Matteo BassettiJan J. De WaelePhilippe EggimannJose Garnacho-MonteroGunnar KahlmeterFrancesco MenichettiDavid P. NicolauJose Arturo PaivaMario TumbarelloTobias WelteMark WilcoxJean Ralph ZaharGaryphallia Poulakou

Preventive and therapeutic strategiesin critically ill patients with highly resistantbacteria

Received: 20 January 2015Accepted: 24 February 2015Published online: 20 March 2015� Springer-Verlag Berlin Heidelberg andESICM 2015

Electronic supplementary materialThe online version of this article(doi:10.1007/s00134-015-3719-z) containssupplementary material, which is availableto authorized users.

M. BassettiInfectious Diseases Division, Santa MariaMisericordia University Hospital, Udine,Italy

J. J. De WaeleDepartment of Critical Care Medicine,Ghent University Hospital, Ghent, Belgium

P. EggimannAdult Critical Care Medicine and BurnUnit, Centre Hospitalier UniversitaireVaudois (CHUV), Lausanne, Switzerland

J. Garnacho-MonteroCritical Care Unit, Virgen del RocioUniversity Hospital, Seville, Spain

G. KahlmeterClinical Microbiology, Central Hopsital,Vaxjo, Sweden

F. MenichettiInfectious Diseases Unit, Nuovo OspedaleS. Chiara, Pisa, Italy

D. P. NicolauCenter for Anti-Infective Research andDevelopment, Hartford Hospital, Hartford,CT, USA

J. A. PaivaCentro Hospitalar Sao Joao, Faculdade deMedicina, University of Porto, Porto,Portugal

M. TumbarelloInstitute of Infectious Diseases, CatholicUniversity of the Sacred Heart, A. GemelliHospital, Rome, Italy

T. WelteDepartment of Pulmonary Medicine,Hannover Medical School, Hannover,Germany

M. WilcoxMicrobiology, Leeds Teaching Hospitalsand University of Leeds, Leeds, UK

J. R. ZaharUnite de prevention et de lutte contre lesinfections nosocomiales, Universited’Angers, Centre hospitalo-universitaired’Angers, Angers, France

G. Poulakou4th Department of Internal Medicine,Athens University School of Medicine,Attikon University General Hospital,Athens, Greece

M. Bassetti ())Clinica Malattie Infettive, AziendaOspedaliera Universitaria Santa Maria dellaMisericordia, Piazzale Santa Maria dellaMisericordia 15, 33100 Udine, Italye-mail: mattba@tin.itTel.: 39 0432 559355

Abstract The antibiotic pipelinecontinues to diminish and the ma-jority of the public remains unaware

of this critical situation. The cause ofthe decline of antibiotic developmentis multifactorial and currently mostICUs are confronted with the chal-lenge of multidrug-resistantorganisms. Antimicrobial multidrugresistance is expanding all over theworld, with extreme and pandrug re-sistance being increasinglyencountered, especially in healthcare-associated infections in large highlyspecialized hospitals. Antibioticstewardship for critically ill patientstranslated into the implementation ofspecific guidelines, largely promotedby the Surviving Sepsis Campaign,targeted at education to optimizechoice, dosage, and duration of an-tibiotics in order to improve outcomesand reduce the development of resis-tance. Inappropriate antimicrobialtherapy, meaning the selection of anantibiotic to which the causativepathogen is resistant, is a consistentpredictor of poor outcomes in septicpatients. Therefore, pharmacoki-netically/pharmacodynamically opti-mized dosing regimens should begiven to all patients empirically and,once the pathogen and susceptibilityare known, local stewardship prac-tices may be employed on the basis ofclinical response to redefine an ap-propriate regimen for the patient. Thisreview will focus on the mostseverely ill patients, for whom sub-stantial progress in organ supportalong with diagnostic and therapeutic

Intensive Care Med (2015) 41:776–795DOI 10.1007/s00134-015-3719-z REVIEW

strategies markedly increased the riskof nosocomial infections.

Keywords Antibiotic � Bacteria �Resistance � MRSA � Stewardship

Abbreviations

AST Antimicrobialsusceptibility testing

BLBLI b-Lactam/b-lactamaseinhibitors

CDI Clostridiumdifficile infection

CRE Carbapenem-resistantEnterobacteriaceae

ECDC European Center forDiseases Control

ESBL Extended-spectrumb-lactamases

ESBL-PE Extended-spectrumb-lactamase-producingEnterobacteriaceae

EUCAST European Committee onAntimicrobialSusceptibility Testing

FDA Food and DrugAdministration

HAP Hospital-acquiredpneumonia

HCW Healthcare workersICU Intensive care unitIDSA Infectious Diseases

Society of AmericaKPC Klebsiella pneumoniae

carbapenemaseMDR Multidrug-resistant

organisms

MIC Minimum inhibitoryconcentration

MITT Modified intentionto treat

MRSA Methicillin-resistantStaphylococcus aureus

PK/PD Pharmacokinetic/pharmacodynamic

SDD Selective digestivedecontamination

VAP Ventilator-associatedpneumonia

VIM Verona integron-mediatedmetallo-b-lactamase

VRE Vancomycin-resistantenterococci

Introduction

The report of successful treatment of life-threatening infec-tions early in the 1940s opened the ‘‘antibiotic era’’.Stimulated by a widespread use during the Second World Warand by an impressive industrial effort to develop and produceantibiotics, this major progress in the history of medicine isnowadays compromised by the universal spread of antibioticresistance which has largely escaped from hospitals to projectthe human race into the post-antibiotic era [1].

Looking back at this incredible 75-year-long saga, weshould emphasize that antibiotic resistance was describedin parallel with the first antibiotic use and that a directlink between exposure and resistance was recognized inthe late 1940s [2].

This review will focus on the most severely ill patientsfor whom significant progress in organ support as well asdiagnostic and therapeutic strategies markedly increasedthe risk of developing hospital-acquired infections (HAI),and currently most ICUs are confronted with the chal-lenge of multidrug-resistant organisms (MDR) [3].

Epidemiology of highly resistant bacteria worldwidewith a focus on Europe

Antimicrobial multidrug resistance (MDR) is now preva-lent all over the world [4, 5], with extreme drug resistance(XDR) and pandrug resistance (PDR) [6] being encoun-tered increasingly often, especially among HAI occurringin large highly specialized hospitals treating patients.Emergence of antimicrobial resistance is largely attributed

to the indiscriminate and abusive use of antimicrobials insociety and particularly in the healthcare setting and by anincreasing spread of resistance genes between bacteria andof resistant bacteria between people and environments.Even in areas hitherto known for having minor resistanceproblems, 5–10 % of hospitalized patients on a given dayharbored extended-spectrum b-lactamase (ESBL)-produc-ing Enterobacteriaceae in their gut flora, as seen in a recentFrench study conducted in ICU [7].

The number of different resistance mechanisms bywhich microorganisms can become resistant to an agent isincreasing, the variety in resistance genes is increasing,the number of clones within a species which carry resis-tance is increasing, and the number of different speciesharboring resistance genes is increasing. All this leads toan accelerating development of resistance, further en-hanced by the fact that the more resistance genes thereare, the higher the probability that one or more of themwill end up as a so-called successful clone, with excep-tional abilities to spread, infect, and cause disease [8].When this happens, the world faces major ‘‘outbreaks(epidemics) of antimicrobial resistance’’. Sometimesthese are local and occur as outbreaks of Staphylococcusaureus, Escherichia coli, Klebsiella pneumoniae, Acine-tobacter baumannii, Pseudomonas aeruginosa, orEnterococcus faecalis or E. faecium (the latter speciesbeing very difficult to treat when glycopeptide resistant)in highly specialized healthcare settings such as neonatalwards or other ICUs, hematological wards, and transplantunits. With the aforementioned bacteria, major problemsevolved in the USA where outbreaks occurred in trans-plant units on the east coast and in Israel, Greece, andlater Italy. Today smaller or larger outbreaks with

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multidrug-resistant E. coli and K. pneumoniae are seen allover the world. Recently several of these clones also showresistance to last resort agents like colistin making thesituation desperate in some areas, in some hospitals, andfor some patients. Since there is no influx of truly newantimicrobial agents and limited evidence of reversibility[9] of antimicrobial resistance, the future looks grim.Another sign of our desperation is the increasing interestin trying to redevelop old antimicrobials [10].

Microbiological issues: breakpoints, epidemiologicalcut-offs, and other susceptibility and identificationproblems

Methods in clinical microbiology for species identifica-tion and antimicrobial susceptibility testing (AST) haverecently improved dramatically. Consequently, it is todaypossible for the clinical microbiology laboratory to dras-tically improve its turnaround time (the time used by thelaboratory to receive, process, and make available areport).

