The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach

Figures & data

Table 1 Percentage incidence of bacterial species within the spectrum of lower respiratory tract infection (LRTI)-associated pathogens

	CAP	AECB
S.pneumoniae	20–60	20–25
H. influenzae	3–10	40–45
M. catarrhalis	1–3	10–15
S. aureus, Pseudomonas	2–10	10–15
M. pneumoniae	5–50	10–15
C. pneumoniae	5–15	10–15

Notes: CAP: community-acquired pneumonia; AECB: acute exacerbations of chronic bronchitis.

Value are expressed as percentages.

Data from^2,4,21.

Table 2 Statements defined by the scientific steering committee into four main topics and submitted to the expert panel of the Delphi-based consensus. The percentage of consensus reached for each statement is reported

Statement	Consensus (%)
Topic 1: Issues in aetiology and antibiotic resistance involved in the process of prescribing antibiotics
1.1 The aetiologic diagnosis in case of respiratory infections is still hard to be obtained. This also because microbiologic investigations are not frequently performed in the clinical practice of LRTIs. Therefore, treatment of these infections is necessarily empirical in most cases, driven by patient’s risk factor evaluation and by local microbiology	96
1.2 The choice of the antibiotic for the empiric therapy of respiratory infections is based on the knowledge of the most likely bacterial aetiology and of the updated chemoresistance profile of the possibly involved pathogens	100
1.3 When choosing an antibiotic for empiric therapy, potential pathogens involved, local antibiotic resistance profile, patient’s immunocompetence/immunodeficiency status, performance status of the patient and risk factors for specific pathogens must be evaluated	100
1.4 Antibiotics with resistance levels above the 10%-20% threshold should not be used in empiric therapy	71
1.5 Based on observed resistance profile, some antibiotics should not be regarded as first-choice agents for the empiric therapy of LRTIs. This refers to non-protected betalactams (amoxicillin), tetracyclins, trimethoprim/sulphametazole and macrolids in particular	72
1.6 Streptococcus pneumoniae, Haemophilus spp. and Moraxella catarrhalis are responsible for the 85–95% of cases of chronic bronchitis bacterial exacerbation. All these pathogens develop a significant increase of resistance	79
1.7 During COPD exacerbation, the antibacterial activities of aminopenicillins, macrolides, tetracyclins, oral cephalosporins on Streptococcus pneumoniae, Haemophilus spp. and Moraxella catarrhalis do not overlap	92
1.8 Enterobacteriaceae and Pseudomonas aeruginosa must be considered in aetiologic hypotheses in patients with severely compromised respiratory function (FEV1 < 30%) and/or with radiological evidence of bronchectasis	95
1.9 All hospetalized patients with CAP must undergo to at least one set of hemoculture, irrespective of the severity of patient’s conditions	41
1.10 Amongst 3rd-generation oral cephalosporins, cefditoren pivoxil has the highest intrinsic activity on Streptococcus pneumoniae, PEN-R strains included	100
1.11 The activities of fluoroquinonolones (ciprofloxacin, levofloxacin, moxyfloxacin) on Streptococcus pneumonia do not overlap	96
1.12 When an infection is suspected to be caused by resistant bacteria, the antibiotic with highest intrinsic activity must be used	90
1.13 When treating AECB, an highly active antibiotic against BLNAR (Betalactamase Negative Ampicillin Resistant) and BLPACR (Betalactamase-Positive Amoxicillin-Clavulanic Resistant) strains must be used to control the intra-species spread of Haemophilus influentiae resistance	78
Topic 2: Pharmacologic issues involved in the practice of prescribing antibiotics
2.1 To identify the profile of exposure to the drug, for its ability not only to eradicate microorganisms, but also to impair the emergence of resistant subpopulation, the pharmacokinetics/pharmacodynamics relationship must be analyzed	98
2.2 The different pharmacokinetic/pharmacodynamic characteristics of oral cephalosporins (ceftibuten, cefixime, cefditoren pivoxil) establish both dosage and eradication efficacy of the antibiotic	100
2.3 Oral administration is the route of choice for home care of mild LRTIs, if neither contraindications/limitations to absorption nor other patient-related limiting conditions exist	98
