One of the crucial targets to reduce morbidity and mortality in patients with pneumonia is to optimize antibiotic usage . During the past decades, increasing evidence has strengthened recommendations of guidelines concerning antibiotic selection, early initiation of therapy, and switch from intravenous to oral therapy . However, the appropriate duration of antimicrobial treatment still remains a matter of controversy.
A shorter duration of antibiotic course may be favorable due to a potential reduction of adverse events and antibiotic resistance, and the opportunity to enhance patients’ compliance and to decrease healthcare costs. Nevertheless, these considerations must meet all the criteria for effectiveness of treatment and patients’ safety. Most of the recommendations suggested by international guidelines show a weak level of evidence being mostly based on expert opinions rather than results from observational or interventional studies, as recently highlighted (see Table 1) [1,3–5]. Certainly, a point on which experts agree and which is suggested by some guidelines is to individualize duration of antibiotic therapy. However, a significant difference in the duration of therapy is observed depending neither on severity on admission nor patients’ response . Conversely, a fixed duration of therapy, ranging from 10 to 14 days in the majority of cases, is detected worldwide, regardless of patients’ clinical response (see Fig. 1).
Different approaches have been used to determine the optimal duration of antimicrobial therapy in patients with pneumonia that are mainly driven either by the antibiotic chosen, isolated pathogen, host characteristics, or severity of the disease.
DURATION OF THERAPY ACCORDING TO THE ANTIBIOTIC CHOSEN
Duration of antibiotic therapy can be chosen according to pharmacokinetic and pharmacodynamic characteristics of the specific antibiotic used. The postantibiotic effect (PAE) is a well defined pharmacodynamic phenomenon that reflects the persistent inhibition of bacterial growth following the removal of an active agent from the culture medium. The clinical significance of PAE pertains primarily to its impact on the dosing schedule of the antimicrobial drug. The most studied antibiotics in terms of PAE include azithromycin, levofloxacin, telithromycin, and beta-lactams [7–15].
Compared to older macrolides, azithromycin is characterized by a prolonged half-life, excellent tissue penetration, and prolonged PAE. Therefore, it is estimated that a significant antibacterial activity against several pathogens might persist in tissue for at least 5 days after a 5-day course of treatment . Several studies compared the efficacy of a 3-versus a 5-day course of azithromycin, showing no differences in the success rate between the two arms [8,9]. Similar results were achieved when azithromycin 500 mg daily for 3 days was compared to a single 1.5 g dose . One of the main advantages of the single dose is represented by its use as a directly observed therapy in patients with low compliance or in the presence of barriers to filling prescriptions. The administration of a single-dose microsphere formulation of azithromycin was as effective as a 7-day course of levofloxacin or clarithromycin [11,16].
In the field of antibiotics with a PAE, a distinction should be made between two different concepts: duration of administration versus duration of therapy. Although the duration of administration would be shortened because of the PAE, the duration of therapy (as the real effect of the antibiotic) still remains the same. For example, a 3-day course of azithromycin (duration of administration) would correspond to a duration of therapy of 7 days. In view of these considerations, the idea of individualizing duration of therapy in patients with pneumonia according to the antibiotic chosen may have some important limitations.
DURATION OF ANTIBIOTIC THERAPY ACCORDING TO THE IDENTIFIED PATHOGEN
The paradigm of targeting duration of antibiotic treatment in patients with pneumonia according to the isolated pathogen has been extensively applied particularly for atypicals, including Legionella spp., as well as Staphylococcus aureus and Pseudomonas aeruginosa[3,4].
In a large double-blind multicenter study, Dunbar et al. compared a 5-day 750 mg levofloxacin regimen to a 10-day 500 mg levofloxacin course for the treatment of pneumonia caused by Legionella pneumophila, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, and no differences in success and relapse rate were shown between the two groups. A randomized controlled trial (RCT) by Yu et al. showed that a short course regimen (levofloxacin 750 mg for 5 days) could be effective in the treatment of L. pneumophila, while previous recommendations of prolonged therapy (14–21 days) were based on observations involving a large number of immunocompromised patients.
Chastre et al. compared an 8-versus a 15-day antibiotic regimen for the treatment of ventilator-associated pneumonia (VAP) showing comparable clinical effectiveness between the two regimens. There was no difference for in-hospital mortality between the two treatment groups in a subpopulation of patients with methicillin-resistant S. aureus (MRSA) pneumonia . Mortality rates associated with bacteremic pneumonia were reported to be high in both methicillin-susceptible S. aureus (MSSA) (41%) and MRSA (56%) patients . No studies have ever assessed the optimal duration of antibiotic treatment in this specific population. However, expert opinion suggests at least 2 weeks of antibiotic for patients with a S. aureus bacteremia mainly because the presence of an unidentified focus of infection outside the blood is still suspected.
