Update on management options in the treatment of nosocomial and ventilator assisted pneumonia: review of actual guidelines and economic aspects of therapy

Figures & data

Table 1 Synopsis of grading systems used in the respective guidelines

Grading		Ref
ATS
Level I (high)	Evidence comes from well-conducted, randomized, controlled trials	5
Level II (moderate)	Evidence comes from well-designed, controlled trials without randomization (including cohort, patient series, and case-control studies). Level II studies also include any large case series in which systematic analysis of disease patterns and/or microbial etiology was conducted, as well as reports of new therapies that were not collected in a randomized fashion
Level III (low)	Evidence comes from case studies and expert opinion. In some instances, therapy recommendations come from antibiotic susceptibility data without clinical observations
BSAC
A	At least one meta-analysis, systematic review, or RCT rated as 1++ and directly applicable to the target population; or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results	7
B	A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+
C	A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++
D	Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+
Good clinical practice points
Recommended best practice based on the clinical experience of the guideline development group
1++	High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
1+	Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias
1−	Meta-analyses, systematic reviews, or RCTs with a high risk of bias
2++	High-quality systematic reviews of case control or cohort studies. High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2+	Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal
2−	Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3	Nonanalytic studies, eg, case reports, case series
4	Expert opinion
CCCTG
Level 1	Randomized, controlled trials, blinded-outcome adjudication, intention-to-treat-analysis, explicit definition of VAP	8,12
Level 2	Any condition mentioned above unfulfilled
Level 3	No randomization
Recommend	“… if there were no reservations about endorsing an intervention.”
Consider	“… if the evidence supported an intervention but there were minor uncertainties about the benefits, harms, or costs.”
No recommendation	“… was made if evidence regarding an intervention was inadequate or if there were major uncertainties about the benefits, harms, and costs.”
Do not recommend	“… if there was no evidence of benefit and there was potential for harm or increased healthcare costs from the intervention.”
G-HAP
1A	Strong recommendation, high evidence – desirable effects clearly outweigh risks or additional resource consumption or vice versa	9
1B	Strong recommendation, moderate evidence
1C	Strong recommendation, low or very low evidence
2A	Weak recommendation, high evidence – desirable effects possibly outweigh risks or additional resource consumption or vice versa
2B	Weak recommendation, moderate evidence
2C	Weak recommendation, low or very low evidence
3	No recommendation – no clear indication for presence of benefit or risk
PEG
A	Ia evidence based on meta-analyses of RCT	11
A	Ib evidence based on at least one RCT
B	IIa evidence based on at least one well-designed controlled study without randomization
B	IIb evidence based on at least one well-designed quasi-experimental study
B	III evidence based on well-designed nonexperimental studies (eg, case-control study)
C	IV evidence based on expert opinions, results of consensus/conferences

Abbreviations: ATS, American Thoracic Society; BSAC, British Society for Antimicrobial Chemotherapy; CCCTG, Canadian Critical Care Trials Group; G-HAP, S3-Guideline for hospital acquired pneumonia in Germany PEG, Paul-Ehrlich-Gesellschaft; RCT, randomized, controlled trial; VAP, ventilator-associated pneumonia.

Table 2 Score for risk factors influencing antibiotic strategy according to the PEG recommendation

Risk factor	Points
Age >65 years	1
Preexisting structural lung disease	2
Recent antibiotic therapy	2
Late onset >4 days in hospital	3
Severe respiratory insufficiency with/without mechanical ventilation	3
Extrapulmonary organ failure	4