2.4 Among third-generation oral cephalosporins, ceftibuten and cefixime display mainly a Gram-negative spectrum, while cefditoren has a balanced spectrum, including Gram+ e Gram- bacteria	96
2.5 In LRTI therapy with cephalosporin, initial dosage and the route of administration depend on the severity of patient’s conditions	97
2.6 During LRTI oral therapy, the antibiotic dosage must not be reduced even in presence of clinical improvement and in absence of adverse events	96
2.7 In patients under poly-pharmacotherapy, oral betalactams are the safest antibiotics according to their pharmacological interaction profile	92
2.8 When switching from parenteral therapy with third-generation cephalosporins (cefotaxime, ceftriaxone) to oral therapy, the most appropriate option is cefditoren pivoxil, due to the similar spectrum and the better intrinsic activity	93
Topic 3: Clinical considerations on the management of patients with CAP, AECB or COPD
3.1 For treatment of pneumonia caused by Chlamydophila pneumonia and Mycoplasma pneumonia, macrolides can be used in monotherapy, mainly in adolescents and younger adults	87
3.2 Number and duration of antibiotic therapies performed by the patient in the past year can be a predictor of a bacterial infection resistant to previously used antibiotics	89
3.3 In respiratory infections, the evaluation of biomarker blood levels (e.g. reactive C protein or procalcitonin) is useful to determine indications, monitoring and discontinuation of antibiotic therapy	90
3.4 Patients with BPCO who undergo exacerbation with purulent sputum should receive antibiotic treatment	100
3.5 For community-acquired infections of the lower respiratory airways, betalactams should be regarded as first-choice antibiotics, also in monotherapy	77
3.6 In mild-moderate AECB and in elderly individuals with risk factors, oral cephalosporins must be considered as first-line treatment, while fluoroquinolone use must be restricted to more severe exacerbations, mainly in patients with bronchectasis	89
3.7 Sending to hospital and/or hospitalizing a CAP patient is a decision of clinical and welfare relevance, which should be supported by a given severity score (e.g. CRB-65, CURB-65 or Pneumonia severity index) and should evaluate the chances of a patient’s accurate home care	100
3.8 The analysis of clinical efficacy of an empiric antibiotic treatment should not be performed before 48–72 h from the treatment start, on the basis of simple clinical and laboratory criteria	97
3.9 The switch from parenteral to oral antibiotic therapy must be driven by the clinical outcome of the patient and occurring when clinical stability is reached	96
3.10 In general, the antibiotic therapy for CAP should last minimum five days and not exceed eight days in responsive patients, irrespective of the causative pathogen	93
3.11 In general, the antibiotic therapy of COPD exacerbations should last minimum five days and not exceed eight days in responsive patients	90
3.12 Discharge of a hospitalized patient with LRTI can be evaluated when clinical stability is reached, in absence of other comorbidity exacerbations and of social issues	100
3.13 In a patient with CAP who responded to the antibiotic therapy, a control chest radiograph is not required before three weeks from therapy discontinuation	92
Topic 4: Pharmacoeconomics viewpoints on the prescribing practice of antibiotics
4.1 The most appropriate choice of antibiotic therapy must consider the efficacy, as well as direct and indirect costs, including those related to the problem of antibiotic resistance	98
4.2 The social/environmental impact originated by the spread of antibiotic resistance is a priority of mine to take a therapeutic decision	94
4.3 In the treatment of LRTIs, the price of the initial antibiotic therapy does not represent the most affecting health care cost.	88
4.4 Method of administration and tolerability of the antibiotic are key issues to enhance adherence to treatment and therefore to limit the therapeutic failure	96
4.5 The switch from parenteral to oral antibiotic therapy reduces length and costs of hospitalization, and the risk of hospital-acquired infections, improving patient’s quality of life as well	100

Figure 1 Constant increase of bacterial non-susceptibility to penicillin in S. pneumoniae, expressed as percentage of intermediate and resistant strains (% I+R) observed in Italy from 2011 to 2014 and further raising trend in the following years.

