Surveillance and Management of Multidrug-resistant Microorganisms

Giovanni Battista Orsi; Marco Falcone; Mario Venditti

Expert Rev Anti Infect Ther. 2011;9(8):653-679.

Surveillance & Infection Control

Surveillance is a critical and important component of any infection control program, allowing the detection of MDR pathogens, monitoring epidemiologic trends and measuring the effectiveness of interventions. Strategies range from surveillance of clinical microbiology laboratory results, obtained as part of routine care, up to active surveillance cultures (ASCs) to detect asymptomatic colonization.^[242] Most studies have focused surveillance efficacy on MRSA and VRE, and to a much lesser extent on MDR Gram-negatives.^[243]

Routine Clinical Culture Surveillance

Monitoring clinical microbiology isolates resulting from tests ordered as part of routine clinical care represents the simplest form of MDRO surveillance. This method is particularly useful to detect the emergence of new MDRO not previously detected, either within an individual healthcare facility or community wide.^[242] Furthermore, the data may be used to prepare antimicrobial susceptibility reports describing pathogen specific prevalence of resistance among clinical isolates. Such reports may be useful to monitor changes in known resistance patterns that might signal emergence or transmission of MDROs and also to provide clinicians with information to guide antimicrobial prescribing practices.^[244] Furthermore, surveillance of routine clinical microbiology cultures needs limited resources and is less time consuming than ASC strategy.

Active Surveillance Culture

Isolating a MDRO from a clinical culture several days after patient admission to a ward does not establish that the colonization was acquired in the unit, also the colonization may remain undetected in uninfected patients, therefore, ASCs to identify patients who are colonized with a specific MDRO have been implemented.^[242,245] This approach is based on the observation that detection of colonization may be delayed or missed completely if culture results obtained in the course of routine clinical care are the primary means of identifying colonized patients.^{[242,245–247]}

Active surveillance culture efficacy to reduce the spread of infection in outbreak settings, particularly MRSA, is recognized, but its role in endemic conditions remains unclear.^[248–250]

Several reports have concluded that ASCs, in combination with contact precautions for the colonized patients, contributed directly to the decline or eradication of MDRO.^{[242,243,245,248]} A recent systematic review of the literature performed by McGinigle et al. summarized the evidence of the efficacy of ASCs in the ICU setting on several clinical and economic outcomes.^[251] Furthermore, wide hospital ASC programs were shown to be cost effective.^[252] The authors also noted that methodologic weakness and inadequate reporting in published research make it difficult to precisely assess the contribution of active surveillance and isolation control is difficult to assess.^[253]

However, not all of the studies reached the same conclusion and poor control of MRSA despite the use of ASCs has been described.^[254,255] The role of ASCs may be different according to the baseline prevalence of MRSA and the hospital setting.^[243]

Target Surveillance

Active surveillance culture programs, compared with routine culture surveillance, are labor and resource intensive, and the use of ASC for MRSA may quadruple the number of patients under contact precautions.^[256]

Therefore, targeted surveillance based on patients risk factors might provide the most effective use of resources.^[243,257] There is a consensus that ASC should be performed for patients who are transferred from other hospitals, for patients who are related by proximity to an index patient, if there is evidence of transmission of an MDRO within a unit or if the resistance patterns threaten the ability to treat infection (e.g., VRSA). The selection and profile of patients screened should be defined locally by the infection control team, after considering the local epidemiology, the principal risk factors for Gram-positive and Gram-negative MDRO reported in Table 4. Whether to perform ASC routinely for all patients at admission remains controversial.^[258,259]

The screening of healthcare personnel remains controversial and recommended only during outbreaks.^[242]

Sampling & MDRO Detection

For several years conventional culture methods, which can take ≥48–72 h to obtain a result, have been considered to be the gold standard to detect colonization. In the absence of a pre-emptive room isolation, this time might be sufficient to spread the bacterium among patients. The effective culture screening method for MRSA and MR-CoNS is direct inoculation of pooled nose, throat and perineal swabs on MRSA-selective chromogenic agar. If present, areas of skin breakdown and foreign body insertion sites should be collected, as well as sputum for productive cough.^[260] VRE screening is carried out on stool specimen or rectal/perirectal specimen. ESBL bacteria are cultured on rectal/perirectal specimen, oropharyngeal, endotracheal, inguinal, wounds and urine.^[242]

Recently, rapid methods for molecular detection of MRSA-colonized patients with available results in 2 h have been developed with high sensitivity and specificity.^[261] In comparison with culture-based methods, PCR tests are costly and some may have relatively high false-positivity rates, therefore definitive evidence of their clinical cost–effectiveness is needed.^[262] A recent review and meta-analysis on rapid MRSA screening tests by Tacconelli et al. concluded that active screening is more important than the type of test used.^[263] MRSA decrease could be achieved both with conventional and rapid molecular tests.

