropriate antibiotic therapy of more than 24 hours and 48 hours after culture collection, or in culture and susceptibility reporting, can increase the risk of mortality: OR 1.60 (95% CI, 1.25–2.50) and OR 1.76 (95% CI, 1.27–2.44) respectively [39]. A prospective cohort study in patients with VAP showed that for thirty-three patients (30.8%) the appropriate antibiotic treatment was delayed for >24 hours after they first met the diagnostic criteria for VAP; this initially delayed appropriate antibiotic treatment was a risk factor for increasing the hospital mortality rate (adjusted odds ratio, 7.68; 95% CI 4.50 to 13.09; p < 0.001) [40].

The British Thoracic Society Guidelines for the Management of Community-Acquired Pneumonia in Adults recommends the administration of antibiotics within four hours of admission to hospital for adults with radiologically confirmed CAP [41]. A large study (n = 13,725 from 188 institutions) conducted among adults hospitalized with CAP indicated that 37% of patients failed to receive antibiotics within four hours of admission. Delay time of the first antibiotic was associated with a greater OR of 30-day inpatient mortality. The adjusted 30-day inpatient mortality was lower for adults who received their initial antibiotic within four hours, compared with >4 hours (adjusted OR 0.84, 95% CI 0.74 to 0.94; p = 0.003) [42]. A retrospective study (n = 18,209) of Medicare patients older than 65 years who were hospitalized with CAP revealed that 39.1% did not receive antibiotics within four hours of admission. Initial administration of antibiotics within four hours, versus more than four hours, after arrival at the hospital was associated with reduced in-hospital mortality (6.8% vs. 7.4%; adjusted odds ratio (AOR)), 0.85; 95% CI, 0.74–0.98), versus mortality within 30 days of admission (11.6% vs. 12.7%; AOR, 0.85; 95% CI, 0.76–0.95), and length of stay exceeding the 5-day median (42.1% vs. 45.1%; AOR, 0.90; 95% CI, 0.83–0.96) [43].

For a long time, a seven-day application of antibiotic therapy to treat infectious diseases was standard procedure [44]. However, the duration of antibiotic treatment should be based on the severity of the disease, patient characteristics, patients’ clinical stability, and the causative organisms [45]. Long-term antibiotic treatment is associated with increased side- effects, antibiotic-resistant organisms, and C. difficilediarrhea [46, 47]. Unfortunately, a large study in 66,901 long-term care residents showed that 44.9% of patients were prescribed antibiotic treatment lasting longer than 7 days, and prescriptions tended not to be based on patient characteristics and comorbidities [14]. Furthermore, a retrospective cohort of 152,874 patients hospitalized for CAP found that more than 70% were prescribed antibiotics in excess of recommendations [48]. A large US study found that for 93% and 71% of patients with uncomplicated CAP and healthcare-associated pneumonia, respectively, lengthy durations of antibiotic treatment were indicated [49].

In addition, a systematic review of HAP in critically ill adults (including VAP) manifested that a short duration of antibiotic therapy (7 to 8 days) versus conventional antibiotic therapy (10 to 15 days) did not increase mortality rate, duration of mechanical ventilation, and length of hospital stay; however, a rise in recurrence was discovered in the subgroup of patients with VAP, caused by non-fermenting Gram-negative bacilli [50]. An RCT study in neonatal pneumonia conducted to compare the efficacy of a short course (4 days, intervention group) with a traditional antibiotic regimen (7 days, control group) demonstrated that treatment in the intervention group had the same success rate as in the control group, but the group intervention significantly reduced the length of the hospital stay, as well as antibiotic use and treatment costs [51].

For adults with CAP, although more relevant antibiotic studies are needed in the future to support a short-term therapy, clinicians should always be aware that the duration of antibiotic treatment should be based on the clinical improvement of the patient rather than mechanical practice. ATS/IDSA guidelines recommend a total duration of antibiotic therapy of 5 days for most outpatients and inpatients with CAP, except for cases of suspected MRSAor P. aeruginosa. According to the guidelines, the patient will achieve clinical improvement after the first 48–72 hours, after which antibiotics should be continued for 2–3 days [45]. Pending further studies, adherence to guidelines is one of the keys to limiting DRPs in treatment.

For pediatric patients with CAP, according to the 2011 PIDS/IDSA guidelines, which are still applicable today, the duration of treatment depends upon the severity. Treatment courses of 10 days are recommended, although the guidelines suggest that shorter courses may be just as effective, especially in mild patients. CA-MRSA patients may need a longer treatment period [26].

For adults with HAP/VAP, although the duration of antibiotic use is determined based on patients’ conditions like a clinical improvement, as well as radiological and laboratory parameters, the current recommendation for most patients is a 7-day course of antimicrobial therapy rather than longer treatment [52].

In conclusion, the high rate of prolongation of antibiotic treatment and inappropriate initiation of therapy in patients with pneumonia indicates the great need for improvement to reduce drug-related problems. Antimicrobial stewardship, biomarkers, and clinical stability scores should be applied to decrease the duration of antibiotic therapy [53, 54].

2.4 Comorbidities

Respiratory diseases have been found to be associated with multi-morbidity patterns [55]. Patients with pneumonia often have a broad range of comorbid conditions [37, 56]. While short-term mortality is directly associated with the severity of pneumonia, long-term mortality is associated with comorbid conditions [56]. Most patients who die from pneumonia have one or more severe chronic diseases, such as cerebrovascular disease, chronic cardiac or renal disease, dementia, cachexia, mobility impairment, neoplastic metastatic disease, or sepsis. Patients with either MRSA or Pseudomonas were found to have an increased risk of dying of pneumonia [57]. In patients with pneumonia, comorbidities are also associated with poor response to treatment. Moreover, patients older than 80 years with comorbidities also have a higher mortality rate than patients from other age groups [58].

All-cause mortality has been found to increase in relation to the number of comorbid conditions. Every comorbid condition has been found to correlate with a 9% higher risk of death [56]. Some comorbid conditions that influence mortality (cardiovascular and lung diseases, diabetes, etc.) are also particular risk factors for pneumonia [37].

The Charlson Comorbidity Index measures comorbidity. Patients with a higher Charlson pathology index score were found to have a higher risk of death due to hospitalization (OR 1.28; 95% CI 1.07–1.53). These findings indicate a relationship between a patient’s comorbid burden and the consequences of community-acquired pneumonia [59]. Results of a study among 108 patients by Franzen et al. indicated that the death risk of hospitalized pneumonia patients tended to increase with a higher CCI [58].

