Hospital-acquired Pneumonia and Ventilator-associated Pneumonia

Recent Advances in Epidemiology and Management

François Barbier; Antoine Andremont; Michel Wolff; Lila Bouadma

Curr Opin Pulm Med. 2013;19(3):216-228.

Conclusion

An increasing burden of HAP/VAP may be expected in the coming years, as a result of intensification of care, progressive ageing and a growing prevalence of severe underlying diseases in ICU patients. The current epidemiology of bacterial resistance is more alarming than ever. In this context, the implementation of preventive policies is of major importance.^[17] Both diagnosis and treatment of HAP/VAP remain challenging and justify intensive research work for the development and validation of molecular diagnostic tools, new drugs for MDR pathogens, and nonantibiotic therapeutic options.

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Acknowledgements
None

Table 1. Effects of the main preventive measures for ventilator-associated pneumonia prevention in randomized controlled studies or last meta-analyses
Intervention	Year, design	References	Patients (n)	RRR of VAP (%)
Reducing the time at risk
NPPV	2005, meta-analysis (12 studies)	[18]	3030	↓ 25%
Daily SBT	2000, RCT (two ICUs)	[19]	385 No effect
	2006, RCT (five ICUs)	[20]	144	No effect
Daily sedation interruption	2000, RCT (one ICU)	[21]	128 No effect
Early tracheotomy	2012, meta-analysis (7 RCTs)	[22]	1044	No effect
Preventing endotracheal tube colonization and minimizing contaminated microaspirations
Silver-coated ET	2008, RCT (54 ICUs)	[23]	1509	↓ 36%
Saline instillation before tracheal suctioning	2009, RCT (one ICU)	[24]	262	↓ 54%
ET with SSD	2010, meta-analysis (13 RCTs)	[25]	2442	↓ 48% (four RCTs)
ET with ultrathin membrane and SSD	2007, RCT (one ICU)	[26]	280	↓ 64%
ET with an ultrathin and tapered-shape cuff membrane	2008, RCT (one ICU)	[27]	134	↓ 45%
Continuous control of tracheal cuff pressure	2007, RCT (two ICUs)	[28]	142	No effect
	2011, RCT (one ICU)	[29]	122	↓ 63%
Head-of-bed elevation	1999, RCT (two ICUs)	[30]	86	↓ 78%
	2006, RCT (four ICUs)	[31]	221	No effect
Prone position	2008, meta-analysis (five RCTs)	[32]	1372	No effect
Kinetic beds	2006, meta-analysis (15 RCTs)	[33]	1169	↓ 53% (10 RCTs)
Positive end-expiratory pressure	2008, RCT (three ICUs)	[34]	131	↓ 63%
Physiotherapy	1998, RCT (one ICU)	[35]	46	No effect
	2002,RCT (one ICU)	[36]	60	↓ 79%
	2007, RCT (one ICU)	[37]	180	No effect
	2009, RCT (one ICU)	[38]	144	No effect
Modulation of colonization
Oral care with chlorhexidine	2010, meta-analysis (12 RCTs)	[39]	2341	↓ 24%
Probiotics	2010, RCT (one ICU)	[40]	146	↓ 47%
Iseganan	2006, RCT (one ICU)	[41]	709	No effect
Closed tracheal suction system	2008, meta-analysis (nine RCTs)	[42]	1292	No effect

Data from [17]. ET, endotracheal tube; NPPV, noninvasive positive pressure ventilation; RCT, randomized controlled trial; RRR, relative risk reduction; SBT, spontaneous breathing trial; SSD, subglottic secretion drainage; VAP, ventilator-associated pneumonia.