Time of flight mass spectrometry has brought downthe time required for species identification to 1 h from1 day, and sometimes several days, for both bacteria andfungi. Blood cultures are most often positive within8–20 h from the start of incubation [11]. With the noveltechniques, species identification is feasible directly onthe positive blood culture bottle [12] and within 1 h froma positive blood culture signal. Time wasted on trans-portation of blood culture bottles becomes important.Ideally bottles should be under incubation within 1 h frominoculation; if this time exceeds 4 h it constitutesmalpractice.

AST can be performed using traditional methods forphenotypic antimicrobial susceptibility testing. These arebased on the minimum inhibitory concentration (MIC) ofthe antibiotic and the application of breakpoints tocategorize isolates as susceptible (S), intermediate (I), andresistant (R). AST can also be performed using genotypicmethods, most commonly in the form of direct gene de-tection using polymerase chain reaction methods for thedetection of specific resistance genes, such as the mecAgene encoding for methicillin-resistance in staphylococcior the vanA gene encoding for glycopeptide resistance inenterococci and staphylococci. The research communityis currently exploring the use of whole genome se-quencing for AST. The advantage of phenotypic methodsis that they are quantifiable and can predict both sensi-tivity and resistance. Phenotypic methods, both MICs anddisk diffusion, traditionally need 18 h of incubation—constituting the classical ‘‘overnight’’ incubation. How-ever, the incubation time can, if traditional systems arerecalibrated, be brought down to 6–12 h depending on the

microorganism and the resistance mechanism. The ad-vantage of the genotypic methods is that they are rapidand specific but so far they predict only resistance andthey are not quantitative.

There is now international agreement on a standardmethod for the determination of the MIC, but for break-points there is still more than one system. Europe had formany years seven systems in use, including the Clinicaland Laboratory Standards Institute (CLSI) system fromthe USA. The European Committee on AntimicrobialSusceptibility Testing (EUCAST) managed in the period2002–2010 to unite the six European national systems andharmonize systems and breakpoints in Europe. Since then,many non-European countries have joined EUCAST.Both EUCAST [13] and CLSI [14] breakpoints areavailable in all internationally used susceptibility testingmethods. EUCAST recommendations are freely availableon the Internet [15], whereas the CLSI recommendationsmust be purchased. As a general rule, clinical breakpointsfrom EUCAST are somewhat lower than CLSI break-points. This is mainly because EUCAST breakpoints weresystematically revised on the basis of recent information,whereas many breakpoints from CLSI were neither re-viewed nor revised for more than 15–25 years.

Antibiotic stewardship

Targeted at education to provide assistance for optimalchoice, dosage, and duration of antibiotics to improveoutcome and reduce the development of resistance, an-tibiotic stewardship programs for critically ill patientstranslated into the implementation of specific guidelines,largely promoted by the Surviving Sepsis Campaign [16,17]. Very early and adequate antibiotic treatment sig-nificantly improved the outcome of critically ill patientssuffering from severe infections [18].

However, the very early start of antibiotics decreasedthe proportion of microbiological documentation which ismandatory for a successful subsequent de-escalation [19].Adequate coverage for potential resistant microorganismsresults in a vicious circle characterized by a progressiveenlargement of the spectrum to be covered (Fig. 1). Theconcept of antibiotic stewardship then progressivelyevolved to individualize prescriptions by the introductionof new concepts such as avoiding unnecessary adminis-tration of broad-spectrum antibiotics and systematic de-escalation [20].

This has been further demonstrated to have a positiveimpact in critically ill settings. A systematic reviewshowed that despite the relative low level of the 24 studiespublished from 1996 to 2010, including only three ran-domized prospective studies and three interrupted timeseries, antibiotic stewardship was in general beneficial

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[21]. This strategy has shown a reduction of the use ofantimicrobials (from 11 to 38 % of defined daily doses), alower antimicrobial cost (US$5–10 per patient day), ashorter average duration of treatment, less inappropriateuse, and fewer adverse events. Interventions beyond6 months resulted in reductions in the rate of antimicro-bial resistance. Importantly, antibiotic stewardship wasnot associated with increases in nosocomial infectionrates, length of stay, or mortality.

Moreover, in the context of high endemicity for me-thicillin-resistant S. aureus (MRSA), antibioticstewardship combined with improved infection controlmeasures achieved a sustainable reduction in the rate ofhospital-acquired MRSA bacteremia [22].

Accordingly, as strongly recommended by ICU ex-perts and supported by several national and internationalinitiatives, antibiotic stewardship programs should bedeveloped and implemented in every ICU or institution incharge of critically ill patients (Table 1).

Treatment strategies

Adequate, prompt therapy and duration

Inappropriate antimicrobial therapy, meaning the selec-tion of an antibiotic to which the causative pathogen isresistant, is a consistent predictor of poor outcomes inseptic patients [23]. On the other hand, several studieshave shown that prompt appropriate antimicrobial treat-ment is a life-saving approach in the management ofsevere sepsis [24–26]. The concept of ‘‘adequate antimi-crobial therapy’’ was defined as an extension of‘‘appropriate antimicrobial therapy’’, meaning appropriateand early therapy at optimized doses and dose intervals.

The most impressive data probably comes from Ku-mar et al. [27], who showed that inadequate initialantimicrobial therapy for septic shock was associated witha fivefold reduction in survival (52.0 vs. 10.3 %),

Fig. 1 Vicious circle starting from the implementation of earlyand adequate empirical antibiotic treatment. Adequate coverage forpotential resistant microorganisms results in vicious circle charac-terized by the need to enlarge the spectrum to be covered, withfurther continuous increase of the proportion of resistant microor-ganisms resulting in a progressive increase of inadequate empiricaltreatments and death from bloodstream infections (BSI), ventilator-associated pneumonia (VAP), and surgical site infections (SSI)

Table 1 Suggested components of ICU-specific antibiotic stewardship programs

Leadership commitmentHead of ICU should endorse the responsibility for implementing specific antibiotic stewardshipDirection of the institution should be supportive and provide resources required to implement and follow the ICU antibiotic stewardshipRegular feedback on the impact of the ICU antibiotic stewardship should be supported by both hospital and ICU directionsImprove communication between laboratory and clinical staffImplement local resistance data for developing local antibiotic guidelines

Multidisciplinary approachA multidisciplinary team including infectious diseases specialists, microbiologists, pharmacists, and ICU physicians and nurses shouldbe in charge of developing a specific ICU antibiotic stewardship

Weekly round for cases discussionImplementation based on specific education and training of ICU physicians (and all new introduced HCWs) about resistance and optimal

prescribing including the following items:Aggressive good quality microbiological sampling to document the microorganism potentially responsible for the infection (bloodcultures; distal airway sampling; urine culture; systematic sampling of wound, drain discharge, and any collection suspected ofinfection)

Selection of empirical antimicrobials according to the clinical documentation of any suspected site of infection (clinical examination,adequate imaging), to the presence of risk factors for resistant microorganisms, and to the local epidemiology of the microorganism

Achievement of adequate pharmacokinetic/pharmakodynamic parameters of the antimicrobial agents usedSystematic de-escalation (see specific paragraph)Systematic reduction of the duration of antimicrobial treatment according to the clinical evolution and the kinetics of biomarkers such asprocalcitonin

Software—implementation of alerts in the prescription software to help clinicians in several issues of antibiotic prescriptionMonitoring and feedback

Monitoring antibiotic prescribing and resistance patternsRegular reporting of information on antibiotic use and resistance to doctors, nurses, and relevant staff

HCWs healthcare workers

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remaining highly associated with risk of death even afteradjustment for other potential risk factors (odds ratio/OR8.99). Differences in survival were seen in all majorepidemiologic, clinical, and organism subgroups, rangingfrom 2.3-fold for pneumococcal infection to 17.6-fold forprimary bacteremia. This obviously means that, in severeinfections, antimicrobial therapy must almost always beempiric, before isolation and identification of the causa-tive organism and determination of the organism’ssensitivity, to achieve a timely initiation.

Unfortunately, the rising incidence of MDR microor-ganisms leads, at least, to one of two consequences:increased incidence of inappropriate antimicrobial ther-apy or higher consumption of broad-spectrum antibiotics[28]. The way out of this vicious spiral is to assume thatthe best antibiotic selection is the choice of the antibioticwith the best possible combination of high effectivenessfor infection cure and relapse avoidance on the one handand low collateral damage on the other.