Children with comorbidities were more likely to be hospitalized for community-acquired pneumonia, compared to those without comorbidities. Approximately 50% of children and adolescents with community-acquired pneumonia had comorbidities related to malnutrition, as well as the use of antibiotics and hospitalization for community-acquired pneumonia during the previous 24 months. Bivariate analysis showed that patients with comorbidities demonstrated higher chances of malnutrition (p = 0.002), previous use of antibiotics (p = 0.008), and previous hospitalization for community-acquired pneumonia in the last 24 months (p = 0.004). In multivariate analysis, the following variables were independent predictors of community-acquired pneumonia in patients with comorbidities: malnutrition (p = 0.008; RR = 1.75; 95%CI 1.75–44.60); previous use of antibiotics (p = 0.0013; RR = 3.03; 95%CI 1.27–7.20); and previous hospitalization for community-acquired pneumonia (p = 0.035; RR = 2.91; 95%CI 1.08–7.90) [60].

In addition, pneumonia influenced concurrent comorbid conditions, resulting in a subsequent impact on the incidence of events like acute myocardial infarction, heart failure, stroke, venous thromboembolism, and cancer [56]. Recognition of the mutual relationship between pneumonia and comorbidities will help to identify patients at high risk. Though no specific guideline for multi-morbidities currently exists, close monitoring of patients during hospitalization and long-term follow-up may result in better outcomes.

2.5 Risk factors for DRP-readmission and pneumonia re-hospitalization

According to a review on drug-related hospital readmissions, an average of 21% of such readmissions were drug-related, and 69% were considered preventable [61]. Some predictive factors that can be considered to avoid hospital readmissions due to DRPs include limiting the number of drugs prescribed on a particular day, and the number of drug classifications according to the day of hospitalization [62]. Healthcare professionals should focus more on identifying risk factors related to drug-related readmissions, and on finding appropriate interventions.

Among the known risk factors for DRPs is non-adherence to medication, which may be aggravated by the complexity of the medication regimen. The medication regimen complexity index (MRCI) is a tool that assesses the complexity of a medication list in terms of dosage form, dosing frequency, and additional directions required for administration. Higher MRCI scores indicate greater regimen complexity. MRCI scores were significantly higher in patients readmitted (within 30 days) than those not readmitted [63, 64]. The MRCI can thus be used as a predictor of drug-related readmissions.

Another risk factor associated with 30-day readmission rates was the presence of comorbidities [65]. Comorbidities weaken the immune system and worsen a patient’s condition. The Charlson Comorbidity Index (CCI) is a tool that adds weighted scores to each illness predictive of mortality. Some studies have reported a higher mean CCI in patients who were re-admitted [62, 65]. As the CCI apparently has a strong potential to be a readmission predictor, it has been recommended for inclusion in readmission prediction tools [63].

Risk factors for pneumonia re-hospitalization are currently among the most important problems to be dealt with. Possible risk factors for early re-hospitalizations include male gender, age 70 years, the longer length of stay during the first admission, and a Multisource Comorbidity Score (MCS) 10. As for therapy, for readmitted CAP patients whose underlying respiratory disease has not yet been determined, the value of inhaled therapy has not definitely been decided. “Inhaled steroids may favor CAP in COPD patients, whereas anticholinergics may favor CAP in asthma patients. It is difficult to differentiate the effect of inhaled therapy from the effect of COPD or asthma severity on the risk of CAP, and these relationships may not be causal, but could call attention to inhaled therapy in COPD and asthma patients.” [66]. In pediatric patients infected with Mycoplasma pneumonia, readmission before 90 days after discharge is influenced by age, body temperature, and influenza Aco-infection during hospitalization [67]. However, in adult patients, risk factors for readmission within 30 days after hospital discharge include the person’s age, hospitalization frequency during 3 months, chronic respiratory failure, heart failure, chronic liver disease, and the (non)availability of home healthcare [68].

A post-discharge study was performed in which researchers phoned every patient within 48–96 hours after they left the hospital to ask about their medication adherence, any adverse drug events (ADEs), and their use of medication. The process of medication reconciliation identified 103 errors, or 2.4 errors per patient, especially errors related to inaccurate doses, frequency, or medications not included on the list of home medications (Table 1) [69].

Interventions (n = 186)n (%)
Medication reconciliation (n = 103)
Incorrect dose or frequency49 (48)
Medication omitted33 (32)
Medication added14 (14)
Duplicate therapy4 (4)
Counseled in nonadherence3 (3)
Mean errors per patienta2.4
Therapeutic recommendations (n = 38)
Change route29 (76)
Optimize therapy7 (18)
De-escalate therapy2 (5)
Discharge counseling (n = 45)
Counseling on antibioticsb33 (73)
Counseling on chronic medication changes12 (27)

Table 1.

Medication errors identified, and pharmacist interventions.

n = 43 patients.


n = 39 patients were prescribed discharge antibiotics.


Note: All data are given as n (%) unless otherwise specified, and all percentages are rounded to the nearest whole number.

Multivariable analysis showed pneumonia-related readmission to be connected to para/hemiplegia, malignancy, pneumonia severity index class ≥4, and clinical instability ≥1 upon hospital discharge. Comorbidities such as chronic lung disease and chronic kidney disease, treatment failure, and decompensation of comorbidities were correlated with the pneumonia-unrelated 30-day re-hospitalization rate [65].

Advertisement

3. Strategies for reducing DRPs in pneumonia

3.1 Role of a clinical hospital pharmacist in patient care

Various interventions are needed, focused on reducing the risk of hospital readmissions by choosing transitional and territorial care and synchronizing post-discharge care [66]. Pharmacist-bundled interference was associated with a decline in the 30-day readmission rate for high-risk patients with pneumonia. Consequently, reducing hospital readmissions by supplying the greatest possible quality of health care is now becoming an essential consideration, also for the institutions themselves [69]. Also, identifying drug-resistant pathogens in pneumonia patients may help to determine the appropriate choice of empirical antibiotics. Further, building a model to define the patient’s risk factors may help with the prescription of broad-spectrum antibiotics [70]. Antibiotic administration for outpatients can be improved by predicting factors related to inappropriate antibiotic regimens. Patients at risk of drug resistance are now among the predictors of unsuitable antibiotic regimens [21].