Several studies addressed the question of the optimal duration of therapy in pneumonia due to nonfermenting Gram-negative rods (NF-GNRs) with different results [20–23]. In patients with NF-GNR VAP, a short-course treatment was associated with a higher relapse rate than the long-term treatment, whereas no difference in mortality rate was reported . However, Hedrick et al., in their retrospective analysis, showed similar mortality and recurrence rates comparing VAP patients with NF-GNRs treated less and more than 8 days. Finally, when a short course of therapy was used to treat Gram-negative hospital-acquired pneumonia (HAP), relapse rates were significantly higher among patients with NF-GNRs than in patients with other Gram-negative organisms .
Duration of therapy tailored to the isolated pathogen may help physicians in de-escalating and shortening the antibiotic treatment, according to the evidence published so far. However, since the causative agent is identified only in a small proportion of patients with pneumonia, this approach cannot be extensively applied in daily clinical practice [3,4].
DURATION OF ANTIBIOTIC THERAPY ACCORDING TO HOST FACTORS
Bacteremia and pneumonia are common complications in neutropenic patients. The Infectious Diseases Society of America (IDSA) guidelines recommend starting empiric antibiotic therapy within 2 h from patient presentation and to continue appropriate treatment until bone marrow recovery or longer if necessary . Pizzo et al. compared fixed versus personalized duration of therapy in neutropenic patients with pneumonia. Patients with no fever at day 7 were randomized to either discontinue therapy, regardless of the absolute neutrophil count, or to continue it until the resolution of granulocytopenia. Forty-one percent of patients who discontinued therapy at day 7 experienced recrudescence of fever, suggesting the importance of prolonged antimicrobial treatment in neutropenic patients.
Lower respiratory tract infections (LRTIs) are 25 times more common in patients with HIV than in the general community [26,27]. The British Thoracic Society (BTS) guidelines 2009 do not consider HIV-infected patients and the American Thoracic Society (ATS) guidelines 2007 can be applied to HIV patients whose CD4+ cell count is at least 350/μl [4,6]. In a prospective study performed in Uganda in 1996–1998, Yoshimine et al. evaluated the outcome of a 3-day parenteral ampicillin regimen followed by 4–7 days of oral amoxicillin in HIV-negative and HIV-positive patients with community-acquired pneumonia (CAP), with success rates similar in the two groups. Further studies are needed to tackle this issue in patients with profound immunodeficiency (CD4+ <200/μl) in which case opportunistic infections are more likely.
DURATION OF ANTIBIOTIC THERAPY ACCORDING TO SEVERITY OF THE DISEASE
Two meta-analyses evaluated the effectiveness and safety of short versus long-course antibiotic therapy for mild to moderate CAP, involving inpatient and outpatient adults with no need of ICU, and showed no differences in terms of bacteriologic eradication, clinical success, clinical failure, and mortality [29,30]. Few data are available regarding short versus long-course antibiotic regimens in patients with severe CAP. Choudhury et al. performed a prospective observational study on CAP patients with a CURB-65 score of 3–5, showing no difference in terms of in-hospital and 30-day outcomes between patients with a short (7 days) versus long-course (>7days) therapy.
To date, there is a lack of data regarding the duration of antibiotic therapy in patients with pneumonia associated with severe sepsis and septic shock or requiring mechanical ventilation. Dellinger et al., in the International Guidelines for Management of Severe Sepsis and Septic Shock published in 2008, recommended a duration of antibiotic therapy typically limited to 7–10 days, with a longer course in case of slow clinical response, undrainable foci of infection, or immunologic deficiencies. In the update published in 2013, the authors suggested including bacteremia with S. aureus and some fungal and viral infections among the conditions that may require a prolonged course .
Although bacteremia may increase mortality in patients with pneumonia, Bordon et al. showed, in a retrospective study, that pneumococcal bacteremia seems not to increase mortality in CAP patients and concluded that pneumococcal bacteremia should not be a contraindication for de-escalation of therapy in clinically stable patients [34,35]. A recent meta-analysis by Havey et al. including six trials on adult CAP and two trials on adult VAP patients with bloodstream infection evaluated short versus long-course antimicrobial therapy showing no difference in clinical effectiveness between the two groups.
Despite the lack of data, severity assessment is of primary importance in deciding both switch from intravenous to oral and duration of antimicrobial treatment. Most guidelines consider hemodynamic stability and resolution of acute respiratory failure to be the main criteria to switch from intravenous to oral antibiotics (see Table 2) [4,6].
DURATION OF ANTIBIOTIC THERAPY ACCORDING TO LABORATORY BIOMARKERS
A comprehensive evaluation of the interaction among host, pathogen, and antibiotic characteristics might be the key to choosing the correct duration of antibiotic therapy in patients with pneumonia (see Fig. 2). Ideally, shortening the duration of therapy should follow a marker of a favorable response of the immune system to the antibiotic acting on the pathogen causing pneumonia. The first patient response that could be appreciated in daily clinical practice is a reduction of systemic inflammation by an improvement of biomarkers.
