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Recently, De Bus [ 48 ] et al. Interestingly, Carlier et al. Combination antimicrobial therapy exploits the synergistic effect of some antibiotic groupings in addition to broadening the spectrum of activity against a suspected pathogen to ensure adequate coverage. The synergistic effect of combination therapy has been shown to be beneficial in vivo in invasive pneumococcal disease and toxic shock syndrome. Randomized controlled trials RCTs , on the other hand, have failed to demonstrate a mortality benefit with B-lactam and aminoglycoside combinations, but renal damage was more frequent [ 50 ].

However, a survival benefit when using combination treatment for infections caused by multidrug-resistant Gram-negative bacteria is questionable [ 53 — 55 ]. As almost all these data originate from observational studies, the need for RCTs is clear. On the one hand, the critically ill patient has a higher than normal volume of distribution, impaired renal and hepatic clearance, altered plasma protein content and they also tend to be elderly with significant comorbidities.


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On the other hand, there is growing evidence that in selected patient populations renal clearance is actually augmented, which can lead to inadequate plasma concentrations for some of the important antibiotic groups like carbapenems, beta-lactams and cephalosporins. In patients with multiorgan failure and renal replacement therapy, residual diuresis, type of membrane and body weight should be considered for beta-lactam dose titration [ 57 , 58 ]. Another frequently used drug class to treat MDROs are the aminoglycosides.

Recent studies have highlighted the need for dose adjustment in critically ill patients. De Montmollin et al. This suggests the need for dose optimization based on creatinine clearance, total body weight and positive h fluid balance in order to reach adequate therapeutic targets [ 60 , 61 ]. Until drug assays are routinely available, a personalized approach to dosing should be considered for each patient based on local AMS. Because of the increasing prevalence of Gram-negative MDROs worldwide, previously discarded antibiotics are being re-evaluated.

Recent data suggest that the current dosage regimens of colistin are suboptimal in many critically ill patients [ 62 ]. To optimize the plasma level the administration of a loading dose has been proposed [ 63 ]. Infection control teams play a definitive role in antibiotic AMS programs by assisting with prompt detection of MDROs and promoting compliance with standard and transmission-based precautions.

They also facilitate the use of other infection prevention strategies, such as implementing care bundles to prevent hospital-acquired infections, ensuring hand hygiene compliance and educating not only staff and patients, but also visitors about infection prevention topics. Therefore, infection control teams play a crucial part in AMS. This initiative has three key aims: It is frequently treated with vancomycin, linezolid, daptomycin, ceftaroline or tigecycline.

Daptomycin is a good alternative, but not licensed for pneumonia as the drug is inactivated by surfactant [ 68 ]. As a new alternative for MRSA, the novel tedizolid was found to be non-inferior to linezolid in early clinical response for an acute bacterial skin and skin structure infections ABSSSI [ 69 ]. Antimicrobial susceptibility testing revealed that the MIC 90 of tedizolid was 0.

Enterococci are Gram-positive facultative anaerobes that live as commensals in the gastrointestinal tract, but they are not as virulent as S. Limiting the use of such agents may help decrease the spread of VRE. It is important to highlight that there is a relatively high rate of VRE not susceptible to linezolid observed in ICU patients [ 31 ].

New agents like dalbavancin, oritavancin and telavancin seem promising [ 74 ]. Treatment of carbapenem-resistant Enterobacteriaceae spp. Aminoglycosides, polymyxins, tigecycline, fosfomycin and occasionally fluoroquinolones form the backbone of treatment. Recently, the US Food and Drug Administration FDA issued a warning regarding the risk of increased mortality in patients treated with tigecycline, observed in the clinical trials [ 75 ]. An observational study by Montravers et al. Combination antimicrobial therapy has been shown to be superior in terms of cure rate when compared to monotherapy in multiple observational studies [ 77 ].

Emerging treatment options include ceftazidime—avibactam. Ceftazidime—avibactam was approved by the Food and Drug Administration FDA in for the treatment of complicated intra-abdominal infections and complicated UTIs [ 79 ]. A newly released fifth-generation cephalosporin ceftolozane combined with a beta-lactamase inhibitor tazobactam has potent activity against P.