The outcomes of this pilot research show that a pharmacist-specific bundled intervention, involving medication reconciliation, curative advice, patient discharge direction, and a research phone call, was associated with a decreased 30-day readmission rate for high-risk patients with pneumonia. The more than 200 total interventions reported suggest countless promising opportunities for increased pharmacist participation in care. Permitting pharmacists to devote time and effort to high-risk patient populations could confirm their value in supporting and expanding services to other people in the future, as well as reduce health care prices, and eventually the extent of welfare patient care [69].

Modifying the route of administration (ex- or intravenous to oral) was the most popular intervention, second to optimizing therapy. Optimizing therapy included making suitable renal doses and suggesting substitute regimens, especially if a patient’s inpatient antibiotic regimen was the same as an outpatient regimen that had failed, or if he or she had risk factors for a healthcare-associated infection. Regarding the element of discharge counseling in the intervention, 91% of patients chosen prospectively for a pilot study received such counseling. This single-center pilot research concentrated on the influence pharmacists can have on transitions of care and readmission rates, using interventions like medication reconciliation, therapeutic recommendations, discharge instructions, and follow-up [66].

3.2 Antibiotic stewardship programs

J.E. McGowan Jr. and D.N. Gerding were the first to create the term “antimicrobial stewardship” in an article published in 1996. They wanted to emphasize the need for appropriate antibiotic prescription in order to prevent resistance [71]. IDSA defined these as “antibiotic stewardship programs referring to coordinated interventions designed to improve and measure the appropriate use of antimicrobial agents” [72]. The 5 “Rs” of anti-microbial stewardship are: “the right drug at the right time with the right dose for the right bug for the right duration” [16]. The goals of ASP increase treatment effectiveness while reducing C. difficileinfections, adverse effects, antibiotic resistance, hospital costs, and lengths of stay. Some activities related to antibiotic stewardship in CAP include monitoring the de-escalation and duration of antibiotic treatment, complying with treatment guidelines, switching from intravenous to oral antibiotic treatments, prospective auditing, and developing the multidisciplinary team [73]. Antibiotic stewardship contributes to rational prescription of antibiotics, increases treatment effectiveness, and reduces side-effects and antibiotic resistance. A multi-center, pre-empirical, quasi-experimental study including 600 CAP patients (307 in the historical control group and 293 in the stewardship intervention group) showed that antibiotic stewardship helped to increase guideline-concordance to the duration of antibiotic therapy from 5.6% in the historical group to 42% in the intervention group (P = 0.001). The intervention group received a significantly shorter mean duration of treatment than the historical group (6 (5–7) versus 9 (7–10) days, P = 0.001). Antibiotic stewardship helped to avoid a total of 586 days of unnecessary antibiotics during the 6-month intervention period, while incidence of readmission for CAP, mortality rate within 30 days post-discharge were similar in both groups [54]. A multicenter randomized trial including 312 hospitalized CAP patients found that the duration of antibiotic therapy as determined by the physician (control group) was longer than in the guideline-concordant group (intervention group): (median, 10 days [interquartile range, 10–11]) versus 5 days (interquartile range, 5–6.5), respectively; P < .001). Clinical success was similar between both groups, at both 10 days (48.6% versus 56.3%) and 30 days (88.6% versus 91.9%) after admission [73].

The major activities and elements of ASPs include [74]:

  • Hospital Leadership Commitment

  • Accountability

  • Pharmacy Expertise

  • Action

  • Tracking

  • Reporting

  • Education

Hospital Leadership Commitment: The senior leadership of the hospital, especially the chief medical officer, plays an important role in the success of ASPs. Hospital leadership helps to provide ASPs with the resources needed to achieve their goals.

Accountability: ASPs must have a designated leader or co-leaders, such as a physician and pharmacist, who have effective leadership, management, and communication skills, and are responsible for program management and outcomes.

Pharmacy Expertise: The participation of pharmacists, ideally as co-leaders of ASPs, will help to make ASPs highly effective. In large hospitals, pharmacists with infectious disease training are designated, but in hospitals without infectious disease trained pharmacists, general clinical pharmacists are appointed to help lead implementation efforts to improve antibiotic use.

Action: Antibiotic stewardship interventions are initiated to improve antibiotic use. Some activities related to antibiotic stewardship in CAP include prospective audit and feedback, such as monitoring the de-escalation and duration of antibiotic treatment, complying with treatment guidelines, switching from intravenous to oral antibiotic treatments, and preauthorization. The three priority interventions are: prospective audit and feedback, preauthorization, and facility-specific treatment guidelines.

  • Preauthorization: This requires prescribers to gain approval prior to the use of certain antibiotics. This can help to optimize initial empiric therapy. The development of preauthorization for necessary antibiotics can be based on standard guidelines; limited antibiotics can be prescribed based on consultation, or more easily, referring to the WHO antibiotic classification. In 2017, WHO proposed categorizing antibiotics into three groups: ACCESS, WATCH, and RESERVE groups [75]. For the WATCH group, antibiotics with a high risk of resistance, such as 3rd-generation cephalosporins, carbapenems, and fluoroquinolones, should be preauthorized; for the RESERVE group, antibiotics such as colistin, ceftaroline, tigecycline, and aztreonam are indicated when other prescribed antibiotics have failed or are inadequate (e.g., serious life-threatening infections due to multidrug-resistant bacteria), and must be authorized and discussed before prescribing.

  • Prospective audit and feedback: This is an external assessment of antibiotic therapy by ASP experts at some point after the agent has been prescribed. The ASP prospective audit and feedback team usually consists of a physician (an infectious disease specialist or a clinical microbiologist) and a clinical pharmacist. Prospective audit and feedback are performed as follows: On the first day of prescribed antibiotics, the team audits the suitability of doses and the routes of empirical antibiotic therapy. After 72 hours, the team reviews the patient’s response (clinical stability, biomarkers, renal function), along with microbiological culture results, to give feedback to the treating physician in case a need to change the therapy is indicated: change of antibiotic, the addition of antibiotic, de-escalation of antibiotic treatment, dose adjustment. The cycle of audit and feedback is performed continuously. On day 7, the team evaluates the duration of antibiotic treatment (Figure 1) [76]. Preauthorization and prospective audit and feedback are complementary processes that optimize antibiotic therapy. Preauthorization resembles an antibiotic input “filter” that improves initiation of antibiotics, and prospective audit and feedback help to optimize continued therapy.