Table 2. Current bacterial epidemiology of hospital-acquired pneumonia and ventilator-associated pneumonia (first episodes only): data from recent clinical trials and surveys
Study/reference	ACURASYS [13•]	Ferrer et al. [53]	Ferrer et al. [53]	ANSRPSG [50]	SENTRY [54]
Country	France	Spain	Spain	Asia	Worldwide
Setting	20 ICUs	Six ICUs, one hospital	Six ICUs, one hospital	73 hospitals	Surveillance System
Type of pneumonia	VAP in ARDS patients	HAP and VAP^a	HAP and VAP^b	HAP and VAP	HAP and VAP
Patients, n	98	38 (VAP, n=18)	238 (VAP, n=128)	2554 (VAP, n=977)	31 436
Bacterial documentation	100	63	54	67	–
Gram-negative bacteria
Haemophilus influenza	3	5	3	1	3
Enterobacteriaceae	35	22	19	23	26
Escherichia coli	11	8	6	5	7
Klebsiella pneumoniae	4	3	3	14	10
Enterobacter sp.	10	3	5	4	6
Serratia marcescens	3	–	2	<1%	3
Other enterobacteria	7	8	3	–	–
Pseudomonas aeruginosa	34	16	18	19	22
Stenotrophomonas maltophilia	5	–	3	4	3
Acinetobacter baumannii	–	–	1	22	7
Gram-positive bacteria
Staphylococcus aureus	21	27	16	14	28
Methicillin-susceptible	12	11	8	3	–
Methicillin-resistant	9	16	8	11	–
Streptococcus pneumoniae	Other GP: 10	5	2	2	3
Other streptococci		–	–	–	–
Enterococcus sp. vancomycin-resistant		–	–	–	–

Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; ARDS, acute respiratory distress syndrome; GP, Gram-positive bacteria; HAP, hospitalacquired pneumonia; VAP, ventilator-associated pneumonia.
^aNo risk factor of multidrug-resistant (MDR) bacteria according to the 2005 Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) criterion [1].
^bAt least one risk factor of MDR bacteria according to the 2005 IDSA/ATS criterion.

Table 3. Current guidelines for the empirical treatment of hospital-acquired pneumonia, including ventilatorassociated pneumonia
	Reference	Early-onset HAP/VAP (≤day 4 of hospital stay/MV) without risk factors for MDR pathogen^a	Late-onset HAP/VAP (≥day 5 of hospital stay/MV) OR presence of ≥1 risk factor for MDR pathogen^b
Most common (i.e. targeted) pathogens		MSSA Streptococcus pneumonia and other streptococci, Haemophilus sp. Wild-type Enterobacteriaceae	MRSA Pseudomonas aeruginosa Drug-resistant Enterobacteriacae Acinetobacter baumannii Stenotrophomonas maltophilia
Society which issued the guidelines (date of publication)
American Thoracic Society/Infectious Diseases Society of America (2005)	[1]	Ceftriaxone or Levofloxacin, moxifloxacin, or ciprofloxacin or Ampicillin/sulbactam or Ertapenem	Cefepime or ceftazidime or Imipenem/cilastatin or meropenem or Piperacillin/tazobactam plus Ciprofloxacin or levofloxacin or Amikacin, gentamicin, or tobramycin
European Respiratory Society/European Society of Clinical Microbiology and Infectious Diseases/European Society of Intensive Care Medicine (2009)	[10]	Ampicillin/sulbactam or amoxicillin/clavulanate or Cefuroxime, cefotaxime or ceftriaxone or Moxifloxacin or levofloxacin (not ciprofloxacin)	Ceftazidime or Imipenem/cilastatin or meropenem or Piperacillin/tazobactam plus Ciprofloxacin or levofloxacin
British Society of Antimicrobial Chemotherapy (2008)	[8]	Aminopenicillin/b-lactamase inhibitor or Cefuroxime	Early-onset pneumonia with risk factor for MDR pathogen: Cefotaxime or ceftriaxone or Fluoroquinolone or Piperacillin/tazobactam Late-onset pneumonia: Depending on local epidemiology If Pseudomonas aeruginosa is suspected, treatment options include ceftazidime, ciprofloxacin, meropenem and piperacillin/tazobactam
Association of Medical Microbiology and Infectious Disease Canada/Canadian Thoracic Society^c (2008)	[9]	Only if severity criteria are lacking: Cefotaxime or ceftriaxone or cefepime or Piperacillin-tazobactam or Imipenem/cilastatin or meropenem or Levofloxacin or moxifloxacin	Also to be applied for severe early-onset pneumonia^d: Ceftazidime or cefepime or Piperacillin/tazobactam or Imipenem/cilastatin or merepenem plus Ciprofloxacin or levofloxacin or Gentamicin, tobramycin or amikacin
In all guidelines	[1,8–10]		Add vancomycin or linezolid if MRSA is suspected