In mechanically ventilated patients, the use of ITA for prevention or treatment of VAP has shown less toxicity as compared to systemic formulations [ 81 ]. A recent international survey reported that intra-tracheal antibiotic administration is a common therapeutic modality in ICUs; however, practice varies widely [ 82 ].

Of greatest significance is the production of beta-lactamases and aminoglycoside-modifying enzymes [ 18 ]. Combination therapy including a polymyxin has commonly been the mainstay of treatment for Acinetobacter spp. However, a recent paper has highlighted the risk of nephrotoxicity when colistin and vancomycin are used in combination with no benefit to clinical outcome [ 83 ]. As the vast majority of the antibiotic treatment is short term, many companies struggle to generate profit from the sales of anti-infective agents.

The majority of products being approved are second-, third- or fourth-generation antibiotics, meaning they are follow-up compounds, without a novel mechanism of action. In addition to this, many novel antibiotics have struggled to reach the market due to difficulties in demonstrating efficacy or unacceptable side effects.

Furthermore, for licensing purposes, new antibacterials must demonstrate non-inferiority against already marketed drugs. Finally, healthcare authorities are frequently reluctant to pay the high costs associated with clinical trials, hindering the development of novel antimicrobial agents. As a result of the declining effectiveness of existing antibiotics and the steady decrease in new antibiotic development, alternative approaches to antibiotic therapy are appearing including immunotherapy and the use of bacteriophages.

Immunotherapy initiated at the outset of an antibiotic course has the potential to result in beneficial effects; however, use is frequently limited by a narrow spectrum of action against specific target antigens. Another attractive approach to address the critical need for new antibiotics is the engineering of various components of the immune response such as monoclonal antibodies.

For instance, a randomized, placebo-controlled phase I study found that IC43 recombinant outer membrane protein-based vaccine against P. Another cutting edge approach is the use of bacteriophages or phages. These are bacterial viruses that invade bacterial cells, disrupt metabolism, cause bacteriolysis and are highly specific and effective [ 87 ].

Infections with MDROs are already a threat in a number of countries. These infections are associated with an increased consumption of healthcare resources manifested by a prolonged hospital stay and an augmented mortality. In order to reduce antibiotic resistance rates, a strategy minimizing the use of broad-spectrum antibiotics and ensuring prompt antibiotic administration should be adopted. The development of rapid diagnostic tests will help by both shortening duration of therapy and allowing prompt-targeted therapy.

The implementation of more accessible therapeutic drug monitoring will help to optimize drug administration and enable a more personalized approach to treatment. Some points require further investigation in clinical trials, such as the heterogeneity of patients admitted to ICU and the need for new drug development.

Since late s, no new class of antibiotics has been discovered that is available for treatment of systemic bacterial infections. This discovery void is still impacting the therapeutic options to treat infections caused by multidrug- or extensively drug-resistant bacteria. Recent findings regarding existing antibiotics combinations should also be mentioned. Certainly, it would need a deep remodel of the current drug regulation for new antibacterials and to adequately stimulate investment by the industry for new antimicrobial developments and ultimately to non-antibiotic approaches.

In summary, a steady resistance increase particularly to Gram-negatives, rising minimum inhibitory concentration in methicillin-resistant Staphylococcus aureus and the spread of multiresistant strains of pathogens in patients without classic risk factors in the ICU are key areas to delineate in future studies. Guidelines and recommendations will need to incorporate the ecology of the hospital setting and the severity of patient illness to provide a personalized patient approach to antimicrobial treatment in the future.

All authors read and approved the final manuscript. National Center for Biotechnology Information , U. Journal List Ann Intensive Care v. Published online Oct 6. Received Jun 20; Accepted Sep This article has been cited by other articles in PMC. Abstract Over the last several decades, antibacterial drug use has become widespread with their misuse being an ever-increasing phenomenon. Epidemiology of highly resistant bacteria A number of studies have been performed to assess the burden of infection in critical illness.