In a recent multicenter study on hospital-acquiredbacteremia [25], the incidence of MDR and XDR mi-croorganisms was 48 and 21 %, respectively; in themultivariable model, MDR isolation and timing to ade-quate treatment were independent predictors of 28-daymortality. The same occurs in the community, with risingprevalence of MDR bacteria, for instance, among patientswith community-acquired pneumonia who were admittedto the ICU (7.6 % in Spain and 3.3 % in the UK) [29].Therefore, there is evidence that infection by MDR bac-teria often results in a delay in appropriate antibiotictherapy, resulting in increased patient morbidity andmortality, as well as prolonged hospital stay [30]. Con-versely, there is also proof that appropriate initialantibiotic therapy, early ICU admission, and maximizedmicrobiological documentation are modifiable process-of-care factors that contribute to an improved outcome [31].

To help in reducing the antibiotic treatment duration,the most promising parameters appear to be plasma levelsof procalcitonin (PCT). Besides PCT, no other sepsisbiomarker has achieved universal use throughout differenthealthcare settings in the last decade. High PCT concen-trations are typically found in bacterial infection, incontrast to lower levels in viral infection and levels below0.1 ng/mL in patients without infection. Furthermore,serum PCT concentrations are positively correlated withthe severity of infection. Thus, adequate antibiotic treat-ment leads to a decrease in serum PCT concentrations. Arecent metanalysis showed a significant reduction of thelength of antibiotic therapy in favor of a PCT-guidedtherapy strategy [32].

Monotherapy versus combination therapy

Basically, there are two reasons to favor antibiotic com-bination therapy over monotherapy. Firstly, there is a

potential synergy of combined antibiotics in order tomaximize clinical efficacy or prevent development ofresistance. Synergistic effects, however, were provenin vitro for many combinations of antibiotics, but a clearbenefit has only been demonstrated in vivo in the treat-ment of invasive pneumococcal disease and in toxic shocksyndrome. In these two clinical situations, the combina-tion of b-lactams with macrolides or lincosamides,respectively, was able to inhibit bacterial pathogenicityfactors and was associated with improved survival. Thesecond reason for the selection of a combination therapyis the desired extension of the expected spectrum ofpathogens (so-called gap closing). However, none of therandomized controlled trials (RCTs) in patients withsepsis could demonstrate any advantage of combinationtherapies. A meta-analysis of RCTs comparing the com-bination therapy of a b-lactam plus an aminoglycosideversus a monotherapy with a beta-lactam alone did notshow any benefits of the combination therapy in terms ofmorbidity and mortality [33]. Similarly, a subgroup ana-lysis of septic patients in a Canadian ventilator-associatedpneumonia (VAP) study comparing meropenem mono-therapy with meropenem/ciprofloxacin combinationtherapy also found no differences in morbidity, mortality,or adverse reactions between the groups [34]. Finally, theMAXSEPT study of the German Study Group Compe-tence Network Sepsis (SepNet) comparing meropenemwith meropenem/moxifloxacin combination in severesepsis and septic shock could not demonstrate a differencebetween the groups either for changes in SOFA scores orfor 30-day mortality [35].

Results in favor of combination therapy were found incohort studies only, in which benefits of combinationtherapy have been shown in terms of lower mortality,especially in patients with septic shock [36, 37]. Thedrawback of these studies was that various b-lactams andvarious combination partners were chosen.

An important difference between these observationalstudies and RCTs should be mentioned; the former wereconducted in countries with significantly higher rates ofMDR pathogens than the latter. In both the Canadian andthe MAXSEPT studies mentioned above, resistantpathogens were found in less than 10 % of cases. Thissuggests that combination therapy may be rational when,as a result of the anticipated resistance pattern, treatmentfailure of a b-lactam monotherapy is likely. Several ob-servational studies looking at carbapenem-resistant (CR)pathogens demonstrated a survival benefit for a combi-nation therapy using a carbapenem together with colistinand/or tigecycline in comparison to meropenem alone[38, 39]. In addition, intravenous fosfomycin has beenrecently administered as part of combination regimens inpatients with XDR K. pneumoniae infections to improvethe effectiveness and decrease the rate of emergence ofresistance [40]. Also aminoglycosides have been recentlyused in combination regimens in patients with difficult-to-

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treat infections, including XDR K. pneumoniae infections[41].

In conclusion, combination therapy should be recom-mended only in patients with severe sepsis and when aninfection with a resistant organism is likely. De-escalationto an effective monotherapy should be considered whenan antibiogram is available.

De-escalation

De-escalation of antimicrobial therapy is often advocatedas an integral part of antibiotic stewardship programs [16,17] and has been defined as reducing the number of an-tibiotics to treat an infection as well as narrowing thespectrum of the antimicrobial agent. Essentially this is astrategy that is applicable after starting a broad-spectrumempirical therapy prior to identification of the causativepathogen. Intuitively this would limit the applicability ofde-escalation as a concept in MDR infections as afteridentification of an MDR pathogen, often the opposite—escalation of antimicrobial therapy—is required.Depending on the pathogen involved, even multiple an-tibiotics may be required, even with the same antibioticclass such as combination therapy with ertapenem andanother carbapenem for K. pneumoniae carbapenemase(KPC) producers.

Not surprisingly, several clinical studies found that thepresence of MDR pathogens was a motivation not to de-escalate [42, 43], even in situations where the patient wascolonized with MDR organisms at sites other than the in-fection site. Other studies have reported de-escalation to besafe in MDR-colonized patients [44]. This does, however,not mean that the concept of de-escalation is not applicablein MDR infections. Depending on antibiotic susceptibility,an antimicrobial agent with a narrower spectrum may beavailable, or combination therapy may be stopped afterinitial therapy. If the infection is resolving, de-escalationmay prove a valid option in order to avoid further antibioticpressure [45]. However, the value of de-escalation in thesetting of MDR infections has not been extensively exploredand application should be considered on an individual pa-tient basis [45]. Retrospective analyses have found de-escalation to be a safe approach when applied in selectedpatients [23], but in a recent, non-blinded RCT [19], de-escalated patients had more superinfections and increasedantibiotic use. Although intuitively logical and frequentlysuggested [16, 46, 47], de-escalation of antibiotic therapyhas not been clearly associated with lower rates of antibioticresistance development.

PK/PD optimization

It is known that antimicrobial resistance, as defined in theclinical laboratory, often translates into insufficient

in vivo exposures that result in poor clinical and economicoutcomes [48]. In addition to resistance, it is now becomingincreasingly recognized that the host’s response to in-fection may in and of itself contribute to considerablereductions in antimicrobial exposures due to alterations inthe cardiovascular, renal, hepatic and pulmonary systems[49]. A recent ICU study has highlighted the potentialimpact of adaptations in the renal system as more than65% of these critically ill patients manifested augmentedrenal function, defined by a creatinine clearanceC130 mL/min/1.73 m2, during their initial week of hos-pitalization. This finding is particularly concerningbecause the backbones of most antimicrobial regimens inthe ICU such as penicillins, cephalosporins or carbapen-ems are predominantly cleared via the renal route [50]. Tothis end, Roberts and colleagues have recently reportedthe results of a prospective, multinational pharmacoki-netic study to assess b-lactam exposures in the criticallyill population [51]. In that study, the investigators notedthat among 248 infected patients, 16% did not achieveadequate antimicrobial exposures and that these patientswere 32% less likely to have a satisfactory infectionoutcome. While a personalized approach to dosing that isbased on a given patient’s specific pharmacokinetic pro-file for b-lactams is not yet the standard of practice asmight be expected for the aminoglycosides and van-comycin due to lack of routinely available drug assays,the pharmacokinetic and pharmacodynamic (PK/PD)profile of b-lactams as well as other agents may be in-corporated into treatment algorithms to optimizeoutcomes. To this end, we developed and implementedpharmacodynamically optimized b-lactam regimenswhich incorporated the use of higher doses as well asprolonged or continuous infusion administration tech-nique to enhance in vivo exposures in patients with VAP[52]. Utilization of these regimens was shown to improvethe clinical, microbiologic and economic outcomes as-sociated with this ICU based infection. Clinicians need torecognize that in the early stages of infection, alterationsin metabolic pathways as well as the reduced suscepti-bility of target pathogens may result in inadequateantimicrobial exposures if conventional dosing regimensare utilized. Therefore, pharmacodynamically optimizeddosing regimens should be given to all patients em-pirically and once the pathogen, susceptibility and clinicalresponse are known, local stewardship practices may beemployed to redefine an appropriate regimen for the pa-tient [53].