Also a rapid real-time PCR test that detects the presence of vanA and/or vanB genes has been proposed for rapid screening to identify patients harboring VRE at hospital admission.^[264]

In Gram-negative bacteria, particularly carbapenemase producing organisms, MDR cannot simply be inferred from the resistance profile. Criteria must be established for which isolates should be suspected and screened for carbapenemase production, and which tests (phemotypic and/or genotypic) should be adopted for confirmation of the resistance mechanism. Strategies should be devised for surveillance of carbapenemase producers in order to enable the implementation of effective surveillance programs.^[204]

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Table 1. Agents for the treatment of severe infections caused by multidrug-resistant organisms: summary of pharmacokinetic/pharmacodynamic properties, antimicrobial spectra, clinical indications and dosages.
Agent (PK/PD predictors of efficacy)	Antimicrobial spectrum	Current and potential indications	Current dosages	Proposed dosages	Additional notes	Ref.
Daptomycin (C_max/MIC bactericidal)	Gram-positive bacteria (including VISA, hVISA, VICons, VRE). Activity into the biofilm	SSTIs BSI, NVE PJIs	4 mg/kg q.d. 6 mg/kg q.d.	¹Up to 8 mg/kg q.d. ²10 mg/kg q.d.	¹Dosage suggested by some IDSA experts for MRSA BSI ²Dosage suggested for PJIs based on experimental animal models. Italian guidelines and a consensus article support this agent as second-choice therapy for PJIs	[61,88,98,99]
Telavancin (C_max/MIC bactericidal)	Gram-positive bacteria (including VISA, hVISA, VICons, VRE). Activity into the biofilm	SSTIs, HCAP, HAP, VAP¹ BSIs, PM-IE, IE	10 mg/kg q.d. 10 mg/kg q.d.	10 mg/kg q.d.²	¹Noninferior to vancomycin for Gram-positive pneumonia ²Based on sporadic case reports of successful treatment	[92–94]
Linezolid (T>/MIC bacteriostatic)	Gram-positive bacteria (including VISA, hVISA, VICoNS, VRE). Poor activity into the biofilm	SSTIs, MRSA pneumonia Empiric therapy of HCAP HAP and VAP CNSIs¹, BJIs, PJIs²	600 mg b.i.d. 600 mg b.i.d. 600 mg b.i.d. 600 mg b.i.d.	1200 mg/day CI³ 1200 mg/day CI³ 1200 mg/day CI³	¹Small series showed excellent results after vancomycin failure ²Italian guidelines and a consensus article support this agent as second-choice therapy ³CI allows better PK/PD parameters for positive outcome in critically ill patients	[82,83,98,99]
Tigecycline (T>/MIC bacteriostatic)	Gram-positive bacteria and Gram-negative bacteria (except Pseudomonas aeruginosa and Proteus spp.; poor activity vs Serratia spp.)	SSTIs, IAIs, CAP BSI secondary to SSTIs, IAIs CAP UTIs HAP¹, VAP	50 mg/kg b.i.d. (LD 100 mg) 50 mg/kg b.i.d. (LD 100 mg) 50 mg/kg b.i.d. (LD 100 mg)¹	Up to 200 mg b.i.d.²	¹Controversial data on efficacy with HAP/VAP; use of combination with colistin for carbapenem-resistant Acinetobacter or Klebsiella pneumoniae is adopted by many clinicians despite definite evidence of efficacy lacking ²Based on some case reports	[219–223,228]
Colistin (C_max/MIC bactericidal)	Gram-negative bacteria (except Proteus spp.)	SSTIs, BSIs HAP, VAP Meningitis/ventriculitis	2–3 MU t.i.d. 2–3 MU t.i.d. 2–3 MU t.i.d.	4.5 MU b.i.d. (LD 9 MU)¹ 4.5 MU b.i.d. (LD 9 MU) ± 1 MU aerosol t.i.d.² 4.5 MU b.i.d. (LD 9 MU) + 10–20 mg intrathecally¹	¹No clinical data; dosage suggested by a PK/PD study ²Experimental animal studies suggest aerosol therapy, but this seems not supported by data in humans. Reports of in vivo colistin resistance during colistin therapy of Klebsiella infections ¹Almost all reported cases are carbapenem-resistant Acinetobacter infections	[215–217,232,234]
Fosfomycin (T>/MIC bacteriostatic)	Gram-positive (including some MRSA) and Gram-negative bacteria (including some P. aeruginosa)	BSIs, HAP, VAP, UTIs (old reports of efficacy with UTIs, SSTIs, BJIs, CNSIs)		4 g q.i.d.¹ or 8 g b.i.d. or t.i.d.²	¹Based on a small series showing encouraging data with fosfomycin always in combination with colistin or gentamycin ²Based on a PK study	[238,239]