Open in a separate window. Rapid methods to diagnose multidrug resistance One of the key aspects of avoiding the spread of resistant strains is early detection with the use rapid diagnostic tests. Contributor Information Gabor Zilahi, Email: The antimicrobial resistance crisis: Resistance patterns and outcomes in intensive care unit ICU -acquired pneumonia. Assessment of risk factors for multi-drug resistant organisms to guide empiric antibiotic selection in long term care: J Am Med Dir Assoc.

Off-label abuse of antibiotics by bacteria. Accessed 20 Sept Assessment of the worldwide burden of critical illness: International study of the prevalence and outcomes of infection in intensive care units. Antibiotic resistance in China—a major future challenge. Non prescribed sale of antibiotics in Riyadh, Saudi Arabia: Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: Bad bugs, no drugs: Non-susceptibility trends among Enterobacteriaceae from bacteraemias in the UK and Ireland, Incidence of multidrug-resistant Pseudomonas spp. J Glob Infect Dis.

Bonomo RA, Szabo D.

Study Finds High Rate of Infection at Hospital Intensive Care Units

Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. The antibiotic resistance crisis: Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: Nosocomial bloodstream infections in Brazilian hospitals: The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Global spread of carbapenemase-producing Enterobacteriaceae. Survival in patients with nosocomial pneumonia: Pneumonia caused by oxacillin-resistant Staphylococcus aureus treated with glycopeptides. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.

Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens. Potentially resistant microorganisms in intubated patients with hospital-acquired pneumonia: Management of adults with hospital-acquired and ventilator-associated pneumonia: The role of intestinal colonization with gram-negative bacteria as a source for intensive care unit-acquired bacteremia.

Value of lower respiratory tract surveillance cultures to predict bacterial pathogens in ventilator-associated pneumonia: Evaluation of rapid screening and pre-emptive contact isolation for detecting and controlling methicillin-resistant Staphylococcus aureus in critical care: Rapid detection of polymyxin resistance in Enterobacteriaceae. Quality of care is improved by rapid short incubation MALDI-ToF identification from blood cultures as measured by reduced length of stay and patient outcomes as part of a multi-disciplinary approach to bacteremia in pediatric patients.

Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria. Guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis Oxford J. Impact of antimicrobial stewardship in critical care: Combatting resistance in intensive care: Colonization status and appropriate antibiotic therapy for nosocomial bacteremia caused by antibiotic-resistant gram-negative bacteria in an intensive care unit.

Infect Control Hosp Epidemiol. Accordingly, MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories; XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories and PDR was defined as non-susceptibility to all agents in all antimicrobial categories.

Applying the suggested definitions could make data from relevant studies comparable allowing therefore, the extraction of reliable conclusions. In the present review, since we included studies between and , the definitions used by different authors of the included studies vary. Some of them define the resistance as resistance only to carbapenems while others to several classes of antimicrobial agents. Twenty four studies were identified during the predefined period according to the search criteria[ 9 , 30 - 56 ].

Nine out of the twenty three studies had a retrospective study design, ten were prospective and in two studies the type was not reported. Two studies were part of secondary analysis of large prospective studies.

What’s new in multidrug-resistant pathogens in the ICU?

Several differences regarding definitions, design, control group selection and the sample size were observed. The causative pathogen was only one in thirteen studies P. The remaining studies examined the impact of all three important gram-negative pathogens, some of them involving also other Enterobacteriacae such as E. Four studies have focused exclusively on carbapenem-resistant compared to carbapenem-susceptible strains of P. The site of infection differed among studies. Eight studies examined bloodstream infections; four studies examined respiratory infections related to mechanical ventilation, one study enrolled patients with pneumonia or bloodstream infection and nine studies enrolled patients affected by infections of any origin.

Finally, in two studies colonization with or without infection was examined. One of them is the recent large, two-center prospective cohort study, which quantified the effects of carbapanemase-producing Enterobacteriaceae carriage on patient outcome in the ICU MOSAR study [ 30 ]. Although this study did not explore any association with infection, being focused on colonization, it was included because colonization precedes infection in most instances and, therefore, it represents an indirect marker of a patient being at risk of a possible poorer outcome.