Table 3 Consensus on the management of acute LRTIs. Percentage of agreement to the statements of topic 1: Issues in aetiology and antibiotic resistance involved in the process of prescribing antibiotics

							Panel responses
Statement							1	2	3	4	5
1.4 Antibiotics with resistance levels above the 10%-20% threshold should not be used in empiric therapy							29%			71%
1.5 Based on observed resistance profile, some antibiotics should not be regarded as first-choice agents for the empiric therapy of LRTIs. This refers to non-protected betalactams (amoxicillin), tetracyclines, trimethoprim/sulphametazole and macrolides in particular							28%			72%
1.6 Streptococcus pneumoniae, Haemophilus spp. and Moraxella chatarrhalis are responsible of the 85-95% of cases of chronic bronchitis bacterial exacerbation. all these pathogens develop a significant increase of resistance							21%			79%
1.9 All hospitalized patients with CAP must undergo to at least one set of hemoculture, irrespective of the severity of patient’s conditions							59%			41%
1.10 Amongst 3^rd-generation oral cephalosporins, cefditoren pivoxil has the highest intrinsic activity on Streptococcus pneumoniae, PEN-R strains included							0%			100%
1.13 When treating AECB, an highly active antibiotic against BLNAR (Betalactamase Negative Ampicillin Resistant) and BLPACR (Betalactamase Positive Amoxicillin-Clavulanic Resistant) strains must be used to control the intra-species spread of Haemophilus influentiae resistance							22%			78%
Legend:			No consensus			Consensus

Note: Panel responses were: 1, Disagree; 2, Somewhat disagree; 3, Neither agree nor disagree; 4, Somewhat agree; 5, Agree. Each percentage in the second column is the sum of subjects choosing 1-2-3, and the percentage in the third column is the sum of subjects selecting 4-5.

Table 4 Different spectrum of activity among oral cephalosporins on S. pneumoniae

Classification	Activity	Antibiotic	MIC90 (mg/L)			Ref.
			PS	PI	PR
1st generation	Prevalently active against Gram-positive bacteria	Cephalexin	na	128^(a)	na	[55]
				>64^(a)
		Cefadroxil
2nd generation	Less active than first generation against Gram-positive bacteria	Cefaclor	1	64	>64	[22,40]
	More active against Gram-negative bacteria, but poorly active against H. influenzae and M. catarrhalis	Cefprozil	0.25	8	>16
		Cefuroxime	0.12	4	8
3rd generation	Less active against Gram-positive bacteria, including S. pneumoniae	Cefpodoxime	0.06–0.12	2	4	[22,40]
		Cefixime	0.12–1	16	>16
	Prevalently active against Gram-negative bacteria
		Ceftibuten	0.25–4	8–16	>8–>16
	Active against a broad spectrum of Gram- positive and Gram- negative bacteria	Cefditoren	0.015–0.03	0.25–0.50	0.5–1	[22,40]

Note: na, not available P_S penicillin-sensitive; P_I penicillin-intermediate; P_R penicillin-resistant.

^(a) susceptibility to penicillin not determined.

Figure 2 Structural formulas of three representative cephem molecules and functional groups determining spectrum activity. Ceftaroline (Fifth generation) (a) is characterized by the presence of the thiazole-pyridine rings in C3 position conferring broad-spectrum activity against Gram-positive species. Ceftriaxone (Third generation) (b) carries the methoxyimino group and the aminothiazole substitution in the C7 side chain, granting a good β-lactamase stability and a higher activity on Gram-negative bacteria. Cefditoren (Third generation) (c) possess all these functional groups and possess full spectrum of activity both on Gram-positive and Gram-negative bacteria. Black circle, methoxyimino group (beta-lactamase stability); grey circle, aminothiazole group (activity against Gram-); dashed circle, methylthiazole group (activity against Gram+).