b.i.d.: Two-times a day; BJI: Bone and joint infection; BSI: Bloodstream infection; CAP: Community-acquired pneumonia; CI: Continuous infusion; CNSI: CNS infection; HAP: Hospital-acquired pneumonia; HCAP: Healthcare-associated pneumonia; hVISA: Heteroresistant vancomycin intermediate susceptibility Staphylococcus aureus; IAI: Intra-abdominal infection; IDSA: Infectious Diseases Society of America; IE: Infective endocarditis; LD: Loading dose; MRSA: Methicillin-resistant Staphylococcus aureus; MU: Million units; NVE: Native valve endocarditis; PD: Pharmacodynamic; PJI: Prosthetic joint infection; PK: Pharmacokinetic; PM-IE: Pacemaker-associated infective endocarditis; q.d.: Once a day; q.i.d.: Four-times a day; SSTI: Skin and soft tissue infection; t.i.d.: Three-times a day; UTI: Urinary tract infection; VAP: Ventilator-associated pneumonia; VICoNS: Vancomycin intermediate coagulase-negative staphylococci; VISA: Vancomycin intermediate susceptibility Staphylococcus aureus; VRE: Vancomycin-resistant enterococci.

Table 2. Most recent studies on multidrug-resistant Gram-positive bacteria prevalences in various parts of the world.
Study (year)	Reference	Region	Settings	Patient population	Percentage of isolated pathogens	Multidrug-resistant pathogens	Resistance range		Ref.
Study (year)	Reference	Region	Settings	Patient population	Percentage of isolated pathogens	Multidrug-resistant pathogens	High	Low	Ref.
EARSS (2008)	EARSS 2008	Europe	900 hospitals in 28 countries	General hospital population		MRSA (21%) VRE (<1 to >30%)	Portugal 49% Greece 40% Italy 37% Ireland 38% Greece 27% Portugal 23%	Norway <1% Sweden 1% Holland 1% France <1% Finland <1% Holland <1%	[401]
NHSN (2006–2007)^†	Hidron AI ICHE 2008	USA	463 hospitals	88% ICU population	CoNS 15.3%^†, Staphylococcus aureus 14.5%^† Enterococcus faecalis 3.5%^†, Enterococcus faecium 5.6%^†	MRSA (56.2%)^† VRE (33%)	CAUTI 65.2%^† VR E. faecium (80%)^†	VAP 54.4%^† VR E. faecalis (6.9%)^†	[6]
TSN (1998–2005)	Styers D ACMA 2006	USA	300 microbiology laboratories	Inpatient and outpatient population	S. aureus 18.7% (inpatients), S. aureus 14.7% (outpatients)	MRSA (59–48%)	Non-ICU inpatients 59.2%	Outpatients 47.9%	[7]
INICC (2003–2008)^†	Rosenthal VD AJIC 2010	World-wide	173 ICUs, in 25 countries	ICU population		CL-BSI MRSA (84.1%)^† CL-BSI VRE (8.7%)^†			[10]
Canada (2005–2006)	Zhanel GG AAC 2008	Canada	19 ICUs	ICU population	S. aureus 21.1% Enterococcus spp. 6.1%	MRSA (22.3%) VRE (6.7%)	HA-MRSA (90.9%) Blood 36.0%	CA-MRSA (10.1%) Wound 19.3%	[11]

^†Pathogens responsible for hospital-acquired infection.
CA: Community-acquired; CAUTI: Catheter-associated urinary tract infection; CL-BSI: Central line-associated bloodstream infection; CoNS: Coagulase-negative staphylococci; EARSS: European Antimicrobial Resistance Surveillance System; HA: Hospital-acquired; ICU: Intensive care unit; INICC: International Nosocomial Infection Control Consortium; MRSA: Methicillin-resistant Staphylococcus aureus; NHSN: National Healthcare Safety Network; TSN: The Surveillance Network; VAP: Ventilator-associated pneumonia; VR: Vancomycin resistant; VRE: Vancomycin-resistant enterococci.