Concerning the control group selection, in nine studies both cases and controls came from the pool of patients presenting an infection due to a MDR pathogen and survivors were compared to non-survivors. In eight studies patients infected with a MDR strain were compared to those with a susceptible one or to those without any infection. Comparative data on the appropriateness of empirical antibiotic treatment were provided by only seven[ 48 , 50 , 51 , 52 , 54 , 55 ] out of twenty-four studies.

As for the main target of this review, i. In the remaining studies a positive result was noted, though with different endpoints.

What’s new in multidrug-resistant pathogens in the ICU?

Among the latter, the hospital-associated mortality was affected in two studies while in another study both ICU and hospital mortality were influenced. In two other studies, the increased mortality was considered as the indirect consequence of the inappropriate therapy. Finally, in the study by Dautzenberg et al[ 30 ] patients colonized with carbapenemase-producing Enterobacteriaceae had a 1.

Additionally, 3 review articles summarizing the published data on this issue were identified[ 31 - 33 ] as well as another one presenting the clinical consequences of specific MDR pathogen, namely P. The collective findings of these studies suggested that gram-negative bacterial resistance increases the burden in the ICU in terms of mortality, length of stay and charges. Of note, associations between gram-negative resistance and mortality or prolonged length of stay sometimes disappeared in multivariate analyses after adjusting for confounding factors. The clinical consequences of the common MDR gram-negative bacilli on the critically ill patients have been the subject of examination in a number of studies presented in this review.

Several studies found a significant impact of antibiotic resistance on mortality whereas others did not show such impact. However, as shown in Table 1 , there was a considerable heterogeneity of published studies with respect to study design, definitions and outcomes measured. As a result, some confusion with regard to the actual antibiotic resistance impact on mortality from gram-negative infections is unavoidable. Assessing the contribution of infections caused by antimicrobial resistant pathogens to an adverse clinical outcome in ICU patients is difficult, given the confounding created by crucial factors such as the illness severity, co-morbidities, infection site, treatment strategy and others[ 9 , 57 ].

Large, well-conducted epidemiological studies, focusing on the association between gram-negative bacterial resistance to antimicrobial agents and mortality in the ICU setting are limited in the currently available literature. Most of the studies identified suffer from a number of limitations. Firstly, nine studies were retrospective and, therefore, prone to several forms of potential biases.

Background

As a result, according to in vitro susceptibilities some patients would have been classified into the opposite category or vice versa. Thirdly, different outcome definitions could have also influenced the results. For example, some studies assess the overall ICU mortality, while others the in-hospital or the attributable mortality[ 57 ]. Finally, the small sample size of cases in some studies was a restricting factor for the detection of any significant difference.

Important methodologic issues addressing the choice of reference group might influence the conduct and the results of studies evaluating the relationship between acquisition of antimicrobial-resistant organisms and outcome, as discussed in detail elsewhere[ 57 - 59 ].

Briefly, instead of the standard case-control method, a case-case-control study design has been proposed with two separate case-control analyses to overcome limitations of the conventional studies assessing the effect of hospital or ICU-acquired infections by a particular pathogen. A complete analysis might include two groups of case patients; those infected with resistant pathogens and those with susceptible ones, compared with the control group, i.

To our knowledge, only few studies have included double-case patients in similar efforts and none of the studies that have been included in the present review. In several studies all patients infected with antimicrobial resistant gram-negative pathogens are analyzed together. This is due, in part, to the small size of studies; insufficient numbers of the patients included do not allow stratification. However, certain types of infection as pneumonia or peritonitis may carry greater mortality than other infection types[ 35 , 60 , 61 ].

Antimicrobial resistance

Indeed, among bacteremic patients, high-risk source of bacteremia including the lung, abdominal or unknown sources were more prevalent among nonsurvivors[ 35 , 60 ]. Whether the association of antimicrobial resistance with an increased risk of death, found in some studies, is exclusively related to the risk of receiving inappropriate initial empirical antimicrobial treatment, or it is also related to a higher virulence of pathogens exhibiting higher MICs to certain antimicrobials is not clear[ 62 ].