Table 5 Consensus on the management of acute LRTIs. Percentage of agreement to the statements of topic 2: Pharmacological issues involved in the practice of prescribing antibiotics

									Panel responses
Statement									1	2		3	4	5
2.1 To identify the profile of exposure to the drug, for its ability not only to eradicate microorganisms, but also to impair the emergence of resistant subpopulation, the pharmacokinetics/pharmacodynamics relationship must be analyzed									2%				98%
2.3 Oral administration is the route of choice for home care of mild LRTIs, if neither contraindications/limitations to absorption nor other patient-related limiting conditions exist									2%				98%
2.4 Among third-generation oral cephalosporins, ceftibuten and cefixime display mainly a Gram-negative spectrum, while cefditoren has a balanced spectrum including Gram+ e Gram- bacteria									4%				96%
2.5 In LRTI therapy with cephalosporin, initial dosage and the route of administration depend on the severity of patient’s conditions									3%				97%
2.6 During LRTI oral therapy the antibiotic dosage must not be reduced even in presence of clinical improvement and in absence of adverse events									4%				96%
2.7 In patients under poly-pharmacotherapy oral betalactams are the safest antibiotics according to their pharmacological interaction profile									8%				92%
2.8 When switching from parenteral therapy with third-generation cephalosporins (cefotaxime, ceftriaxone) to oral therapy, the most appropriate option is cefditoren pivoxil, due to the similar spectrum and the better intrinsic activity									7%				93%
Legend:			No consensus			Consensus

Note: Panel responses were: 1, Disagree; 2, Somewhat disagree; 3, Neither agree nor disagree; 4, Somewhat agree; 5, Agree. Each percentage in the second column is the sum of subjects choosing 1-2-3, and the percentage in the third column is the sum of subjects selecting 4-5.

Table 6 Consensus on the management of acute LRTIs. Percentage of agreement to the statements of topic 3: Clinical considerations on the management of patients with CAP, AECB and COPD

									Panel responses
Statement									1	2		3	4	5
3.2 Number and duration of antibiotic therapies performed by the patient in the past year can be a predictor of a bacterial infection resistant to previously used antibiotics									11%				89%
3.5 For community-acquired infections of the lower respiratory airways, betalactams should be regarded as first-choice antibiotics, also in monotherapy									23%				77%
3.6 In mild-moderate AECB and in elderly individuals with risk factors, oral cephalosporins must be considered as first-line treatment, while fluoroquinolone use must be restricted to more severe flare up, in patients with bronchectasis in particular									11%				89%
3.10 In general, the antibiotic therapy for CAP should last minimum 5 days and not exceed 8 days in responsive patients, irrespective of the causative pathogen									7%				93%
3.11 In general, the antibiotic therapy of COPD exacerbations should last minimum 5 days and not exceed 8 days in responsive patients									10				90%
Legend:			No consensus			Consensus

Note:

Panel responses were: 1, Disagree; 2, Somewhat disagree; 3, Neither agree nor disagree; 4, Somewhat agree; 5, Agree. Each percentage in the second column is the sum of subjects choosing 1-2-3, and the percentage in the third column is the sum of subjects selecting 4-5.

Figure 3 Schematic representation portraying the consequences of the emergence of bacterial resistance to antibiotics. The risk of therapeutic failure favours relapses and exacerbation of LRTI symptoms, leading to increased incidence of hospitalization with consequent increase of health costs. This scenario abates the cost effectiveness of antibacterial therapy.

Table 7 Consensus on the management of acute LRTIs. Percentage of agreement to the statements of topic 4: Pharmacoeconomics viewpoints on the prescribing practice of antibiotics

									Panel responses
Statement									1	2		3	4	5
4.1 The most appropriate choice of antibiotic therapy must consider the efficacy, as well as direct and indirect costs, including those related to the problem of antibiotic resistance									2%				98%
4.3 In the treatment of LRTIs the price of the initial antibiotic therapy does not represent the most affecting health care cost.									12%				88%
Legend:			No consensus			Consensus

Note: Panel responses were: 1, Disagree; 2, Somewhat disagree; 3, Neither agree nor disagree; 4, Somewhat agree; 5, Agree. Each percentage in the second column is the sum of subjects choosing 1-2-3, and the percentage in the third column is the sum of subjects selecting 4-5.

Hsueh PR, Huang WK, Shyr JM, Lau YJ, Liu YC, Luh KT. Multicenter surveillance of antimicrobial resistance of Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to 14 oral antibiotics. J Formos Med Assoc. 2004 Sep;103(9):664–70.

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