  • Facility-specific treatment guidelines: A clear guideline on antibiotic use will help to make prospective audit and feedback easier and more effective. Recommendations should be developed based on national and international guidelines, local susceptibilities, and hospital antibiotic management policies.

Figure 1.

Schema for prospective audit and feedback, and formulary restriction and preauthorization, for ASPs.

Tracking: Measurement is crucial to identify opportunities for improvement and to assess the impact of interventions. Measurement of antibiotic stewardship interventions may include measures of antibiotic use, and measures of outcomes like C. difficileinfections, antibiotic resistance, and financial impact.

Reporting: A comprehensive picture of antibiotic use and antibiotic resistance, along with the work of the antibiotic stewardship program, should be provided in regular updates to prescribers, pharmacists, nurses, and leadership. This helps make medical staff aware of the situation of antibiotic use and antibiotic resistance at their facility, thereby promoting rational use of antibiotics.

Education: Interventions (preauthorization, prospective audit, and feedback) and measurement of antibiotic use and outcomes, can reveal gaps in antibiotic prescribing in hospitals. This helps to make the education of medical professionals realistic and effective, thereby gradually improving the effectiveness of antibiotic treatment, reducing adverse effects, antibiotic resistance, and treatment costs. There are many ways to provide education regarding antibiotic use, such as presentations; posters, flyers, and newsletters; and/or electronic communication to staff groups.

In summary, ASP interventions applied in hospitals, such as audit and feedback, updating of treatment guidelines along with local susceptibility patterns, and training of medical staff, can reveal individual or departmental cases of high antibiotic use by infectious disease specialists, clinical pharmacists, and microbiologists in order to promote rational antibiotic use [77].

3.3 Technological tools

3.3.1 Biomarkers

Among the oldest and most frequently used biomarkers for predicting a patient’s response to antibiotic therapy are fever and leukocytosis. A decline in both indicates that an infectious disease has been adequately treated with a chosen course of antibiotics. More recently, studies have shown that another biomarker, procalcitonin (PCT), can be combined with clinical criteria to help physicians to decide whether to de-escalate or discontinue antibiotic therapy, without affecting outcomes [78]. A systematic review of 26 RCTs involving 6708 participants (acute respiratory infections) from 12 countries found that the duration of antibiotic therapy using PCT concentration reduced mortality, decreased antibiotic consumption, and lowered the risk of antibiotic side-effects. The length of hospital stay and ICU stay were similar in both groups [79]. A randomized trial of 621 patients with suspected community or hospital infection showed that the intervention group (using PCT) had a significantly shorter duration of antibiotic treatment than the control group (14.3 days (SD 9.1) vs. 11.6 days (SD 8.2); absolute difference 2.7 days, 95% CI 1.4 to 4.1, p < 0.0001) [80]. Similarly, an RCT of 101 patients with VAP indicated that antibiotic discontinuation based on serum PCT decreased their duration of antibiotic use compared with the control group (p  =  0.038) [81]. A novel multicenter quality control survey study, including 1759 patients from Switzerland, France, and the United States who had respiratory tract infections, revealed that antibiotic therapy duration based on PCT concentration was shorter than without PCT concentration (5.9 vs. 7.4 days; the absolute difference in days (95% CI), −1.51 (−2.04 to −0.98); P < 0.001) [82]. The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) suggest using PCT levels plus clinical criteria, rather than clinical criteria alone (weak recommendation, low-quality evidence), to guide discontinuation of antibiotic therapy [52].

Besides PCT, another biomarker useful in the management of pneumonia is C-reactive protein (CRP). Together with clinical criteria, low levels of CRP and PCT at 72 h of CAP treatment may improve the prognosis of an absence of severe complications [83]. In a study by Shuren Guo et al., performed on 350 hospitalized CAP patients, CRT and PCT levels on day 3 were statistically lower in the survivors compared to non-survivors [84]. The European Respiratory Society recommended that for patients with suspected pneumonia, along with observing clinical signs and symptoms, a CRP test may be indicated. A CRP level of >100 mg/L, with symptoms for >24 hours makes pneumonia likely; a CRP level < 20 mg/L at presentation, with symptoms for >24 hours, is possibly caused by another respiratory tract infection [85].

Antibiotic resistance is one of the greatest threats to global health, and pneumonia is one of several infections that are becoming less responsive to antibiotic treatment. Antibiotic resistance increases the risk of mortality, prolongs hospital stays, and increases treatment costs. The unnecessary and prolonged use of antibiotics is an important cause contributing to the growth of multidrug-resistant bacteria [86]. This “one size fits all” approach can result in overtreatment, increased side effects, and antibiotic resistance. Therefore, individualization in treatment is important. In addition to clinical assessment, the physician may further consider assessing serum PCT and CRP levels to guide clinical decision-making.

3.3.2 Computerized provider order entry (CPOE) and clinical decision support system (CDSS)

Two useful tools which help in the prevention of ADEs are the computerized physician order entry (CPOE) and clinical decision support systems (CDSS). Compared with conventional medication control, the computerized alert system ADEAS selected different patients based on the risk of an ADE. For the hospital pharmacist, this makes ADEAS a valuable and appropriate tool in reducing the number of preventable ADEs [87].

The implementation of CPOE and advanced CDSS tools substantially increases the number of possible ADE alerts for pharmacist review, and the number of true-positive ADE alerts per 1000 admissions [88].

In a statistical study involving 592 patients during the paper-based prescribing period and 603 patients in the CPOE/CDSS period, the total cost of the paper-based system was €12.37 per patient/day, and of CPOE/CDSS was €14.91 per patient/day. Incremental Cost-Effectiveness Ratios (ICER) for medication errors and for preventable adverse drug events were 3.54 and 322.70, respectively; this indicates the additional amount (€) necessary to prevent a medication error or an ADE. CPOE with primary CDSS contributes to the reduction of the risk of preventable harm. Overall, the additional CPOE/CDSS costs required to prevent medication errors or ADEs appear to be acceptable [89].

However, another study indicated a need to optimize the sensitivity of CPOE/CDSS to detect certain classes of problems, because most DRPs identified by clinical pharmacists were not detected in daily clinical practice by CPOE/CDSS. This underlines the importance of the clinical pharmacist’s involvement to reduce DRPs [90].

Advertisement

4. Conclusion

Pneumonia is one of the respiratory diseases causing the highest mortality rate in children and the elderly. As the elderly often have many comorbidities, DRPs also greatly affect their condition and ability to recover.

