The characteristics, clinical outcomes and hospital resource use of patients included in the REACH study were analysed according to their TCS using Halm’s criteria. Achieving early clinical stabilization (≤ 4 days) in patients with CAP appears to be associated with shorter hospital length of stay, lower incidence of admission to ICU or readmission to hospital for the same infection, and lower resource use compared with patients with a later response. The results presented here highlight how early identification of patients with a higher risk of a later response to treatment could assist the clinician in improving the chance of an early response by careful microbial stewardship, more aggressive treatment, early initiation of antibiotics and closer monitoring of response in these patients of concern.
Patients showing early or later response to treatment were similar in terms of demographics; however, there was a numerical tendency for those with a later response to have more comorbidity, or to have been in receipt of prior medication, in particular antivirals or antibiotics, in the 3 months prior to hospitalization. Data obtained from patients who were assessed for severity of disease with either the PORT/PSI or CURB-65 scoring systems suggest that patients with a later response had more severe disease than early responders. Intuitively it might make sense that patients with more severe disease will reach clinical stability later, and might require more aggressive treatment and closer follow-up, compared with patients who responded early to treatment. More patients with a later response had severity scores recorded than those with an early response. Moreover, use of severity scoring was variable or even absent in some countries (e.g. Belgium) and in those that did use a scoring system, PORT/PSI in particular, there was a trend to more patients being classed as moderate (III/IV) or high (V), which may suggest that physicians tend to score those patients with more severe disease.
The limitations associated with the retrospective design of this study, and the consequent unavailability of some values, have been discussed previously . Significant heterogeneity in the use of Halm’s criteria for the assessment of clinical stability across the participating countries, ranging from 0% in Belgium, where TCS was not assessed using the Halm criteria in any patient, to 49.1% in the UK, and averaging only 28.7% overall, is in itself an important observation but highlights a limitation of this subanalysis. A higher mortality rate was observed in patients not assessed by Halm’s criteria. This may be because this sub-population had more severe disease according to the PORT/PSI and CURB-65 indices, but it is also possible that the use of Halm’s criteria indicates adherence to guidelines, and thus its use might be a surrogate of quality of healthcare.
Patients in both groups were treated largely following current ERS/ESCMID guidelines: aminopenicillin ± β-lactamase inhibitor ± macrolide; levofloxacin or moxifloxacin . The observation that more early responders had been treated with amoxicillin–clavulanate monotherapy than later responders may be an indication that this treatment is recommended in local hospital guidelines for the treatment of CAP. In a recent study of treatment failure in patients hospitalized with CAP in Switzerland, it was found that those patients who had been treated initially with moxifloxacin or a β-lactam plus macrolide combination experienced lower treatment failure rates and reduced hospital stay, and thus reduced treatment costs, compared with patients receiving β-lactam monotherapy or a non-standardized antibiotic therapy .
Aliberti et al.  found that the interaction between host characteristics (immune status and comorbidities), pathogen characteristics (virulence, susceptibility and resistance to antibiotics) and antibiotic characteristics (timing, adequacy of therapy and pharmacokinetic factors) determines the time in which a patient reached clinical stability, and that the duration of IV therapy was, in most cases, found to be tailored to the patient’s clinical response. REACH was a retrospective observational study; thus, physicians were not required to report the decision-making process in the treatment of individual patients. However, the data obtained do illustrate the importance of identifying those patients of increased concern or at higher risk of being a later responder to treatment, such as patients with comorbidities. The high number of patients without a microbiological diagnosis indicates that treatment is, of necessity, empiric, with the potential for treatment failure, which impacts on clinical outcomes and healthcare resource use . However, an understanding of the local epidemiology can inform the physician’s choice of treatment.
The higher frequency of initial antibiotic treatment modification due to insufficient response or treatment failure seen in the later responders group, compared with the early responders, may be explained by a higher incidence of inappropriate or discordant choice of initial antibiotic. It has been previously reported that the incidence of failure in patients with CAP ranges from 6 to 24% and may reach 31% in patients with severe CAP [13, 20, 21]. Factors most often associated with early failure have been reported to be more severe pneumonia, Legionella pneumonia, Gram-negative pneumonia, or mixed infections and discordant antimicrobial therapy [13, 22]. Adherence or non-adherence to guidelines has been shown to be dependent on the hospital, and the speciality and training status of the prescribing physicians, and is thus an independent risk factor for treatment failure and mortality . Empiric treatment that follows guidelines is associated with earlier TCS, and non-adherence may result in longer hospital length of stay and greater use of resources . Data from the REACH study confirm that a longer TCS is associated with a longer length of hospital stay, and increased resource use such as more admissions to, and longer time in, ICU, mechanical ventilation, parenteral nutrition, acute renal failure and a higher incidence of home-based care after discharge, compared with patients with an early response.
In addition, recent data in patients with CAP have shown an association between a longer TCS and a significantly higher rate of adverse outcomes within 30 days of discharge compared with patients with a shorter TCS, which, the authors suggest, may be due to patients being discharged with a systemic inflammatory response . In our study, later responders were found to have higher levels of reinfection/recurrence, compared with early responders. These observations reinforce the requirement for patients with a later response to treatment to receive closer clinical observation and management and a shorter time for follow-up visit after discharge. Our analysis of the effect of TCS on subsequent outcomes is slightly limited since some variables were not, or could not be, measured specifically before and after clinical stability. However, data on the length of hospitalization and on admissions to ICU after achievement of clinical stability show relatively small differences between early and later responders in this study and suggest such differences are more evident when looking at hospitalization as a whole and not at the post-clinical stability phase alone. In a recent retrospective analysis of the FOCUS comparative efficacy and safety trials of IV ceftaroline fosamil for the treatment of CAP , an advantage was seen versus the comparator ceftriaxone in response rates at Day 4 after initiation of treatment, using IDSA/ATS guidelines  for clinical stability.
In summary, this retrospective analysis of the data obtained in the observational REACH study of patients hospitalized with CAP, and with TCS assessment using Halm’s criteria, emphasizes the importance of an early response to treatment in terms of reduced morbidity and corresponding hospital resource use.
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