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Hospital-Acquired Infections Due To Gram-Negative Bacteria: Review Article
Hospital-Acquired Infections Due To Gram-Negative Bacteria: Review Article
review article
Current Concepts
H
From the Division of Infectious Diseases, ospital-acquired infections are a major challenge to patient
Massachusetts General Hospital (A.Y.P., safety. It is estimated that in 2002, a total of 1.7 million hospital-acquired
D.C.H.), the Division of Infectious Dis-
ease, Beth Israel Deaconess Medical Cen- infections occurred (4.5 per 100 admissions),1 and almost 99,000 deaths
ter (A.Y.P.), and Harvard Medical School resulted from or were associated with a hospital-acquired infection,1 making hos-
(A.Y.P., D.C.H.) — all in Boston; and the pital-acquired infections the sixth leading cause of death in the United States2;
Department of Infectious Diseases, Alfred
Hospital, and the Department of Micro- similar data have been reported from Europe.3 The estimated costs to the U.S.
biology, Monash University (A.Y.P.) — health care budget are $5 billion to $10 billion annually.4 Approximately one third
both in Melbourne, Australia. Address or more of hospital-acquired infections are preventable.5
reprint requests to Dr. Peleg at the Divi-
sion of Infectious Disease, Beth Israel Infections caused by gram-negative bacteria have features that are of particular
Deaconess Medical Center, 110 Francis concern. These organisms are highly efficient at up-regulating or acquiring genes
St., Boston, MA 02215, or at apeleg@ that code for mechanisms of antibiotic drug resistance, especially in the presence
bidmc.harvard.edu.
of antibiotic selection pressure. Furthermore, they have available to them a pleth-
N Engl J Med 2010;362:1804-13. ora of resistance mechanisms, often using multiple mechanisms against the same
Copyright © 2010 Massachusetts Medical Society.
antibiotic or using a single mechanism to affect multiple antibiotics (Fig. 1). Com-
pounding the problem of antimicrobial-drug resistance is the immediate threat of
a reduction in the discovery and development of new antibiotics.6 Several factors
have contributed to this decline, including the increasing challenges of screening
for new compounds, the high capital costs and long time required for drug devel-
opment, the growing complexity of designing and performing definitive clinical
trials, and the concern about reduced drug longevity due to the emergence of re-
sistance. As a consequence, a perfect storm has been created with regard to these
infections: increasing drug resistance in the absence of new drug development.
T y pe s of Infec t ions
Ventilator-Associated Pneumonia Central Venous Catheter–Associated Bloodstream Infection Catheter-Associated Urinary Tract Infection
Follow effective hand-hygiene procedures Before insertion, educate health care personnel involved Implement written catheter-care protocols, including guide-
Educate health care personnel who care for patients on with central venous catheterization about prevention lines on catheter insertion
ventilators about the local epidemiology of VAP, risk of infection Insert urinary catheter only when necessary and leave in only
factors, and outcomes Use a catheter-insertion checklist to ensure adherence to as long as indicated
Implement policies and practices for disinfection, steril- infection-prevention practices Consider other methods for management, including
ization, and maintenance of respiratory equipment Follow hand-hygiene procedures before catheter insertion or condom catheters or in-and-out catheterization, as
according to evidence-based standards29 manipulation appropriate
Provide regular antiseptic oral care according to product Avoid use of the femoral vein in adults Maintain a sterile, continuously closed drainage system
The
guidelines Use an all-inclusive catheter kit and maximal sterile-barrier Do not disconnect the catheter and drainage tube unless the
Ensure that patient is in a semirecumbent position, precautions during catheter insertion catheter must be irrigated
unless contraindicated Use a chlorhexidine-based antiseptic for skin preparation in Maintain unobstructed urine flow
Use noninvasive ventilation in appropriately selected patients >2 mo of age Empty the collecting bag regularly, using a separate collect-
patients with respiratory failure† After insertion, disinfect catheter hubs, needleless connec- ing container for each patient, and take care not to let
Conduct active surveillance for VAP and institute preven- tors, and injection ports before accessing the catheter; the drainage spigot touch the collecting container
tive measures remove nonessential catheters Cleaning the meatal area with antiseptic solutions is unnec-
In hospitals with suboptimal infection control using For nontunneled catheters in adults, change transparent essary; routine hygiene is appropriate
basic practices, use an endotracheal tube with in-line dressings and perform site care with a chlorhexidine Do not routinely use silver-coated or other antibacterial
and subglottic suctioning for all eligible patients antiseptic every 5 to 7 days (every 2 days for gauze catheters
dressings), or more frequently if dressing is soiled, Do not screen for asymptomatic bacteriuria in catheterized
loose, or damp‡ patients
Replace administration sets not used for blood products or Avoid catheter irrigation if possible
lipids at intervals not longer than 96 hr Do not use systemic antibacterial agents routinely as
n e w e ng l a n d j o u r na l
sertion sites
Perform surveillance for bloodstream infection
In hospitals with suboptimal infection control using basic
* These guidelines have been adapted from recent guidelines published by professional societies and organizations committed to improving patient safety and quality of care.5 We report
Downloaded from nejm.org on June 10, 2018. For personal use only. No other uses without permission.