DRPs in pneumonia are a very complex issue, requiring great attention from healthcare professionals and patients in prescribing, dispensing, and administering medications. Moreover, the rate of hospital readmissions for pneumonia is also a challenging burden, for the health system in general and for patients in particular. The application of technological tools such as CPOE and CDSS to prescribing and ordering can reduce the occurrence of DRPs, but it is physicians, clinical pharmacists and health professionals who play the most important role in reducing DRPs and hospital readmissions in pneumonia.

References

  1. 1. Pneumonia [Internet]. Available from:https://www.who.int/westernpacific/health-topics/pneumonia[Accessed: 2021-07-17]
  2. 2. Pneumonia in Children Statistics [Internet]. UNICEF DATA. Available from:https://data.unicef.org/topic/child-health/pneumonia/[Accessed: 2021-07-17]
  3. 3. Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, et al. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015 Jul 30;373(5):415-27. DOI: 10.1056/NEJMoa1500245
  4. 4. Takahashi K, Suzuki M, Minh LN, Anh NH, Huong LTM, Son TVV, et al. The incidence and aetiology of hospitalised community-acquired pneumonia among Vietnamese adults: a prospective surveillance in Central Vietnam. BMC Infectious Diseases. 2013 Jul 1;13(1):296. DOI: 10.1186/1471-2334-13-296
  5. 5. Azmi S, Aljunid SM, Maimaiti N, Ali A-A, Muhammad Nur A, De Rosas-Valera M, et al. Assessing the burden of pneumonia using administrative data from Malaysia, Indonesia, and the Philippines. International Journal of Infectious Diseases. 2016 Aug 1;49:87-93. DOI: 10.1016/j.ijid.2016.05.021
  6. 6. Working groups items - Pharmaceutical Care Network Europe [Internet]. Available from:https://www.pcne.org/working-groups/2/drug-related-problems[Accessed: 2021-07-17]
  7. 7. 417_PCNE_classification_V9-1_final.pdf [Internet]. Available from:https://www.pcne.org/upload/files/417_PCNE_classification_V9-1_final.pdf[Accessed: 2021-07-17]
  8. 8. Kuti EL, Patel AA, Coleman CI. Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and blood stream infection: A meta-analysis. Journal of Critical Care. 2008 Mar 1;23(1):91-100. DOI: 10.1016/j.jcrc.2007.08.007
  9. 9. Guillamet CV, Vazquez R, Noe J, Micek ST, Kollef MH. A cohort study of bacteremic pneumonia: The importance of antibiotic resistance and appropriate initial therapy? Medicine. 2016 Aug;95(35):e4708. DOI: 10.1097/MD.0000000000004708
  10. 10. Bekele F, Fekadu G, Bekele K, Dugassa D, Sori J. Drug-related problems among patients with infectious disease admitted to medical wards of Wollega University Referral Hospital: Prospective observational study. SAGE Open Med. 2021;9:2050312121989625. DOI: 10.1177/2050312121989625
  11. 11. Garin N, Sole N, Lucas B, Matas L, Moras D, Rodrigo-Troyano A, et al. Drug related problems in clinical practice: a cross-sectional study on their prevalence, risk factors and associated pharmaceutical interventions. Sci Rep. 2021 Jan 13;11(1):883. DOI: 10.1038/s41598-020-80560-2
  12. 12. Ngocho JS, Horumpende PG, de Jonge MI, Mmbaga BT. Inappropriate treatment of community-acquired pneumonia among children under five years of age in Tanzania. Int J Infect Dis. 2020 Apr;93:56-61. DOI: 10.1016/j.ijid.2020.01.038
  13. 13. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014 Apr;58(8):1072-83. DOI: 10.1093/cid/ciu027
  14. 14. Daneman N, Gruneir A, Bronskill SE, Newman A, Fischer HD, Rochon PA, et al. Prolonged Antibiotic Treatment in Long-term Care: Role of the Prescriber. JAMA Intern Med. 2013 Apr 22;173(8):673. DOI: 10.1001/jamainternmed.2013.3029
  15. 15. Noor S, Ismail M, Ali Z. Potential drug-drug interactions among pneumonia patients: do these matter in clinical perspectives? BMC Pharmacology and Toxicology. 2019 Jul 26;20(1):45. DOI: 10.1186/s40360-019-0325-7
  16. 16. Wunderink RG, Srinivasan A, Barie PS, Chastre J, Dela Cruz CS, Douglas IS, et al. Antibiotic Stewardship in the Intensive Care Unit. An Official American Thoracic Society Workshop Report in Collaboration with the AACN, CHEST, CDC, and SCCM. Annals ATS. 2020 May;17(5):531-40. DOI: 10.1513/AnnalsATS.202003-188ST
  17. 17. Oliver MB, Fong K, Certain L, Spivak ES, Timbrook TT. Validation of a Community-Acquired Pneumonia Score To Improve Empiric Antibiotic Selection at an Academic Medical Center. Antimicrob Agents Chemother. 2021 Jan 20;65(2):e01482-20. DOI: 10.1128/AAC.01482-20
  18. 18. Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M. A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis. 2014 Jan 9;14:13. DOI: 10.1186/1471-2334-14-13
  19. 19. Cara AKS, Zaidi STR, Suleman F. Cost-effectiveness analysis of low versus high dose colistin in the treatment of multi-drug resistant pneumonia in Saudi Arabia. Int J Clin Pharm. 2018 Oct;40(5):1051-8. DOI: 10.1007/s11096-018-0713-x
  20. 20. Dorj G, Hendrie D, Parsons R, Sunderland B. An evaluation of prescribing practices for community-acquired pneumonia (CAP) in Mongolia. BMC Health Serv Res. 2013 Oct 3;13(1):379. DOI: 10.1186/1472-6963-13-379
  21. 21. Wattengel BA, Sellick JA, Skelly MK, Napierala R, Schroeck J, Mergenhagen KA. Outpatient Antimicrobial Stewardship: Targets for Community-acquired Pneumonia. Clinical Therapeutics. 2019 Mar;41(3):466-76. DOI: 10.1016/j.clinthera.2019.01.007
  22. 22. Wongsurakiat P, Chitwarakorn N. Severe community-acquired pneumonia in general medical wards: outcomes and impact of initial antibiotic selection. BMC Pulm Med. 2019 Dec;19(1):179. DOI: 10.1186/s12890-019-0944-1