MV, mechanical ventilation; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus.
^aRisk factors for MDR pathogen are a current hospitalization of 5 days or more, an antimicrobial therapy within the preceding 90 days, a high frequency of antibiotic resistance in the specific hospital unit, an immunosuppressive disease and/or therapy, and risk factors for healthcare-associated pneumonia (i.e. hospitalization for 2 days or more in the preceding 90 days, residence in a nursing home or extended care facility, home infusion therapy including antibiotics, chronic dialysis within 30 days, home wound care, and known carriage of multidrug-resistant pathogen in family members).
^bThe cephalosporins (ceftazidime and cefepime), carbapenems (imipenem/cilastatin and meropenem), b-lactamin/b-lactamase inhibitor combination (piperacillin/tazobactam), fluoroquinolone (ciprofloxacin and levofloxacin) and aminoglycosides (amikacin, gentamicin, and tobramycin) listed above are all considered as effective against wild-type Pseudomonas aeruginosa.
^cOnly VAP guidelines are shown here (see [9] for nonventilator HAP guidelines).
^dSeverity criteria include hypotension, sepsis syndrome, rapid progression of infiltrates and end organ dysfunction.

Table 4. Prevalence of major antibiotic resistance in *Staphylococcus aureus, Klebsiella pneumoniae*, *Escherichia coli, Pseudomonas aeruginosa* and *Acinetobacter baumannii* strains causing hospital-acquired and ventilator-associated pneumonia: recent data (≥2004) from international multicentric surveillance programs
Study/reference	INICC VAP [14••]	SENTRY HAP/VAP [54]	ANSRPSG HAP + VAP (pooled) [50]
Pathogen, antimicrobial
Staphylococcus aureus
Oxacillin	73	59/51	82
Gentamicin	–	13/22	–
Fluoroquinolones	–	58/48	78
Klebsiella pneumonia
Fluoroquinolones	–	16/24	31
Third-generation/fourth-generation cephalosporins^a	69	23/32	43
Carbapenems^b	7	<1/<1	2
Escherichia coli
Fluoroquinolones	55	28/26	–
Third-generation/fourth-generation cephalosporins^a	67	16/22	–
Carbapenems^b	4	0/0	–
Pseudomonas aeruginosa
Fluoroquinolones	46	40/42	30
Aminosides	28	28/34	–
Piperacillin and/or piperacillin–tazobactam	40	24/29	37
Antipseudomonal cephalosporins	37	32/37	35
Carbapenems^c	43	28/34	30
Acinetobacter baumannii
Carbapenems^c	66	42/54	67
Colistin	–	–	1

Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; HAP, hospital-acquired pneumonia; INICC, International Nosocomial Infection Control Consortium; VAP, ventilator-associated pneumonia.
^aResistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible strains of Escherichia coli and Klebsiella pneumoniae is almost exclusively because of the acquisition of plasmidic Ambler class A extended-spectrum b-lactamases (CTX-M, TEM and SHV) or AmpC-like cephalosporinases [56].
^bCarbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired, plasmidic carbapenemases, either of Ambler class A (mainly KPC), B (mainly VIM and IMP-type metallo-b-lactamases, with the recently described genotype NDM-1 spreading worldwide) or D (oxacillinases, mainly OXA-48) [57]. It is noteworthy that plasmids harbouring ESBL-encoding and/or carbapenemase-encoding genes often carry other resistance genes (e.g. qnr for fluoroquinolones resistance, or aminoglycosides modifying enzymes, including the AAC(60)-1b-cr variant which also confers low level resistance to ciprofloxacin), thus conferring a multidrug-resistant phenotype as the result of a single plasmid conjugation.
^cCarbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii may involve distinct mechanisms including impermeability (loss of outer membrane porins), hyperexpression of efflux pomp systems, and carbapenemase production.