Table 3. Impact of multidrug-resistant bacteria on mortality, length of stay and costs.
Study (year)	Study design	Setting	Infection	MDRO	Cases/controls (n)	Control patient population	Parameter	Finding	p-value	Multivariate analysis OR (95% CI)	p-value	Ref.
Aloush et al. (2006)	Retrospective matched cohort	Tertiary care	All infections	Pseudomonas aeruginosa	82/82	Not colonized patients	Mortality (cases/controls) Length of stay (days)	21.0 vs 12.0% 20 vs 10	0.08 <0.01	4.4 2.0	0.04 <0.01	[179]
Tam et al. (2010)	Retrospective cohort study	Teaching hospital	Bacteremia	P. aeruginosa	25/84	Susceptible organisms	Mortality (cases/controls)	40.0 vs 11.9%	<0.01	6.8 (1.9–23.9)	<0.01	[184]
Zavascki et al. (2006)	Prospective	Tertiary care	All infections	P. aeruginosa	86/212	Susceptible organisms	Mortality (cases/controls)	51.2 vs 32.1%	<0.01			[198]
Schwaber et al. (2008)	Case–control	Teaching hospital	Infection/colonization	Klebsiella pneumoniae	48/56	Susceptible organisms	Mortality (cases/controls)	44.0 vs 12.5%	<0.01	5.4 (1.7–17.1)	<0.01	[197]
Patel et al. (2008)	Matched case–control	Teaching hospital	All infections	K. pneumoniae	99/99	Susceptible organisms	Mortality	48 vs 20%	<0.01	3.71 (1.9–7.0)	<0.01	[196]
Borer et al. (2009)	Retrospective matched cohort	Teaching hospital	Bacteremia	K. pneumoniae	39/39	Not colonized patients	Mortality	71.9 vs 21.9%	<0.01			[194]
Gasink et al. (2009)	Retrospective case–control	Tertiary care	Infection/colonization	K. pneumoniae	56/863	Susceptible organisms	Mortality	32.1 vs 9.9%	<0.01	2.3 (1.2–4.4)	<0.02	[195]
Hautemaniere et al. (2009)	Prospective cohort	Teaching hospital	Infection/colonization	VRE	113/113	Not colonized patients	Mortality	42.5 vs 28.3%		1.6 (1.0–2.6)	<0.04	[128]
Sakka et al. (2008)	Case–control	Teaching hospital	Infection/colonization	VRE	53/106	Not colonized patients	Mortality	24.5 vs 4.7%	<0.01	3.1 (0.6–15.1)	0.2	[129]
Sunenshine et al. (2007)	Retrospective matched cohort	Two teaching hospitals	Infection/colonization	Acinetobacter	96/91	Susceptible organisms	Mortality Length of stay (days)^†	26.0 vs 17.6% 13.3 vs 6.7	0.21 <0.05	2.6 (0.3–26.1)	>0.05	[175]
Lee et al. (2007)	Retrospective matched cohort	Teaching hospital	Bacteremia	Acinetobacter baumannii	48/48	Susceptible organisms	Mortality Length of stay (days)^† Hospitalization cost (US$)	34.8 vs 13.0% 54.2 vs 34.1 9349 vs 4865	<0.01			[183]
Shorr et al. (2006)	Retrospective	59 US hospitals	Early-onset VAP	MRSA	59/95	Susceptible organisms	Length of stay (days)^†	20 vs 15 (median)	<0.05			[36]
Cosgrove et al. (2005)	Cohort study	Teaching hospital	Bacteremia	MRSA	96/252	Susceptible organisms	Length of stay (days)^† Hospitalization cost (US$)	9 vs 7 (median) 14,655 vs 10,655	<0.05 <0.01	1.3 (1.0–1.6)	<0.02	[34]
Filice et al. (2010)	Retrospective case–control	Tertiary care	All infections	MRSA	335/390	Susceptible organisms	Hospitalization cost (US$)	34,657 vs 15,923	<0.01			[37]

^†Mean intensive care unit length of stay after index day.
MDRO: Multidrug-resistant organism; MRSA: Methicillin-resistant Staphylococcus aureus; OR: Odds ratio; VAP: Ventilator-associated pneumonia; VRE: Vancomycin-resistant enterococci.