  23. 23. Leone M, Garcin F, Bouvenot J, Boyadjev I, Visintini P, Albanèse J, et al. Ventilator-associated pneumonia: breaking the vicious circle of antibiotic overuse. Crit Care Med. 2007 Feb;35(2):379-85; quizz 386. DOI: 10.1097/01.CCM.0000253404.69418.AA
  24. 24. Postma DF, van Werkhoven CH, van Elden LJR, Thijsen SFT, Hoepelman AIM, Kluytmans JAJW, et al. Antibiotic Treatment Strategies for Community-Acquired Pneumonia in Adults. New England Journal of Medicine. 2015 Apr 2;372(14):1312-23. DOI: 10.1056/NEJMoa1406330
  25. 25. Tumbarello M, Trecarichi EM, Tumietto F, Del Bono V, De Rosa FG, Bassetti M, et al. Predictive models for identification of hospitalized patients harboring KPC-producingKlebsiella pneumoniae. Antimicrob Agents Chemother. 2014 Jun;58(6):3514-20. DOI: 10.1128/AAC.02373-13
  26. 26. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. The Management of Community-Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clinical Infectious Diseases. 2011 Oct 1;53(7):e25-76. DOI: 10.1093/cid/cir531
  27. 27. Gralnek I, Dumonceau J-M, Kuipers E, Lanas A, Sanders D, Kurien M, et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015 Sep 29;47(10):a1-46. DOI: 10.1055/s-0034-1393172
  28. 28. Thiessen K, Lloyd AE, Miller MJ, Homco J, Gildon B, O’Neal KS. Assessing guideline-concordant prescribing for community-acquired pneumonia. Int J Clin Pharm. 2017 Aug;39(4):674-8. DOI: 10.1007/s11096-017-0489-4
  29. 29. Yu J, Wang G, Davidson A, Chow I, Chiu A. Antibiotics Utilization for Community Acquired Pneumonia in a Community Hospital Emergency Department. Journal of Pharmacy Practice. 2020 Sep 10;089719002095303. DOI: 10.1177/0897190020953032
  30. 30. Research C for DE and. FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes. FDA [Internet]. 2019 Apr 15. Available from:https://www.fda.gov/drugs/drug-safety-and-availability/fda-reinforces-safety-information-about-serious-low-blood-sugar-levels-and-mental-health-side[Accessed: 2021-06-21]
  31. 31. Research C for DE and. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. FDA [Internet]. 2019 Dec 20. Available from:https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics[Accessed: 2021-06-23]
  32. 32. Torumkuney D, Van PH, Thinh LQ, Koo SH, Tan SH, Lim PQ, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2016-18 in Vietnam, Cambodia, Singapore and the Philippines: data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. Journal of Antimicrobial Chemotherapy. 2020 Apr 1;75(Supplement_1):i19-42. DOI: 10.1093/jac/dkaa082
  33. 33. Kulwicki BD, Brandt KL, Wolf LM, Weise AJ, Dumkow LE. Impact of an emergency medicine pharmacist on empiric antibiotic prescribing for pneumonia and intra-abdominal infections. The American Journal of Emergency Medicine. 2019 May;37(5):839-44. DOI: 10.1016/j.ajem.2018.07.052
  34. 34. Galanter KM, Ho J. Impact of an empiric therapy guide on antibiotic prescribing in the emergency department. Journal of Hospital Infection. 2020 Feb;104(2):188-92. DOI: 10.1016/j.jhin.2019.09.017
  35. 35. Gamble J-M, Hall JJ, Marrie TJ, Sadowski CA, Majumdar SR, Eurich DT. Medication transitions and polypharmacy in older adults following acute care. TCRM. 2014 Mar 19;10:189-96. DOI: 10.2147/TCRM.S58707
  36. 36. Wesemann T, Nüllmann H, Pflug MA, Heppner HJ, Pientka L, Thiem U. Pneumonia severity, comorbidity and 1-year mortality in predominantly older adults with community-acquired pneumonia: a cohort study. BMC Infectious Diseases. 2015 Jan 8;15(1):2. DOI: 10.1186/s12879-014-0730-x
  37. 37. Henig O, Kaye KS. Bacterial Pneumonia in Older Adults. Infectious Disease Clinics of North America. 2017 Dec 1;31(4):689-713. DOI: 10.1016/j.idc.2017.07.015
  38. 38. Gülçebi İdriz Oğlu M, Küçükibrahimoğlu E, Karaalp A, Sarikaya Ö, Demirkapu M, Onat F, et al. Potential drug-drug interactions in a medical intensive care unit of a university hospital. Turk J Med Sci. 2016 Apr 19;46(3):812-9. DOI: 10.3906/sag-1504-147
  39. 39. Lodise TP, Zhao Q, Fahrbach K, Gillard PJ, Martin A. A systematic review of the association between delayed appropriate therapy and mortality among patients hospitalized with infections due toKlebsiella pneumoniaeorEscherichia coli: how long is too long? BMC Infect Dis. 2018 Dec;18(1):625. DOI: 10.1186/s12879-018-3524-8
  40. 40. Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH. Clinical Importance of Delays in the Initiation of Appropriate Antibiotic Treatment for Ventilator-Associated Pneumonia. Chest. 2002 Jul;122(1):262-8. DOI: 10.1378/chest.122.1.262
  41. 41. Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C, Jeune IL, et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009 Oct 1;64(Suppl 3):iii1-55. DOI: 10.1136/thx.2009.121434
  42. 42. Daniel P, Rodrigo C, Mckeever TM, Woodhead M, Welham S, Lim WS. Time to first antibiotic and mortality in adults hospitalised with community-acquired pneumonia: a matched-propensity analysis. Thorax. 2016 Jun 1;71(6):568-70. DOI: 10.1136/thoraxjnl-2015-207513
  43. 43. Houck PM, Bratzler DW, Nsa W, Ma A, Bartlett JG. Timing of Antibiotic Administration and Outcomes for Medicare Patients Hospitalized With Community-Acquired Pneumonia. Arch Intern Med. 2004 Mar 22;164(6):637. DOI: 10.1001/archinte.164.6.637
  44. 44. Spellberg B. The New Antibiotic Mantra—“Shorter Is Better.” JAMA Intern Med. 2016 Sep 1;176(9):1254-5. DOI: 10.1001/jamainternmed.2016.3646