Abbreviation: PEG, Paul-Ehrlich-Gesellschaft

Table 3 Overview of recommendations from all examined guidelines

Potential pathogen	ATS	BSAC	CCCTG	G-HAP	PEG
	Early onset, no MDR risk, any disease severity	Early onset, no MDR risk, no other risk factors		No MDR risk	CPR score 0–2
Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Enteric gramnegative bacilli: Escherichia coli Klebsiella pneumoniae Enterobacter sp. Proteus sp. Serratia marcescens	Ceftriaxone (3rd gen cephalosporin) or Levofloxacin, moxifloxacin or Ciprofloxacin (fluoroquinolone) or Ampicillin/sulbactam (aminopenicillin/BLI) or Ertapenem (carbapenem)	Amoxicillin/clavulanic acid (aminopenicillin/BLI) or Cefuroxime (2nd gen cephalosporin) Early-onset, MDR risk and/or other risk factors Cefotaxime or ceftriaxone (3rd gen cephalosporin) or Fluoroquinolone or Piperacillin/tazobactam (acylaminopenicillin/BLI)	Depends on locale spectrum of pathogens and susceptibility	4th gen cephalosporin or Aminopenicillin/BLI or Ertapenem or Fluoroquinolone	Ceftriaxone, cefotaxime (3rd gen cephalosporin) or Levofloxacin or Moxifloxacin (fluoroquinolone) or Ampicillin/sulbactam, amoxicillin/clavulanic acid (aminopenicillin/BLI) or Ertapenem (carbapenem)
	Late onset or MDR risk, any disease severity	Late onset		MDR risk	CPR score 3–5
Above and MDR pathogens: Pseudomonas aeruginosa Klebsiella pneumoniae (ESBL) Acinetobacter sp.	Cefepime, ceftazidime (4th/3rd gen cephalosporin) or Imipenem, meropenem (carbapenem) or Piperacillin/tazobactam (acylaminopenicillin/BLI) plus Ciprofloxacin, levofloxacin (fluoroquinolone) or Amikacin, gentamicin or tobramycin (aminoglycoside)	Depends on locale spectrum of pathogens and susceptibility		Piperacillin/tazobactam or Imipenem, meropenem or 4th gen cephalosporin plus Aminoglycoside or Fluoroquinolone	Cefepime (4th gen cephalosporin) or Doripenem, imipenem, meropenem (carbapenem) or Piperacillin/tazobactam (acylaminopenicillin/BLI) CPR score 6 and more Treatment for CPR 3–5 plus Ciprofloxacin, levofloxacin (fluoroquinolone) or Amikacin, gentamicin or tobramycin (aminoglycoside) or Fosfomycin
Methicillin-resistant	Plus	Linezolid, vancomycin		Linezolid, vancomycin	Linezolid, vancomycin
Staphylococcus aureus (MRSA)	Linezolid, vancomycin
Legionella pneumophila	Macrolide or fluoroquinolone instead of aminoglycoside	–		–	Macrolide or fluoroquinolone

Abbreviations: ATS, American Thoracic Society; BLI, beta-lactamase inhibitor; BSAC, British Society for Antimicrobial Chemotherapy; CCCTG, Canadian Critical Care Trials Group; CPR, clinical patient risk score; G-HAP, S3-Guideline for hospital-acquired pneumonia in Germany; gen, generation; MDR, multidrug resistance; PEG, Paul-Ehrlich-Gesellschaft; ESBL, extended-spectrum beta-lactamase.

Table 4 Most common recommendations risk-adjusted

Risk category	Antibiotic therapy recommended	Recommended in how many guidelines (n=5)
No MDR risk (early onset, no prior antibiotic therapy, no VAP, no comorbidities, no other organ failure)	2nd gen cephalosporin (eg, cefuroxime)	2
	3rd gen cephalosporin (eg, ceftriaxone)	3
	4th gen cephalosporin (cefepime)	1
	Aminopenicillin/BLI (eg, amoxicillin/clavulanic acid)	4
	Quinolones (eg, levofloxacin)	3
	Ertapenem	3
Medium MDR risk (prior antibiotic therapy, late onset, comorbidities)	3rd gen cephalosporin (eg, ceftriaxone)	2
	4th gen cephalosporin (cefepime)	4
	Acylaminopenicillin/BLI (eg, piperacillin/tazobactam)	4
	Doripenem	1
	Imipenem	3
	Meropenem	3
	Quinolones (eg, levofloxacin)	1
High MDR risk (late onset, VAP, prior antibiotic therapy, comorbidities, eventual organ failures)	All substances of medium MDR-risk	3
	Plus combination of Quinolones (eg, levofloxacin)	3
	or
	Aminoglycosides	3
	or
	Fosfomycin	1
Risk of MRSA	Vancomycin	4
	Linezolid	4

Abbreviations: BLI, beta-lactamase inhibitor; gen, generation: MDR, multidrug resistance; MRSA, methicillin-resistant Staphylococcus aureus; VAP, ventilator-associated pneumonia.