Infection control measures

Depending on the ICU setting, one-third to up to half ofpatients may develop a nosocomial infection. Unfortu-nately, host susceptibility to infection can only be slightlymodified; the presence of microorganisms and the high

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density of care are unavoidable. Consequently, the pre-vention of infection dissemination relies on eliminatingthe means of transmission by the use of infection controlmeasures [54]. The global idea of isolation precautioncombines the systematic use of standard precautions(hand hygiene, gloves, gowns, eye protection) and trans-mission-based precautions (contact, droplet, airborne)[55] (Table 2). Conceptually, the objective is not to iso-late, but to prevent transmission of microorganisms byanticipating the potential route of transmission and themeasures to be applied for each action of care.

Physical contact is the main route of transmission forthe majority of bacteria; however, this seems not to betrue for certain bacteria, namely MRSA, as demonstratedin a recent study [56]. It occurs via the hands of health-care workers (HCWs) from a patient or contaminatedsurfaces/instruments nearby to another patient during theprocess of care. Hand hygiene (hand washing and alcoholhand-rub), patient washing, and surface cleansing effi-ciently reduce transmission [57, 58]. Transmission canoccur via droplet or airborne particles. Specific trans-mission-based precautions required to avoid infection aresummarized in Table 2.

Isolation precautions have been widely diffused andthey are nowadays the cornerstone of preventive measuresused to control outbreaks, to decrease the rate of resistantmicroorganisms (MRSA, ESBL) and the spread ofemergent infectious diseases such as respiratory viruses(SARS, influenza, corona virus) or viral hemorrhagicfevers. In this context, enhanced adherence to appropriateisolation precautions can markedly decrease resistancedissemination and potentially further need for broad-spectrum antibiotics.

Selective decontamination of the digestive tract (SDD)has been proposed to prevent endogenous and exogenousinfections and to reduce mortality in critically ill patients.Although the efficacy of SDD has been confirmed byRCTs and systematic reviews, SDD has been the subjectof intense controversy based mainly on insufficient evi-dence of efficacy and on concerns about resistance. Arecent meta-analysis detected no relation between the useof SDD and the development of antimicrobial resistance,suggesting that the perceived risk of long-term harm re-lated to selective decontamination cannot be justified byavailable data. However, the conclusions of the studyindicated that the effect of decontamination on ICU-levelantimicrobial resistance rates is understudied [59].

Although SDD provides a short-term benefit, neither along-term impact nor a control of emerging resistanceduring outbreaks or in settings with high resistance ratescan be maintained using this approach.

In the era of carbapenem resistance, antimicrobialssuch as colistin and aminoglycosides often represent thelast option in treating multidrug-resistant Gram-negativeinfections. In this setting, the use of colistin should be

carefully considered and possibly avoided during out-breaks due to resistant Gram-negative bacilli [60].

New therapeutic approaches

The antibiotic pipeline continues to diminish and themajority of the public remains unaware of this criticalsituation. The cause of the decline of antibiotic develop-ment is multifactorial. Drug development, in general, isfacing increasing challenges, given the high costs re-quired, which are currently estimated in the range ofUS$400–800 million per approved agent. Furthermore,antibiotics have a lower relative rate of return on invest-ment than do other drugs because they are usually used inshort-course therapies. In contrast, chronic diseases, in-cluding HIV and hepatitis, requiring long-term and maybelifelong treatments that suppress symptoms, representmore rational opportunities for investment for the phar-maceutical industry. Ironically, antibiotics are victims oftheir own success; they are less desirable to drug com-panies because they are more successful than other drugs[61].

Numerous agencies and professional societies havehighlighted the problem of the lack of new antibiotics,especially for MDR Gram-negative pathogens. Since2004 repeated calls for reinvigorating pharmaceuticalinvestments in antibiotic research and development havebeen made by the Infectious Diseases Society of America(IDSA) and several other notable societies, including In-novative Medicines Initiative (Europe’s largest public–private initiative) which funds COMBACTE [62, 63].IDSA supported a program, called ‘‘the 10 9 020 Initia-tive’’, with the aim to develop ten new systemicantibacterial drugs by 2020 through the discovery of newdrug classes or new molecules from already existingclasses of antibiotics [63].

The current assessment of the pipeline (last updatedAugust 2014) shows 45 new antibiotics in development orrecently approved (Table 3). Of those, 14 are in phase 1clinical trials, 20 in phase 2, seven in phase 3 (a new drugapplication has been submitted for one, and three wererecently approved) [64]. Five of the seven antibiotics inphase 3, as well as one drug submitted for review to theUS Food and Drug Administration (FDA), have the po-tential to address infections caused by MDR Gram-negative pathogens, the most pressing unmet need [65].Unfortunately there are very limited new options forGram-negative bacteria such as carbapenemase-produc-ing Enterobacteriaceae, XDR A. baumannii, and P.aeruginosa. Aerosol administration of drugs seems to be apromising new approach for treatment of MDR lung in-fections. Nebulized antibiotics achieve good lungconcentrations and they reduce risk of toxicity compared

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een

pat

ien

tco

nta

cts

Glo

ves

Fo

ran

tici

pat

edco

nta

ctw

ith

blo

od

,b

od

yfl

uid

s,se

cret

ion

s,ex

cret

ion

s,co

nta

min

ated

item

sG

lov

esar

ela

rgel

yo

ver

use

din

this

sett

ing

and

may

be

resp

on

sib

lefo

rin

crea

sed

con

tam

inat

ion

of

the

env

iro

nm

ent.

Hen

cem

any

inst

itu

tio

ns

no

wad

ays

rest

rict

the

use

of

glo

ves

for

anti

cip

ated

con

tact

wit

hb

od

yfl

uid

so

rw

ith

mu

cou

sm

emb

ran

es,

or

no

n-i

nta

ctsk

inM

ask

,ey

ep

rote

ctio

nT

op

rote

ctm

uco

us

mem

bra

nes

of

the

eyes

,n

ose

,an

dm

ou

thd

uri

ng

pro

ced

ure

san

dp

atie

nt-

care

acti

vit

ies

lik

ely

tog

ener

ate

spla

shes

or

spra

yo

fb

loo

d,b

od

yfl

uid

s,se

cret

ion

s,an

dex

cret

ion

sG

ow

ns

To

pro

tect

skin

and

pre

ven

tso

ilin

go

fcl

oth

ing

du

rin

gp

roce

du

res

and

pat

ien

t-ca

reac

tiv

itie

sli

kel

yto

gen

erat

esp

lash

eso

rsp

ray

of

blo

od

,b

od

yfl

uid

s,se

cret

ion

s,an

dex

cret

ion

sP

atie

nt

hy

gie

ne

Rep

lace

trad

itio

nal

bo

dy

was

hin

g(w

ater

and

soap

)b

y2

%ch

lorh

exid

ine-

imp

reg

nat

edd

isp

osa

ble

wip

eso

r4

%ch

lorh

exid

ine

bo

dy

was

h

Tra

nsm

issi

on

-bas

edp

reca

uti

on

sT

hes

ead

dit

ion

alp

reca

uti

on

sap

ply

tose

lect

edp

atie

nts

hav

ing

eith

era

susp

ecte

do

rco

nfi

rmed

clin

ical

syn

dro

me

or

asp

ecifi

cd

iag

no

sis

that

pre

dic

tab

lyp

lace

so

ther

sat

incr

ease

dri

sko

fac

qu

irin

gan

infe

ctio

nT

yp

eo

fp

reca

uti

on

Sco

pe

of

use

Co

nta

ctp

reca

uti

on

Ap

ply

for

pat

ien

tsk

no

wn

or

susp

ecte

dto

hav

ed

isea

ses

tran

smit

ted

by

dir

ect

ph

ysi

cal

con

tact

/co

nta

ctw

ith

item

sin

the

pat

ien

t’en

vir

on

men

tIn

fect

ion

/co

lon

izat

ion

wit

hm

ult

idru

g-r

esis

tan

tb

acte

riaa

(MR

SA

,V

RE

,M

DR

Gra

mn

egat

ives

such

asK.pneumonia

,P.

aeruginosa

,Enterobacter

cloacae,

A.baumanni)

En

teri

cin

fect

ion

s(C

.difficile

,E.coli

O1

57

:H7

,Shigella

spp

.,h

epat

itis

Av

iru

s,ro

tav

iru

s)R

esp

irat

ory

infe

ctio

ns

inch

ild

ren

(res

pir

ato

rysy

ncy

tial

vir

us,

par

ain

flu

enza

vir

us,

ente

rov

iral

infe

ctio

ns)

Hig

hly

con

tag

iou

ssk

inin

fect

ion

s(m

uco

cuta

neo

us

her

pes

sim

ple

x,im

pet

igo

,st

aph

ylo

cocc

alfu

run

culo

sis,

ped

icu

losi

s,an

dsc

abie

s)V

iral

hem

orr

hag

icco

nju

nct

ivit

isV

iral

hem

orr

hag

icfe

ver

(Las

sa,

Eb

ola

,M

arb

ug

vir

use

s)D

rop

let

pre

cau

tio

nA

pp

lyfo

rp

atie

nts

kn

ow

no

rsu

spec

ted

toh

ave

dis

ease

str

ansm

itte

db

yla

rge

dro

ple

ts([

5lm

insi

ze).