only those strategies with grade I quality of evidence (i.e., from one or more properly randomized, controlled trials) or grade II quality of evidence (i.e., from one or more well-designed,
nonrandomized clinical trials). ICU denotes intensive care unit, and VAP ventilator-associated pneumonia.
† This strategy is considered grade I in the American Thoracic Society guidelines15 but grade III in the guidelines published more recently by the collaborative group of societies and orga-
nizations.5
‡ Central venous or arterial catheters should not be routinely replaced.
current concepts
Table 4. Recommended Empirical Therapy to Cover Gram-Negative Organisms That Cause Hospital-Acquired Infections.*
* Therapy for staphylococcus or legionella species, which may also require initial empirical coverage, is not described in this article. These
recommendations are based on the treatment of adults with normal renal function.15 HCAP denotes health care–associated pneumonia,
and VAP ventilator-associated pneumonia.
† These recommendations apply when there are no risk factors for a multidrug-resistant pathogen.
‡ Aztreonam is an alternative for patients who are allergic to β-lactams except when allergy is to ceftazidime, in which case a cross-reaction
with aztreonam can occur.
known as sequence type 131.41 Unfortunately, the The polymyxins (colistin and polymyxin B) are
plasmids carrying these ESBL genes often carry an older antibiotic class that has seen a resurgence
resistance determinants targeting fluoroquino- of use in recent years and deserves mention. Dis-
lones as well. To reduce the morbidity associated covered in the late 1940s, polymyxins have
with hospital-acquired urinary tract infections and specificity for lipopolysaccharides on the outer
prevent the dissemination of drug-resistant gram- cell membrane of gram-negative bacteria. Organ-
negative organisms, adherence to evidence-based isms inherently resistant to polymyxins include
prevention guidelines is strongly recommended serratia, proteus, Stenotrophomonas maltophilia, Burk
(Table 3). Until further data are available, we do holderia cepacia, and flavobacterium. Their use was
not recommend the use of antibiotic-impregnat- initially hampered by nephrotoxicity and then
ed or silver-coated urinary catheters. rapidly declined with the advent of newer antibiot-
ics. However, this class of antibiotic has been
Treatment Options reinstated as a key therapeutic option for carba
The importance of knowing local antimicrobial penem-resistant organisms, particularly P. aerugi
susceptibility to direct empirical antibiotic therapy nosa, A. baumannii, and carbapenemase-producing
cannot be overemphasized. Recommendations re- Enterobacteriaceae (Table 4). It is still a challenge
garding empirical therapy for the hospital-acquired to determine the appropriate dosage, since the
infections discussed here and definitive therapy polymyxins were never subjected to the rigorous
for infections caused by drug-resistant gram-neg- drug-development process we now expect for new
ative organisms are presented in Tables 4 and 5, antimicrobial agents.42 Despite in vitro data sug-
respectively. gesting that colistin’s antimicrobial activity is de-
Table 5. Recommended Definitive Therapy for Serious Infections, Including VAP and Bloodstream Infections, Caused by Drug-Resistant
Gram-Negative Bacteria.*
* The bacteria listed here are often resistant to fluoroquinolones and aminoglycosides; however, these agents can be used if the bacteria are
susceptible to them.
† This regimen is based on the current parenteral formulation in the United States (Coly-Mycin M Parenteral [Parkdale Pharmaceuticals]).
‡ This regimen would not be recommended for bloodstream infection, owing to low serum drug levels.
§ Use of these antibiotics is based on in vitro data and animal models and on clinical case reports and studies of small series of patients.