Recently, several biomarkers of inflammation/infection have been tested in patients with pneumonia and, among them, procalcitonin (PCT) seems to be the most promising [42–45]. A recent meta-analysis included 14 RCTs with a total of 4221 patients with acute respiratory tract infections assigned to receive antibiotics based on a PCT-guided algorithm versus usual care . PCT-guided strategy was confirmed to lead to lower antibiotic exposure, and when considering CAP and VAP independently, similar results were reported. Albrich et al. performed an international observational quality surveillance on 1759 patients with a diagnosis of LRTI. Every participant center was provided with a published PCT algorithm for antibiotic guidance. Antibiotic duration was significantly shorter if the PCT algorithm was followed compared with when it was overruled. No increased risk of adverse outcomes was associated with holding the antibiotic therapy on admission or ceasing it early when the decision was guided by the PCT algorithm.
According to recent evidence on the use of biomarkers, a marked reduction in antibiotic exposure has been detected in all different settings, diseases, and study populations. However, one of the biggest concerns is that all the studies used PCT and no other biomarker-oriented approaches in discontinuing antibiotic therapy in LRTI. Furthermore, most of the studies came from Europe, especially Switzerland, which may not reflect the broader experience, and PCT threshold varies significantly from study to study. The PCT-guided algorithms were very heterogeneous, as well as the values of PCT cut-offs chosen to make therapeutic decisions. Finally, severely immunocompromised and neutropenic patients were mostly excluded from RCTs and this could preclude the generalizability of the results. Major limitations to the implementation of a biomarker-based approach in clinical practice are the availability and cost of these biomarkers that mainly depend on the site of care and the resources available.
INDIVIDUALIZING DURATION OF ANTIBIOTIC THERAPY ACCORDING TO PATIENTS’ CLINICAL RESPONSE
Outside of the ICU where patients with pneumonia are intubated and cannot interact with their treating physicians, patients’ response to antibiotics could be easily evaluated according to their signs and symptoms. One of the first and most important clinical outcomes in patients with pneumonia is the time in which they reach clinical stability. Several criteria of clinical stability have been suggested, including an improvement of patient symptoms, signs of systemic response, vital parameters, and oxygenation (see Table 2) . Clinical stability criteria have been proven to be useful in guiding the switch of antibiotic therapy from intravenous to oral formulations, and we could speculate that clinical stability criteria could also be useful to decide the duration of antimicrobial treatment .
Recently, an international, noninferiority, pragmatic RCT has been designed in patients hospitalized due to CAP to assess the efficacy of an individualized approach to the duration of antibiotic therapy: a treatment duration based on each patient's clinical response compared to local standard approach (clinical trial: NCT01492387). The ‘Duration trial’ is currently ongoing and so far no significant difference has been shown between the two study groups regarding 30-day clinical outcomes.
A prolonged exposure to antibiotics may encourage the development of acquisition of antibiotic-resistant organisms and may be associated with serious adverse reactions. The need to move towards an individualized approach to duration of therapy in pneumonia should be emphasized. The individualized approach in determining the duration of antibiotic therapy in CAP patients is still a recommendation based only on expert opinion. Future research in this area should include prospective, randomized, clinical trials enrolling patients who receive antibiotics using the current standard approach versus an individualized strategy based on the patients’ clinical response.
Members of the DURATION Study Group are: Bonaiti Giulia, MD, Faverio Paola, MD (Health Science Department, University of Milan Bicocca, Milan, Italy); Carugati Manuela, MD (University of Milan, Milan, Italy), Spoletini Giulia, MD (Department of Pathophysiology and Transplantation, University of Milan, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy), Fantini Riccardo, MD (University of Modena Reggio Emilia), Tedeschi Sara, MD (University of Bologna), Milani Giuseppe, MD (Sant’Anna Hospital, Como, Italy), Villani Massimiliano, MD (Ospedale San Carlo, Milano, Italy), Del Forno Manuela, MD (University of Bologna, Bologna, Italy), Piro Roberto, MD (Arcispedale S. Maria Nuova, Reggio Emilia, Italy), Deotto Martina, MD (AO Sanata Maria della Misericordia, Udine, Italy), Pancini Lisa, MD (University of Milan, IRCCS San Donato, San Donato Milanese, Italy), Voza Antonio, MD (ICH, Rozzano, Italy).
Financial support and sponsorship
No financial support/sponsorship has been requested for this manuscript.
Conflicts of interest
Outside of the submitted work, A.S. had relationship with Astrazeneca (consultancy), B.F. with Almirall, Munipharma, GSK, Menarini, Guidotti-Malesci, Novartis (board membership); GSK and Menarini (consultancy); Pfizer, Zambon, Chiesi (grants), Astrazeneca, Novartis, Pfizer, Almirall, Menarini, Guidotti-Malesci, Chiesi, GSK, Zambon (lectures).
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