Indir

ect

tran

smis

sion

can

occ

ur

wh

end

rop

lets

con

tain

ing

mic

roo

rgan

ism

sco

nta

min

ate

surf

aces

or

item

sin

the

pat

ien

t’s

env

iro

nm

ent

wit

hin

ad

ista

nce

of

1m

(co

ug

h,

snee

ze,

and

talk

ing

,o

rd

uri

ng

pro

ced

ure

ssu

chas

bro

nch

osc

op

yan

dsu

ctio

nin

g).

Dir

ect

tran

smis

sio

no

ccu

rsw

hen

dro

ple

tsar

ed

epo

site

do

nm

uco

us

mem

bra

nes

.M

ask

,ey

ep

rote

ctio

n,

and

face

shie

ldar

ere

qu

ired

tosp

ecifi

call

yav

oid

mu

cou

sm

emb

ran

eco

nta

min

atio

nS

yst

emic

syn

dro

mes

(Neisseria

meningitides

infe

ctio

ns,Haem

ophilusinfluenzae

men

ing

itis

,G

rou

pA

Streptococci

infe

ctio

ns,

scar

let

fev

er,

tox

icsh

ock

syn

dro

me)

Res

pir

ato

ryin

fect

ion

s(M

DR

,Mycoplasm

apneumonia

,p

ertu

sis)

Ser

iou

sv

iral

infe

ctio

ns

(ad

eno

vir

us,

infl

uen

za,

mu

mp

s,p

arv

ov

iru

sB

19

,ru

bel

la)

Air

bo

rne

pre

cau

tio

nA

pp

lyfo

rp

atie

nts

kn

ow

no

rsu

spec

ted

toh

ave

dis

ease

str

ansm

itte

db

yai

rbo

rne

par

ticl

es(\

5lm

insi

zeo

rd

ust

par

ticl

es).

Th

ese

par

ticl

esca

nre

mai

nsu

spen

ded

inth

eai

rfo

rlo

ng

per

iod

san

dtr

avel

lon

gd

ista

nce

s.S

pec

ial

air

han

dli

ng

(hig

hef

fici

ency

mas

k:

N-9

5st

and

ard

)an

dv

enti

lati

on

(ro

om

sw

ith

neg

ativ

ep

ress

ure

)ar

ere

qu

ired

top

rev

ent

tran

smis

sio

nR

esp

irat

ory

infe

ctio

ns

(mea

sles

,v

aric

ella

,an

dd

isse

min

ated

zost

er,

tub

ercu

losi

s,p

ulm

on

ary

and

lary

ng

eal)

Vir

alh

emo

rrh

agic

fev

er(L

assa

,E

bo

la,

Mar

bu

gv

iru

ses)

Adap

ted

from

Hea

lthca

reIn

fect

ion

Contr

ol

Pra

ctic

esA

dvis

ory

Com

mit

tee

(HIC

PA

C)

guid

elin

es[4

8],

avai

lab

leo

n-l

ine

ath

ttp

://w

ww

.cd

c.g

ov

/nci

do

d/h

ip/i

sola

t/is

ola

t.h

tma

Fo

rex

ten

ded

-sp

ectr

um

b-l

acta

mas

e-p

rod

uci

ngEnterobacteriaceae,

po

licy

may

dif

fer

bet

wee

nh

osp

ital

sd

epen

din

go

nth

eir

end

emic

ity

783

Table

3A

nti

bio

tics

curr

entl

yin

clin

ical

dev

elopm

ent

[54

]

Dru

gcl

ass

Dru

gnam

eD

evel

opm

ent

phas

eC

om

pan

yP

ote

nti

alac

tivit

y

agai

nst

Gra

m-

neg

ativ

epat

hogen

s

Pote

nti

alin

dic

atio

ns

Cep

hal

osp

ori

nG

SK

-2696266

Phas

e1

Gla

xoS

mit

hK

line

(par

tner

ed

pro

duct

)

No

Bac

teri

alin

fect

ions

Novel

cephal

osp

ori

n?

bet

a-

lact

amas

ein

hib

itor

Cef

tolo

zane?

tazo

bac

tam

New

Dru

gA

ppli

cati

on

(ND

A)

subm

itte

d(f

or

com

pli

cate

duri

nar

y

trac

tin

fect

ion

and

com

pli

cate

din

tra-

abdom

inal

infe

ctio

n

indic

atio

ns)

Cubis

tP

har

mac

euti

cals

Yes

Com

pli

cate

duri

nar

ytr

act

infe

ctio

ns,

com

pli

cate

din

tra-

abdom

inal

infe

ctio

ns,

acute

pyel

onep

hri

tis

(kid

ney

infe

ctio

n),

hosp

ital

-acq

uir

edbac

teri

alpneu

monia

/

ven

tila

tor-

asso

ciat

edpneu

monia

Cef

taro

line?

avib

acta

mP

has

e2

Ast

raZ

enec

a/F

ore

stL

abora

tori

esY

esC

om

pli

cate

duri

nar

ytr

act

infe

ctio

ns

Cef

tazi

dim

e?

avib

acta

m(C

AZ

-AV

I)P

has

e3

Ast

raZ

enec

a/F

ore

stL

abora

tori

esY

esC

om

pli

cate

duri

nar

ytr

act

infe

ctio

ns,

com

pli

cate

din

tra-

abdom

inal

infe

ctio

ns,

acute

pyel

onep

hri

tis

(kid

ney

infe

ctio

n),

hosp

ital

-acq

uir

edbac

teri

alpneu

monia

/

ven

tila

tor-

asso

ciat

edbac

teri

alpneu

monia

Monobac

tam

?novel

bet

a-la

ctam

ase

inhib

itor

Azt

reonam

?av

ibac

tam

(AT

M-A

VI)

Phas

e1

Ast

raZ

enec

a/F

ore

stL

abora

tori

esY

esB

acte

rial

infe

ctio

ns

Car

bap

enem

?novel

bet

a-

lact

amas

ein

hib

itor

Car

bav

ance

Phas

e1

Rem

pex

Phar

mac

euti

cals

/The

Med

icin

esC

om

pan

y

Yes

Com

pli

cate

duri

nar

ytr

act

infe

ctio

ns,

com

pli

cate

din

tra-

abdom

inal

infe

ctio

ns,

hosp

ital

-acq

uir

edbac

teri

alpneu

monia

/

ven

tila

tor-

asso

ciat

edbac

teri

alpneu

monia

,

febri

leneu

tropen

ia

MK

-7655?

imip

enem

/cil

asta

tin

Phas

e2

Car

bap

enem

?novel

bet

a-

lact

amas

ein

hib

itor

Yes

Com

pli

cate

duri

nar

ytr

act

infe

ctio

ns,

acute

pyel

onep

hri

tis,

com

pli

cate

din

tra-

abdom

inal

infe

ctio

ns

Am

inogly

cosi

de

Pla

zom

icin

Phas

e3

Ach

aogen

Yes

Blo

odst

ream

infe

ctio

ns

and

noso

com

ial

pneu

monia

cause

dby

carb

apen

em-r

esis

tant

Enterobacteriaceae

Flu

oro

quin

olo

ne

WK

C771

Phas

e1

Wock

har

dt

Yes

Bac

teri

alin

fect

ions

WK

C2349

(WC

K771

pro

-dru

g)