  45. 45. 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. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67. DOI: 10.1164/rccm.201908-1581ST
  46. 46. Gaynes R, Rimland D, Killum E, Lowery HK, Johnson TM, Killgore G, et al. Outbreak ofClostridium difficileinfection in a long-term care facility: association with gatifloxacin use. Clin Infect Dis. 2004 Mar 1;38(5):640-5. DOI: 10.1086/381551
  47. 47. Chastre J, Wolff M, Fagon J-Y, Chevret S, Thomas F, Wermert D, et al. Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults: A Randomized Trial. JAMA. 2003 Nov 19;290(19):2588. DOI: 10.1001/jama.290.19.2588
  48. 48. Yi SH, Hatfield KM, Baggs J, Hicks LA, Srinivasan A, Reddy S, et al. Duration of Antibiotic Use Among Adults With Uncomplicated Community-Acquired Pneumonia Requiring Hospitalization in the United States. Clinical Infectious Diseases. 2018 Apr 17;66(9):1333-41. DOI: 10.1093/cid/cix986
  49. 49. Madaras-Kelly KJ, Burk M, Caplinger C, Bohan JG, Neuhauser MM, Goetz MB, et al. Total duration of antimicrobial therapy in veterans hospitalized with uncomplicated pneumonia: Results of a national medication utilization evaluation: Pneumonia Treatment Duration. J Hosp Med. 2016 Dec;11(12):832-9. DOI: 10.1002/jhm.2648
  50. 50. Pugh R, Grant C, Cooke RPD, Dempsey G. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev. 2015 Aug 24;(8):CD007577. DOI: 10.1002/14651858.CD007577.pub3
  51. 51. Mathur NB, Murugesan A. Comparison of Four Days Versus Seven Days Duration of Antibiotic Therapy for Neonatal Pneumonia: A Randomized Controlled Trial. Indian J Pediatr. 2018 Nov;85(11):963-7. DOI: 10.1007/s12098-018-2708-y
  52. 52. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clinical Infectious Diseases. 2016 Sep 1;63(5):e61-111. DOI: 10.1093/cid/ciw353
  53. 53. Karakioulaki M, Stolz D. Biomarkers and clinical scoring systems in community-acquired pneumonia. Ann Thorac Med. 2019;14(3):165. DOI: 10.4103/atm.ATM_305_18
  54. 54. Foolad F, Huang AM, Nguyen CT, Colyer L, Lim M, Grieger J, et al. A multicentre stewardship initiative to decrease excessive duration of antibiotic therapy for the treatment of community-acquired pneumonia. Journal of Antimicrobial Chemotherapy. 2018 May 1;73(5):1402-7. DOI: 10.1093/jac/dky021
  55. 55. Menditto E, Gimeno Miguel A, Moreno Juste A, Poblador Plou B, Aza Pascual-Salcedo M, Orlando V, et al. Patterns of multimorbidity and polypharmacy in young and adult population: Systematic associations among chronic diseases and drugs using factor analysis. PLoS One. 2019;14(2):e0210701. DOI: 10.1371/journal.pone.0210701
  56. 56. Yousufuddin M, Shultz J, Doyle T, Rehman H, Murad MH. Incremental risk of long-term mortality with increased burden of comorbidity in hospitalized patients with pneumonia. European Journal of Internal Medicine. 2018 Sep 1;55:23-7. DOI: 10.1016/j.ejim.2018.05.003
  57. 57. Hespanhol V, Bárbara C. Pneumonia mortality, comorbidities matter? Pulmonology. 2020 Jun;26(3):123-9. DOI: [51]
  58. 58. Franzen D, Lim M, Bratton DJ, Kuster SP, Kohler M. The Roles of the Charlson Comorbidity Index and Time to First Antibiotic Dose as Predictors of Outcome in Pneumococcal Community-Acquired Pneumonia. Lung. 2016 Oct;194(5):769-75. DOI: 10.1007/s00408-016-9922-z
  59. 59. Nguyen MTN, Saito N, Wagatsuma Y. The effect of comorbidities for the prognosis of community-acquired pneumonia: an epidemiologic study using a hospital surveillance in Japan. BMC Res Notes. 2019 Dec 19;12(1):817. DOI: 10.1186/s13104-019-4848-1
  60. 60. Aurilio RB, Sant’Anna CC, March M de FBP. CLINICAL PROFILE OF CHILDREN WITH AND WITHOUT COMORBIDITIES HOSPITALIZED WITH COMMUNITY-ACQUIRED PNEUMONIA. Rev Paul Pediatr. 2020;38:e2018333. DOI: 10.1590/1984-0462/2020/38/2018333
  61. 61. El Morabet N, Uitvlugt EB, van den Bemt BJF, van den Bemt PMLA, Janssen MJA, Karapinar-Çarkit F. Prevalence and Preventability of Drug-Related Hospital Readmissions: A Systematic Review. J Am Geriatr Soc. 2018 Mar;66(3):602-8. DOI: 10.1111/jgs.15244
  62. 62. Saldanha V, Araújo IB de, Lima SIVC, Martins RR, Oliveira AG. Risk factors for drug-related problems in a general hospital: A large prospective cohort. PLoS One. 2020;15(5):e0230215. DOI: 10.1371/journal.pone.0230215
  63. 63. Abou-Karam N, Bradford C, Lor KB, Barnett M, Ha M, Rizos A. Medication regimen complexity and readmissions after hospitalization for heart failure, acute myocardial infarction, pneumonia, and chronic obstructive pulmonary disease. SAGE Open Med. 2016;4:2050312116632426. DOI: [37]
  64. 64. Willson MN, Greer CL, Weeks DL. Medication regimen complexity and hospital readmission for an adverse drug event. Ann Pharmacother. 2014 Jan;48(1):26-32. DOI: 10.1177/1060028013510898
  65. 65. Jang JG, Ahn JH. Reasons and Risk Factors for Readmission Following Hospitalization for Community-acquired Pneumonia in South Korea. Tuberc Respir Dis (Seoul). 2020 Apr;83(2):147-56. DOI: 10.4046/trd.2019.0073
  66. 66. Faverio P, Compagnoni MM, Della Zoppa M, Pesci A, Cantarutti A, Merlino L, et al. Rehospitalization for pneumonia after first pneumonia admission: Incidence and predictors in a population-based cohort study. PLoS One. 2020;15(6):e0235468. DOI: 10.1371/journal.pone.0235468
  67. 67. Wang L, Feng Z, Shuai J, Liu J, Li G. Risk factors of 90-day rehospitalization following discharge of pediatric patients hospitalized withmycoplasma Pneumoniaepneumonia. BMC Infectious Diseases. 2019 Nov 12;19(1):966. DOI: 10.1186/s12879-019-4616-9