Probably, this question cannot be answered by such type of clinical studies where different gram-negative bacteria of nonsimilar virulence are usually examined together[ 60 ]. Theoretically, an increased intrinsic virulence of resistant gram-negative strains could explain, at least in part, an adverse clinical outcome. However, to date, no studies have demonstrated such an association; thus, in general, antibiotic resistance is not believed to be itself a virulence factor as compared to similar susceptible species[ 57 ]. Treatment factors may contribute to adverse outcomes in patients infected with a resistant pathogen[ 57 ].

The importance of an early and appropriate antimicrobial treatment and its favorable impact on the clinical outcome is well known[ 60 , 65 ]. Inappropriate empirical antimicrobial therapy is one of the major confounders in studies aiming to assess the impact of MDR to mortality[ 32 ]. This issue was not assessed in sixteen out of the twenty-three studies included in the present review. In most studies which addressed this issue, the presence of MDR pathogens was an important factor for receiving inappropriate empiric treatment. For example, in a recent study[ 51 ], the presence of carbapenem-resistant A.

Failure to receive appropriate therapy further increases the risk of hospital mortality. In the EUROBACT study[ 48 ], even after controlling for adequacy of antimicrobial treatment, antimicrobial resistance, along with the timing to adequate treatment, was an independent predictor of d mortality.

To our knowledge, this is the first review that focuses exclusively on studies conducted in the critical care setting. Studies examining the impact of antimicrobial resistance on the outcome of hospitalized patients in general either in the ICU or in the hospital wards have also shown diverse results[ 66 ]. As a case in point, a prospective observational study, evaluating the impact of VIM production on the outcome of patients with K. However, after adjustment for inappropriate therapy, the effect of carbapenem resistance on outcome was nonsignificant.

Therefore, the higher mortality was probably mediated by the failure to provide effective antimicrobial therapy[ 67 ]. Finally, it should be noted that there is little data assessing whether being admitted to an ICU with high levels of antimicrobial resistance is associated with a worse outcome than being admitted to an ICU with low rates of resistance.

A recent publication using data from the large, international EPIC II study on infections in ICUs[ 1 ] showed that being hospitalized in an ICU in a region with high levels of antimicrobial resistance is not associated per se with a worse outcome[ 68 ]. In this study the selection of countries with high levels of antimicrobial resistance rates was made using reported MRSA rates. According to the authors this could be considered as a selection bias because general resistance rates may have been different.

Although mortality associated with gram-negative infections is high, data from the available literature do not confirm that there is a direct association between antimicrobial resistance and mortality in ICU patients. Appropriate antimicrobial administration remains of paramount importance.

These data support the need of further studies to elucidate the real impact of infections caused by resistant bacteria in ICU patients. Qiu S L- Editor: Academic Rules and Norms of This Article. Citation of this article. Paramythiotou E, Routsi C. Association between infections caused by multidrug-resistant gram-negative bacteria and mortality in critically ill patients. Corresponding Author of This Article. Publishing Process of This Article. Research Domain of This Article. Article-Type of This Article. Open-Access Policy of This Article. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers.

Number of Hits and Downloads for This Article. Total Article Views All Articles published online. Times Cited of This Article. Journal Information of This Article. Published by Baishideng Publishing Group Inc. World J Crit Care Med.

What is antimicrobial resistance?

Both authors designed the review, conducted the literature review, wrote the article, prepared the table and made critical revisions related to the intellectual content. October 3, Peer-review started: October 15, First decision: November 30, Revised: December 30, Accepted: March 7, Article in press: March 9, Published online: Critically ill patients , Infections , Multidrug resistance , Gram-negative pathogens , Mortality. Resistance to at least 3 of the following: Pseudomonas acting beta-lactams, carbapenems, aminoglycosides, and quinolones MDR P. Blood stream infection; VAP: Ventilator associated pneumonia; MDR: Carbapenem — producing enterobactaeriacae; ESBL: Extended spectrum beta lactamases; HAP: Hospital acquired pneumonia; ECDC: Centers for Disease Control and Prevention.

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