Phas

e1

Wock

har

dt

Yes

Bac

teri

alin

fect

ions

Avar

ofl

oxac

inP

has

e2

Furi

exP

har

mac

euti

cals

Yes

Com

munit

y-a

cquir

edbac

teri

alpneu

monia

,

acute

bac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns

Fin

afloxac

inP

has

e2

Mer

Lio

nP

har

mac

euti

cals

Yes

Com

pli

cate

duri

nar

ytr

act

infe

ctio

ns,

acute

pyel

onep

hri

tis

(kid

ney

infe

ctio

n),

acute

intr

a-ab

dom

inal

infe

ctio

ns,

acute

bac

teri

al

skin

and

skin

stru

cture

infe

ctio

ns

Nem

onoxac

inP

has

e2

Tai

Gen

Bio

tech

nlo

gy

Yes

Com

munit

y-a

cquir

edbac

teri

alpneu

monia

,

dia

bet

icfo

ot

infe

ctio

n,

acute

bac

teri

alsk

in

and

skin

stru

cture

infe

ctio

ns

Zab

ofl

oxac

inP

has

e2

Dong

Wha

Phar

mac

euti

cal

No

Com

munit

y-a

cquir

edbac

teri

alpneu

monia

Del

afloxac

inP

has

e3

Mel

inta

Phar

mac

euti

cals

Yes

Acu

tebac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns,

com

munit

y-a

cquir

edbac

teri

al

pneu

monia

,unco

mpli

cate

dgonorr

hea

784

Table

3co

nti

nu

ed

Dru

gcl

ass

Dru

gnam

eD

evel

opm

ent

phas

eC

om

pan

yP

ote

nti

alac

tivit

y

agai

nst

Gra

m-

neg

ativ

epat

hogen

s

Pote

nti

alin

dic

atio

ns

Oxaz

oli

din

one

Ted

izoli

dA

ppro

ved

20

June

2014

Cubis

tP

har

mac

euti

csN

oA

cute

bac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns,

hosp

ital

-acq

uir

edbac

teri

al

pneu

monia

/ven

tila

tor

acquir

edbac

teri

al

pneu

monia

Cad

azoli

d(q

uin

olo

nyl-

oxal

idin

one)

Phas

e3

Act

elio

nP

har

mac

euti

cals

No

C.difficile

-ass

oci

ated

dia

rrhea

Rad

ezoli

dP

has

e2

Mel

inta

Phar

mac

euti

csY

esA

cute

bac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns,

com

munit

y-a

cquir

edbac

teri

al

pneu

monia

MR

X-I

Phas

e1

Mic

uR

xP

har

mac

euti

cals

No

Bac

teri

alin

fect

ions

incl

udin

gco

mm

unit

y-

acquir

edM

RS

Aan

dvan

com

yci

n-r

esis

tant

ente

roco

cci

infe

ctio

ns

LC

B01-0

371

Phas

e1

Leg

oC

hem

Bio

scie

nce

s(S

.K

ore

a)N

oB

acte

rial

infe

ctio

ns

Lip

opep

tide

and

gly

copep

tide

Ori

tavan

cin

Appro

ved

6A

ugust

2014

The

Med

icin

esC

om

pan

yN

oA

cute

bac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns

Gly

copep

tide–

cephal

osp

ori

n

het

erodim

er

TD

-1607

Phas

e1

Ther

avan

ce,

Inc

No

Ser

ious

Gra

m-p

osi

tive

bac

teri

alin

fect

ions

(acu

tebac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns,

hosp

ital

-acq

uir

edpneu

monia

/

ven

tila

tor-

asso

ciat

edpneu

monia

,

bac

tere

mia

)

TD

-1792

Phas

e2

Ther

avan

ce,

Inc

No

Acu

tebac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns,

oth

erse

rious

infe

ctio

ns

cause

dby

Gra

m-p

osi

tive

bac

teri

ain

cludin

ghosp

ital

-

acquir

edpneu

monia

/ven

tila

tor-

asso

ciat

ed

pneu

monia

and

bac

tere

mia

Lip

o-g

lyco

pep

tide

Dal

bav

anci

nA

ppro

ved

23

May

2014

Dura

taT

her

apeu

tics

No

Acu

tebac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns

Ram

opla

nin

Phas

e2

Nan

oth

erap

euti

csN

oC.difficile

-ass

oci

ated

dia

rrhea

Lip

opep

tide

Suro

tom

yci

nP

has

e3

Cubis

tP

har

mac

euti

cals

No

C.difficile

-ass

oci

ated

dia

rrhea

Mac

roli

de

Ket

oli

de

Soli

thro

myci

nP

has

e3

Cem

pra

Phar

mac

euti

cals

Yes

Com

munit

y-a

cquir

edbac

teri

alpneu

monia

,

unco

mpli

cate

duro

gen

ital

gonorr

hea

LptD

inhib

itor

PO

L7080

Phas

e2

Poly

phor

(Roch

eli

cense

e)Y

esV

enti

lato

r-as

soci

ated

bac

teri

alpneu

monia

,

low

erre

spir

atory

trac

tin

fect

ions

Tet

racy

clin

eO

mad

acycl

ine

Phas

e2

Par

atek

Phar

mac

euti

cals

Yes

Com

munit

y-a

cquir

edbac

teri

alpneu

monia

,

acute

bac

teri

alsk

inan

dsk

inst

ruct

ure

infe

ctio

ns,

com

pli

cate

duri

nar

ytr

act

infe

ctio

ns

Era

vac

ycl

ine

Phas

e3

Tet

raphas

eP

har

mac

euti

cals

Yes

Com

pli

cate

din

tra-

abdom

inal

infe

ctio

ns,

com

pli

cate

duri

nar

ytr

act

infe

ctio

ns,

hosp

ital

-acq

uir

edbac

teri

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with intravenous administration. A new vibrating meshnebulizer used to deliver amikacin achieved high con-centrations in the lower respiratory tract. A tenfold higherconcentration than the MIC90 of bacteria that are nor-mally responsible for nosocomial lung infections (8 lg/mL for P. aeruginosa) was documented in epithelial lin-ing fluid for amikacin [66].

Pathogen-based approach

ESBL producers

Infections caused by extended-spectrum b-lactamase-producing Enterobacteriaceae (ESBL-PE) are difficultto treat owing to the resistance of the organisms tomany antibiotics [67]. Since 2010 EUCAST and CLSIrecommended the use of alternatives to carbapenems totreat these organisms. Indeed on the basis of antimi-crobial susceptibility testing, b-lactam/b-lactamaseinhibitors (BLBLIs) and specific fourth-generationcephalosporins (i.e., cefepime) with greater stabilityagainst b-lactamases could be theoretically used to treatESBL-PE infections [68]. As far as we know these‘‘alternatives’’ to carbapenems have not been evaluatedin critically ill patients. Outside the ICU, the data arestill scarce and conflicting [69]. A post hoc analysis ofpatients with bloodstream infections due to ESBL-E. coli from six published prospective cohorts sug-gested that BLBLI (including amoxicillin–clavulanicacid and piperacillin–tazobactam) were suitable alter-natives to carbapenems [70]. A meta-analysis byVardakas et al. [71] compared carbapenems andBLBLIs for bacteremia caused by ESBL-producingorganisms; taking into account the considerableheterogeneity in the trials included, the fact that nonewas powered to detect outcome differences and the factthat most severely ill patients tended to receive car-bapenems, there was no statistically significantdifference in mortality between patients receiving asempirical or definitive therapy BLBLIs or carbapenems.Regarding the use of cefepime in this specific situation,the data available are more confusing but it seems thatthe use of this b-lactam is safe in case of infectionwith isolates with an MIC value of 1 mg/L or less [72–74]. For critically ill patients, dosages of 2 g every12 h or higher are probably preferred. As suggested inrecent studies in this specific situation, practitionersshould be aware of the risk of suboptimal dosage.

According to all the recent data, for critically ill pa-tients carbapenems are still preferable to alternatives asempirical therapy when ESBL-PE is suspected. Alterna-tives as definitive therapy could be possible oncesusceptibilities are known. However, high dosage andsemi-continuous administration of b-lactams should bepreferred.T

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786

Carbapenem-resistant Enterobacteriaceae (CRE)

The vast majority of CRE isolates are resistant to the mostclinically reliable antibiotic classes leaving colistin,tigecycline, and gentamicin as the main therapeutic ap-proaches, whereas several reports have revealed high riskof mortality associated with these infections [38, 75, 76].Given the lack of data from randomized clinical trials,therapeutic approaches in CRE infections are based on theaccumulating clinical experience and particularly frominfections by K. pneumoniae producing either KPC orVerona integron-mediated metallo-b-lactamase (VIM).Recent evidence supports combination treatment con-taining two or three in vitro active drugs, revealingsignificant advantages over monotherapies in terms ofsurvival [38, 39, 77, 78]. Although paradoxical, sinceKPC enzymes hydrolyse carbapenems, the most sig-nificant improvement seems to be obtained when thecombination includes a carbapenem, providing substantialsurvival benefit in patients who are more severely ill and/or those with septic shock [78, 79]. Carbapenems’ in vivoactivity against CRE was compatible with MICs reaching8–16 mg/L [38, 77, 78], probably attributed to an en-hanced drug exposure with high-dose/prolonged-infusionregimens of carbapenems. Aminoglycoside-containingcombinations, particularly gentamicin, were associatedwith favorable outcomes compared to other combinationsand could serve as a backbone, particularly in view ofincreasing rates of colistin resistance [38, 39, 78]. Colistinand tigecycline represent the remaining agents to be se-lected for the combination, based on the sensitivitypattern. A recently reported clinical success of 55 % inthe treatment of infections by XDR and PDR pathogenswith combinations of fosfomycin make it anothertherapeutic candidate, particularly in the treatment ofEnterobacteriaceae against which susceptibility rates arepromising [80]. High doses (up to 24 g/day) and avoid-ance of monotherapy are strongly recommended in thesetting of critically ill patients with MDR pathogens.