  68. 68. Toledo D, Soldevila N, Torner N, Pérez-Lozano MJ, Espejo E, Navarro G, et al. Factors associated with 30-day readmission after hospitalisation for community-acquired pneumonia in older patients: a cross-sectional study in seven Spanish regions. BMJ Open. 2018 Mar 30;8(3):e020243. DOI: 10.1136/bmjopen-2017-020243
  69. 69. Lisenby KM, Carroll DN, Pinner NA. Evaluation of a Pharmacist-Specific Intervention on 30-Day Readmission Rates for High-Risk Patients with Pneumonia. Hosp Pharm. 2015 Sep;50(8):700-9. DOI: 10.1310/hpj5008-700
  70. 70. Gil R, Webb BJ. Strategies for prediction of drug-resistant pathogens and empiric antibiotic selection in community-acquired pneumonia. Curr Opin Pulm Med. 2020 May;26(3):249-59. DOI: 10.1097/MCP.0000000000000670
  71. 71. McGowan JJ, Gerding DN. Does antibiotic restriction prevent resistance. New Horiz. 1996 Aug 1;4(3):370-6. PMID: 8856755
  72. 72. Fishman N, America S for HE of, America IDS of, Society PID. Policy Statement on Antimicrobial Stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infection Control & Hospital Epidemiology. 2012 Apr;33(4):322-7. DOI: 10.1086/665010
  73. 73. Uranga A, España PP, Bilbao A, Quintana JM, Arriaga I, Intxausti M, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016 Sep 1;176(9):1257-65. DOI: 10.1001/jamainternmed.2016.3633
  74. 74. CDC. The Core Elements of Hospital Antibiotic Stewardship Programs. Atlanta, GA: US Department of Health and Human Services [Internet]. CDC; 2019. Available from:https://www.cdc.gov/antibiotic-use/core-elements/hospital.html. [Accessed: 2021-08-05]
  75. 75. EML_2017_ExecutiveSummary.pdf [Internet]. Available from:https://www.who.int/medicines/publications/essentialmedicines/EML_2017_ExecutiveSummary.pdf[Accessed: 2021-08-07]
  76. 76. Chung GW, Wu JE, Yeo CL, Chan D, Hsu LY. Antimicrobial stewardship: a review of prospective audit and feedback systems and an objective evaluation of outcomes. Virulence. 2013 Feb 15;4(2):151-7. DOI: 10.4161/viru.21626
  77. 77. VanLangen KM, Dumkow LE, Axford KL, Havlichek DH, Baker JJ, Drobish IC, et al. Evaluation of a multifaceted approach to antimicrobial stewardship education methods for medical residents. Infect Control Hosp Epidemiol. 2019 Nov;40(11):1236-41. DOI: 10.1017/ice.2019.253
  78. 78. Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Ninth edition. Philadelphia, PA: Elsevier; 2020. 216p. ISBN: 978-0-323-48255-4
  79. 79. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017 Oct 12;10:CD007498. DOI: 10.1002/14651858.CD007498.pub3
  80. 80. Bouadma L, Luyt C-E, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. The Lancet. 2010 Feb 6;375(9713):463-74. DOI: 10.1016/S0140-6736(09)61879-1
  81. 81. Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. European Respiratory Journal. 2009 Dec 1;34(6):1364-75. DOI: 10.1183/09031936.00053209
  82. 82. Albrich WC, Dusemund F, Bucher B, Meyer S, Thomann R, Kühn F, et al. Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in “real life”: an international, multicenter poststudy survey (ProREAL). Arch Intern Med. 2012 May 14;172(9):715-22. DOI: 10.1001/archinternmed.2012.770
  83. 83. Menéndez R, Martinez R, Reyes S, Mensa J, Polverino E, Filella X, et al. Stability in community-acquired pneumonia: one step forward with markers? Thorax. 2009 Nov;64(11):987-92. DOI: [65]
  84. 84. Guo S, Mao X, Liang M. The moderate predictive value of serial serum CRP and PCT levels for the prognosis of hospitalized community-acquired pneumonia. Respiratory Research. 2018 Oct 1;19(1):193. DOI: 10.1186/s12931-018-0877-x
  85. 85. Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M, et al. Guidelines for the management of adult lower respiratory tract infections - Full version. Clin Microbiol Infect. 2011 Nov;17(Suppl 6):E1-59. DOI: 10.1111/j.1469-0691.2011.03672.x
  86. 86. Antibiotic resistance [Internet]. Available from:https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance[Accessed: 2021-07-14]
  87. 87. Rommers MK, Teepe-Twiss IM, Guchelaar H-J. A computerized adverse drug event alerting system using clinical rules: a retrospective and prospective comparison with conventional medication surveillance in the Netherlands. Drug Saf. 2011 Mar 1;34(3):233-42. DOI: 10.2165/11536500-000000000-00000
  88. 88. Roberts LL, Ward MM, Brokel JM, Wakefield DS, Crandall DK, Conlon P. Impact of health information technology on detection of potential adverse drug events at the ordering stage. Am J Health Syst Pharm. 2010 Nov 1;67(21):1838-46. DOI: 10.2146/ajhp090637
  89. 89. Vermeulen KM, van Doormaal JE, Zaal RJ, Mol PGM, Lenderink AW, Haaijer-Ruskamp FM, et al. Cost-effectiveness of an electronic medication ordering system (CPOE/CDSS) in hospitalized patients. Int J Med Inform. 2014 Aug;83(8):572-80. DOI: 10.1016/j.ijmedinf.2014.05.003
  90. 90. Zaal RJ, Jansen MMPM, Duisenberg-van Essenberg M, Tijssen CC, Roukema JA, van den Bemt PMLA. Identification of drug-related problems by a clinical pharmacist in addition to computerized alerts. Int J Clin Pharm. 2013 Oct;35(5):753-62. DOI: 10.1007/s11096-013-9798-4

Written By

Kien T. Nguyen, Suol T. Pham, Thu P.M. Vo, Chu X. Duong, Dyah A. Perwitasari, Ngoc H.K. Truong, Dung T.H. Quach, Thao N.P. Nguyen, Van T.T. Duong, Phuong M. Nguyen, Thao H. Nguyen, Katja Taxis and Thang Nguyen

Submitted: August 20th, 2021 Reviewed: August 25th, 2021 Published: September 10th, 2021