Table 4. Principal risk factors for multidrug-resistant Gram-positive and Gram-negative bacteria.
	MRSA	MR-CoNS	VRE	Pseudomonas aeruginosa	Acinetobacter baumannii	Enterobacteriaceae
LOS	✓	✓	✓	✓	✓	✓
SSI	✓	✓			✓
ICU	✓	✓		✓	✓	✓
Hemodialysis	✓	✓
Prior colonization/infection	✓	✓
Proximity to colonized/infected	✓	✓	✓		✓
Survive underlying disease			✓		✓	✓
Illness severity			✓			✓
Invasive devices				✓	✓	✓
Organ transplant
Malignancy
Immunocompromised status • Immunodepression • Organ transplant • Malignancy				✓ ✓ ✓
Prior antibiotic therapy • Cephalosporins • Fluoroquinolones • Carbapenems • Other	✓	✓	✓	✓ ✓ ✓ ✓	✓ ✓ ✓ ✓	✓ ✓ ✓ ✓

ICU: Intensive care unit; LOS: Length of stay; MR-CoNS: Methicillin-resistant coagulase-negative staphylococci; MRSA: Methicillin-resistant Staphylococcus aureus; SSI: Surgical site infection; VRE: Vancomycin-resistant enterococci.

Table 5. Most recent studies on multidrug-resistant Gram-negative bacteria prevalences in various parts of the world.
Study (year)	Region	Settings	Percentage of isolated pathogens	Multidrug-resistant pathogens	Resistance range		Ref.
Study (year)	Region	Settings	Percentage of isolated pathogens	Multidrug-resistant pathogens	High	Low	Ref.
EARSS (2008)^†	Europe	900 hospitals in 28 countries		Pseudomonas aeruginosa (16%) Escherichia coli (3%) Klebsiella pneumoniae (19%)	Greece 40% Czech Republic 31% Italy 28% Romania 15% Hungary 10% Bulgaria 7% Greece 54% Bulgaria 39% Czech Republic 35%	Sweden 1% Norway 1% UK 2% Norway <1% Sweden <1% Denmark 1% Finland <1% Sweden <1% Norway 1%	[401]
NHSN (2006–2008)^‡§	USA	463 hospitals		P. aeruginosa (10%)^† Acinetobacter baumannii (60%)^† K. pneumoniae (15%)^†	43% strains from CAUTI^† 49% strains from VAP^† 46% strains from CAUTI^†	5% strains from SSI^† 4% strains from SSI^† 13% strains from VAP^†	[165]
TEST study (2004–2005)^¶	USA	76 centers		Acinetobacter calcoaceticus-baumannii (29.3%) Enterobacter spp. (8.2%) E. coli (6.2%) K. pneumoniae (10.5%)	ICU 31.0%	Non-ICU 25.8%	[167]
Canada (2005–2006)^#	Canada	19 ICUs	P. aeruginosa 10.0%	P. aeruginosa (12.6%)			[11]

^†In the EARSS study, for Escherichia coli and Klebsiella pneumoniae multidrug resistance (MDR) was defined as resistance to fluoroquinolones, third-generation cephalosporins and aminoglycosides, irrespective of aminopenicillin susceptibility; for Pseudomonas aeruginosa MDR was defined as resistance to ≥three of the following: piparacillin ± tazobactam, ceftazidime, carbapenems, fluoroquinolones or aminoglycosides.
^‡In the NHSN study, for P. aeruginosa and K. pneumoniae, MDR was defined as resistance to ≥three of the following: penicillins, cephalosporins, aminoglycosides, fluoroquinolones and carbapenems; for Acinetobacter baumannii, MDR was defined as resistance to ≥three of the following: penicillins, cephalosporins, aminoglycosides, fluoroquinolones, carbapenems and sulbactam.
^§Pathogens responsible for hospital-acquired infections.
^¶In the TEST study, MDR was defined as resistance to ≥three of the following: penicillins ± β-lactamase inhibitors, cephalosporins, aminoglycosides, fluoroquinolones, tetracyclines, carbapenems and glycylcyclines. Tigecycline, ampicillin, amoxicillin–clavulanate not included for A. baumannii.
^#In the Canada study, MDR was defined as resistance to ≥three of the following: cefepime, piperacillin–tazobactam, meropenem, amikacin or gentamicin and piperacillin.
EARSS: European Antimicrobial Resistance Surveillance System; CAUTI: Catheter-associated urinary tract infection; ICU: Intensive care unit; MDR: Multidrug resistant; NHSN: National Healthcare Safety Network; TEST: Tigecycline Evaluation and Surveillance Trial; VAP: Ventilator-associated pneumonia.

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Surveillance and Management of Multidrug-resistant Microorganisms

Surveillance & Infection Control

Routine Clinical Culture Surveillance

Active Surveillance Culture

Target Surveillance

Sampling & MDRO Detection

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