Failing monotherapies with colistin or tigecycline maybe explained by a suboptimal exposure to the drug; recentPK/PD data favor dose escalation compared to the ini-tially recommended dose regimens. A small single-centernon-comparative study employing a loading dose (LD) of9 MIU followed by 4.5 MIU bid and adaptation accord-ing to renal function [81, 82] showed that colistinmonotherapy might be adequate [83]. A concise guide tooptimal use of polymyxins is shown in the ElectronicSupplementary Material. Higher doses up to 200 mg/daymay optimize tigecycline PKs and result in improvedclinical outcomes [84].

Double carbapenem combinations, consisting of er-tapenem as a substrate and doripenem or meropenem asthe active compound, have been recently proven suc-cessful in case series and small studies, even when thepathogen expressed high MIC to carbapenems [85].

Finally, decisions regarding the empiric antibiotic treat-ment of critically ill patients must be based on a soundknowledge of the local distribution of pathogens and onanalysis of presence of risk factors for infection caused byCRE [76, 86].

Pseudomonas aeruginosa

P. aeruginosa, along with E. coli, K. pneumoniae, and A.baumannii, is a leading pathogen in the ICU setting,causing severe infections (VAP, bacteremia) with mor-tality directly related to any delay in starting anappropriate antibiotic therapy [87].

In 2011, high percentages of P. aeruginosa isolatesresistant to aminoglycosides, ceftazidime, fluoro-quinolones, piperacillin/tazobactam, and carbapenemswere reported from several countries especially inSouthern and Eastern Europe. Resistance to carbapenemswas above 10 % in 19 of 29 countries reporting to theEuropean Center for Diseases Control (ECDC); MDR wasalso common, with 15 % of the isolates reported as re-sistant to at least three antimicrobial classes. CR-resistantP. aeruginosa now accounts for about 20 % of the isolatesin Italian ICUs, with few strains (2–3 %) being also re-sistant to colistin [88].

Primary regimens for susceptible isolates, dependingon the site and severity of infection, are summarized inTable 4. A beta-lactam antibiotic with anti-pseudomonasactivity is generally preferred and administered with ex-tended infusion after a LD to rapidly achieve thepharmacodynamic target [89]. Although there is not clearevidence supporting the advantage of combination ther-apy (i.e., a b-lactam plus an aminoglycoside or afluoroquinolone) over monotherapy [90], many cliniciansadopt this regimen for serious infections (bacteremia,VAP) and in patients with severe sepsis and septic shock.When a combination therapy with an aminoglycoside(amikacin or gentamicin) is preferred, we recommend amaximum duration of 5 days.

For infection caused by a strain susceptible only tocolistin, a regimen of high-dose colistin (9 MU LD, then4.5 MU bid) is recommended. Nebulized administrationof colistin is also considered for VAP, and intrathecal

Table 4 Primary regimens for treating P. aeruginosa infection

Piperacillin–tazobactam (MIC B 16 mg/L): 4.5 g IV q6ha

Ceftazidime or cefepime (MIC B 8 mg/L): 2 g IV q6/8ha

Meropenem (MIC B 8 mg/L): 1–2 g IV q8ha

Aztreonamb (MIC B 8 mg/L): 2 g IV q6ha (for IgE-mediatedb-lactam allergy)

Levofloxacin 750 mg IV q24h or ciprofloxacin 400 mg IV q8h

a Beta-lactam antibiotics are administered as an extended in-fusion (3–4 h) after a LDb For urinary tract infections or as a partner agent

787

administration is required for meningitis [91]. The ad-vantage of adding a carbapenem (in case of a non-carbapenem-susceptible strain) to colistin is unclear, andseveral experts prefer to use a combination showingsynergistic activity ‘‘in vitro’’ (i.e., colistin plus rifampin).Fosfomycin shows variable in vitro activity against P.aeruginosa MDR/XDR strains and may be administered,mainly as part of a combination regimen, for systemicinfections (4 g every 6 h). New drugs with activityagainst P. aeruginosa include ceftazidime/avibactam, anon-lactam inhibitor of class A and C b-lactamases andAmpC from P. aeruginosa, the new aminoglycosideplazomicin, and the combination of the new cephalos-porin ceftolozane with tazobactam, which shows activityalso against MDR and XDR P. aeruginosa strains andcompleted phase 3 trials for the treatment of complicatedintra-abdominal infections (cIAIs) and complicated uri-nary tract infections (cUTIs) [65, 90].

Acinetobacter baumannii

A. baumannii has gained increasing attention because ofits potential to cause severe infections and its ability indeveloping resistance to practically all available antimi-crobials. Adequate empirical therapy of severe infectionscaused by A. baumannii is crucial in terms of survival[92].

The empirical treatment for A. baumannii infectionsoften represents a challenge and might be consideredin case of severe sepsis/septic shock and in centerswith greater than 25 % prevalence of MDR A. bau-mannii [93]. Traditionally, carbapenems have been thedrug of choice and are still the preferred antimicrobialsfor Acinetobacter infections in areas with high rates ofsusceptibility. Sulbactam is a bactericide against A.

baumannii and represents a suitable alternative for A.baumannii susceptible to this agent. Unfortunately, asteady increase in the resistance to sulbactam in A.baumannii has been observed [94]. Nowadays,polymyxins are the antimicrobials with the greatestlevel of in vitro activity against A. baumannii [95, 96].However, their indiscriminate use may contribute tofurther selection of resistance and may also exposepatients to unnecessary toxicity. Thus, selection ofpatients who should receive empirical treatment cov-ering Acinetobacter is essential. Colistin is the mostwidely used in clinical practice although polymyxin Bseems to be associated with less renal toxicity [97].The recommended doses of these antimicrobials areshown in Table 5. Tigecycline, active in vitro against awide range of Gram-negative bacilli including A.baumannii, is approved in Europe for the treatment ofcomplicated skin structure infections and intra-ab-dominal infections. Nevertheless, although diversemeta-analyses have warned about the increased risk ofdeath in patients receiving tigecycline compared toother antibiotics particularly in HAP and VAP [98–100], a high dose regimen (Table 5), usually in com-bination with another antimicrobial, may be a validalternative for severe infections including A. bauman-nii pneumonia [75, 101].

Although in vitro studies have demonstrated synergyof colistin with rifampin, a recent RCT demonstrated noimproved clinical outcomes with the combination ofcolistin/rifampin while better eradication was achieved[102]. Different in vitro studies have documented theexistence of an unforeseen potent synergism of thecombination of colistin with a glycopeptide against car-bapenem-resistant A. baumannii; however, a combinationof colistin plus a glycopeptide in A. baumannii infectionsis actually discouraged [103, 104].

Table 5 Recommended doses of antimicrobials for A. baumannii severe infections in patients with normal renal function

Antibiotic Loading dose Daily dose Observations

Imipenema Not required 1 g/6–8 h Extended or prolonged infusion is not possible due to druginstability

Meropenema Not required 1–2 g/6 h Extended infusion (3–4 h) is recommended. If extendedinfusion is used, the first dose should be administered in30 min

Sulbactama Not required 9–12 g/6–8 h 4-h infusion is recommendedColistina 9 MU 9 MU/day in 2 or 3 dose LD is necessary including patients with renal dysfunction.