pendent on the peak blood concentration and the treatment of ventilator-associated pneumonia
that its effectiveness could be enhanced by once- in a randomized, double-blind trial.45 Given its
daily administration, selection for colistin-resistant rapid movement from the bloodstream into tis-
mutants, regrowth, and increased toxicity in an sues after administration, peak tigecycline se-
animal model have been reported with this dos- rum levels are low (0.63 μg per milliliter) with
ing frequency.43,44 Therefore, two to four divided standard dosing (a 100-mg loading dose followed
doses per day are currently recommended. by 50 mg every 12 hours). Thus, its use for blood-
Recently licensed agents with activity against stream infection due to organisms with a mini-
gram-negative bacteria include tigecycline, which mum inhibitory concentration of 1 μg per millili-
is a parenteral glycylcycline antibiotic, and dori ter or more also remains limited and requires
penem, which is a parenteral carbapenem that caution.46
appears to have activity similar to that of mero- There is still much debate about the role of
penem. Tigecycline, a minocycline derivative with combination therapy versus monotherapy for gram-
a broader spectrum of activity, is approved for negative infections. The results of earlier studies
the treatment of complicated skin, soft-tissue, and meta-analyses are difficult to interpret, but
and intraabdominal infections. In vitro activity more recent evidence is starting to clarify this is-
of tigecycline against a range of troublesome sue. For empirical treatment, combination therapy
gram-negative organisms, including ESBL-produc- improves the likelihood that a drug with in vitro
ing and carbapenemase-producing Enterobac activity against the suspected organism is being
teriaceae, acinetobacter species, and Stenotroph administered (often defined as appropriate ther-
omonas maltophilia, has been reported (P. aeruginosa apy).47 This effect is more pronounced in institu-
and proteus species are intrinsically resistant to tions with a greater prevalence of multidrug-resis-
the drug). Clinical experience with treating these tant organisms. The antibiotics selected for the
multidrug-resistant bacteria remains limited, how- combination, however, need to be tailored to lo-
ever. The urine concentrations of tigecycline are cal susceptibility data, because the benefits can
low, so it is not suitable for the treatment of be lost in the presence of high cross-resistance,
urinary tract infections. Furthermore, it was such as to fluoroquinolones and third-generation
shown to be inferior to imipenem–cilastatin for cephalosporins. When the antibiotic susceptibili-
ties of the infecting organism are known, mono- emergence of resistance has been prevented in in
therapy and combination therapy have similar vitro models.50 Clinical data for extended-infu-
outcomes, including rates of emergence of resis- sion β-lactams remain sparse, with some retro-
tance and recurrence of infection.48 Exceptions spective studies showing improved outcomes, but
include monotherapy with aminoglycosides for results of prospective trials are less consistent.
P. aeruginosa, which is inferior to any other mono- Nebulized antibiotics such as tobramycin, amika-
therapy regimen, and possibly monotherapy for cin, and colistimethate sodium attempt to mini-
patients who have cystic fibrosis. Therefore, we mize systemic toxicity and improve drug delivery
recommend institution-tailored combination at the site of infection. For severe or refractory
therapy for the empirical treatment of serious cases of pneumonia or those caused by highly
hospital-acquired gram-negative infections, fol- drug-resistant organisms, nebulized antibiotics
lowed by de-escalation to monotherapy once given as an adjunct to systemic antibiotics should
susceptibilities have been determined. Although be thought of as a therapeutic option (Table 5).
clinicians have historically preferred dual ther- Respiratory toxicity such as bronchospasm has
apy for serious pseudomonal infections, the data been reported and may be diminished or pre-
support single-agent therapy as long as an active vented by the administration of bronchodilators
β-lactam can be chosen. before dosing. Moreover, a recent Food and Drug
Other strategies currently used to treat multi- Administration alert informed physicians about
drug-resistant gram-negative infections include the importance of using aerosolized colisti
prolonged infusion (3 to 4 hours) or continuous methate sodium soon after preparation to pre-
infusion of β-lactams and aerosolized antibiotics vent lung toxicity from the active colistin form.
for the treatment of ventilator-associated pneu- Prospective studies should be focused on deter-
monia. These strategies are particularly useful for mining the clinical benefits and safety of nebu-
infections caused by multidrug-resistant organ- lized antibiotics and extended-infusion β-lactams,
isms (Table 5). For example, according to pharma- especially for infections caused by nonfermenting
cokinetic and pharmacodynamic data in hospital- gram-negative bacteria.
ized patients, prolonging the infusion of β-lactams Dr. Peleg reports receiving consulting fees from Abbott Mo-
such as cefepime, piperacillin–tazobactam, and lecular and Ortho–McNeil–Janssen; and Dr. Hooper, serving on
scientific advisory boards for Pfizer and Novexel, receiving con-
the carbapenems significantly improves bacteri- sulting fees from Cubist, Johnson & Johnson, and Mutabilis, and
cidal target attainment (i.e., time above the mini- receiving lecture fees from Daiichi–Sankyo. No other conflict of
mum inhibitory concentration for at least 50% for interest relevant to this article was reported. Disclosure forms
provided by the authors are available with the full text of this
cefepime and piperacillin–tazobactam and 40% article at NEJM.org.
for the carbapenems), especially for organisms We thank Howard Gold and David Paterson for their critical
with an elevated minimum inhibitory concentra- review of an earlier version of the manuscript.
tion (8 to 16 μg per milliliter).49 Furthermore, the
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