No dose adjustment in patients on CRRTPolymyxin B Not established 1.5–3 mg/kg/day in 2 doses Continuous infusion may be suitable. Same doses in

patients on CRRTTigecycline 100 mg

200 mg50 mg/12 h100 mg/12 h

May be adequate for approved indications (abdominalinfections and SSTI)

For other indications, especially pulmonary infections.Without approval by regulatory agencies

CRRT continuous renal replacement therapy, SST skin and soft tissue infectiona Dose adjustment is necessary in case of renal dysfunction

788

MRSA

The main treatment options for treating MRSA infectionsin critically ill patients include glycopeptides (van-comycin and teicoplanin), linezolid, and daptomycin;daptomycin is contraindicated for the treatment of pneu-monia because of its inactivation by surfactant.Alternative anti-MRSA agents are tigecycline, for whichthere is a regulatory warning concerning possible smallincreased (unexplained) mortality risk [105], telavancin,which has associated warnings contraindicating its usenotably in patients with renal failure [99], and ceftaroline,dalbavancin, and oritavancin, which have limited evi-dence for their efficacy in very severe infection. Therehave been numerous meta-analyses to compare the effi-cacy of the aforementioned agents in MRSA infection.Four meta-analyses are unusual in that they have assessedall possible treatment options [106–109], although onlyone study [107] examined all MRSA infection types (asopposed to MRSA cSSTIs). This latter (network meta-analysis) study identified 24 RCTs (17 for cSSTI and 10for HAP/VAP) comparing one of six antibiotics withvancomycin. In cSSTI, linezolid and ceftaroline werenon-significantly more effective than vancomycin. Line-zolid ORs were 1.15 (0.74–1.71) and 1.01 (0.42–2.14) andceftaroline ORs were 1.12 (0.78–1.64) and 1.59(0.68–3.74) in the modified intention to treat (MITT) andMRSA m-MITT populations, respectively. For HAP/VAP, linezolid was non-significantly better than van-comycin, with ORs of 1.05 (0.72–1.57) and 1.32(0.71–2.48) in the MITT and MRSA m-MITT popula-tions, respectively. The data of the Zephyr trial suggesteda clinical superiority of linezolid compared with van-comycin with higher rates of successful clinical response,acceptable safety and tolerability profile for the treatmentof proven MRSA nosocomial pneumonia. Microbiologicresponses paralleled clinical outcomes, and MRSAclearance was 30 % greater with linezolid than withvancomycin. A difference of at least 20 % persisted untillate follow-up, suggesting that linezolid treatment mayresult in more complete bacterial eradication [110].

Uncertainties surrounding the relative efficacy ofvancomycin have been fuelled by reports of worse out-comes in patients with MRSA infection caused by strainswith elevated MICs. A recent meta-analysis of S. aureusbacteremia studies failed to find an overall increased riskof death when comparing cases caused by S. aureus ex-hibiting high-vancomycin MIC (at least 1.5 mg/L) withthose due to low-vancomycin MIC (less than 1.5 mg/L)strains [111]. Outbreak of MRSA resistant to linezolidmediated by the cfr gene has been reported and was as-sociated with nosocomial transmission and extensiveusage of linezolid [112]. However, the authors cautionedthat they cannot definitely exclude an increased mortalityrisk, and to emphasize this point it remains possible that

specific MRSA strains/clones are associated with worseoutcomes. Attempts to address elevated MICs and soimprove target attainment by increasing vancomycindosages are associated with more nephrotoxicity [113].

Clostridium difficile

Severe C. difficile infection (CDI) is characterized by atleast one of the following: white blood cell count greaterthan 15 9 109/L, an acute rising serum creatinine (i.e.,greater than 50 % increase above baseline), a temperatureof greater than 38.5 �C, or abdominal or radiologicalevidence of severe colitis. There are currently two maintreatment options for severe CDI: either oral vancomycin125 mg qds for 10–14 days, or fidaxomicin, which shouldbe considered for patients with severe CDI at high risk forrecurrence [114]. The latter include elderly patients withmultiple comorbidities who are receiving concomitantantibiotics. Metronidazole monotherapy should beavoided in patients with severe CDI because of increasingevidence that it is inferior to the alternatives discussedhere [115]. In severe CDI cases who are not responding tooral vancomycin 125 mg qds, oral fidaxomicin 200 mgbid is an alternative; or high-dosage oral vancomycin (upto 500 mg qds, if necessary administered via a nasogastrictube), with or without iv metronidazole 500 mg tds. Theaddition of oral rifampicin (300 mg bid) or iv im-munoglobulin (400 mg/kg) may also be considered, butevidence is lacking regarding the efficacy of these ap-proaches. There are case reports of tigecycline being usedto treat severe CDI that has failed to respond to conven-tional treatment options, but this is an unlicensedindication [116, 117].

In life-threatening CDI (i.e., hypotension, partial orcomplete ileus, or toxic megacolon) oral vancomycin upto 500 mg qid for 10–14 days via nasogastric tube (whichis then clamped for 1 h) and/or rectal installation ofvancomycin enemas plus iv metronidazole 500 mg threetimes daily are used [118], but there is a poor evidencebase in such cases. These patients require closemonitoring, with specialist surgical input, and shouldhave their blood lactate measured. Colectomy should beconsidered if caecal dilatation is more than 10 cm, or incase of perforation or septic shock. Colectomy is bestperformed before blood lactate rises above 5 mmol/L,when survival is extremely poor [119]. A recent system-atic review concluded that total colectomy with endileostomy is the preferred surgical procedure; other pro-cedures are associated with high rates of re-operation andmortality. Less extensive surgery may have a role in se-lected patients with earlier-stage disease [120]. Analternative approach, diverting loop ileostomy and colo-nic lavage, has been reported to be associated withreduced morbidity and mortality [121].

789

Conclusions

Current clinical practice relating to critically ill patientshas been extremely challenged by the emergence ofmultidrug resistance among the commonly encounteredpathogens. Treatment options seem to be more optimisticfor Gram-positive pathogens (including C. difficile), forwhich the pipeline is more promising; however, the re-cently launched anti-MRSA agents have not beenextensively investigated in critically ill populations. In thefield of Gram-negative MDR infections there is greatconcern about the therapeutic future, as only a handful ofthe upcoming agents will address the unmet medicalneeds. Associations of beta-lactams with beta-lactamaseinhibitors seem promising against Gram-negative MDRpathogens, but their real clinical utility will be knownonly after results of large clinical trials are available.Currently, the most effective approach is the PK/PD op-timization of the available antibiotics, particularly giventhe increasing awareness of the pharmacokinetic alter-ations that occur in the critically ill patient. Combinationtreatments seem to be important, at least in the empiricalphase of treatment, to ensure adequate coverage of thepatient and improve clinical outcome. However, ran-domized clinical trials are urgently needed to define thepossible benefit from combinations in various settings.Most importantly, infection control measures and promptdiagnostics are the cornerstones to prevent further

transmission of MDR and XDR pathogens in healthcaresettings and to optimize early antimicrobial treatment.

Acknowledgments Research made in collaboration with theCritically Ill Patients Study Group (ESGCIP) of the European So-ciety of Clinical Microbiology and Infectious Diseases (ESCMID).

Conflicts of interest MB serves on scientific advisory boards forAstraZeneca, Bayer, Cubist, Pfizer Inc, MSD, Tetraphase, andAstellas Pharma Inc.; has received funding for travel or speakerhonoraria from Algorithm, Angelini, Astellas Pharma Inc., As-traZeneca, Cubist, Pfizer MSD, Gilead Sciences, Novartis,Ranbaxy, and Teva. GP has received funding for travel or speakerhonoraria from Astellas, Gilead, MSD, Novartis, and Pfizer. JGMhas received speaker honoraria from Astellas, Gilead, MSD, No-vartis, and Pfizer and a scientific grant from Astellas. DPN:Consultant, member of the speakers bureau, or has received re-search grant funding from AstraZeneca, Bayer, Cubist, Actavis,GSK, Medicines Co., Merck, Pfizer, and Tetraphase. JDW hasserved on advisory boards for Bayer, Cubist, MSD, and SumitomoPharma. PE has received funding for advisory board or speakerhonoraria from Astellas, MSD, and Pfizer. MHW has receivedconsulting fees from Abbott Laboratories, Actelion, Astellas, Astra-Zeneca, Bayer, Cerexa, Cubist, Durata, The European TissueSymposium, The Medicines Company, MedImmune, Merck, MotifBiosciences, Nabriva, Optimer, Paratek, Pfizer, Roche, Sanofi-Pasteur, Seres, Summit, and Synthetic Biologics; and lecture feesfrom Abbott, Alere, Astellas, Astra-Zeneca, and Pfizer; grant sup-port from Abbott, Actelion, Astellas, bioMerieux, Cubist, DaVolterra, The European Tissue Symposium, Merck, and Summit.The other authors declare no conflict of interests.

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