The most recent concepts for the management of bacterial and fungal infections in ICU
The pattern of infections globally is changing as a result of myriad factors including global warming, increasing antimicrobial resistance, and population migration patterns. In Europe large numbers of refugees from the Middle East, Africa and elsewhere have introduced multidrug-resistant (MDR) tuberculosis and MDR Gram-negative bacteria including Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA) . Escherichia coli has the highest resistance rates (up to 38.1%) against broad-spectrum cephalosporins in Southern and Eastern Europe, while carbapenem-resistant Klebsiella pneumoniae is also increasingly common (59.4% in Greece, 34.3% in Italy, 20.5% in Romania and less than 2% in other EU countries) . Carbapenem resistance has also been reported in more than 50% of A. baumannii isolates in Portugal, Greece, Italy, Cyprus, Romania and Bulgaria. The clinical importance of increasing prevalence of MDR bacterial infections was highlighted by a systematic review assessing the impact of non-covering (inappropriate) empirical antibiotic treatment (IEAT) . Multi-covariate analyses demonstrated that the prevalence of any MDR pathogen, Acinetobacter spp. specifically, and more recent study years were associated with IEAT. MDR rates were independently associated with mortality and the prevalence of MDRs was associated with IEAT .
The prevalence of infection in critically ill patients caused by MDR bacteria is rapidly evolving. Clinical studies aimed at improving our understanding of the changing patterns of these infections are urgently needed. A recent article summarizing the discussion of a round table meeting organized by the European Society of Intensive Care Medicine (ESICM) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) highlighted list priorities in the management of MDR pathogens, identified areas that urgently require more research and made recommendations that should be implemented today . Ideal antibiotic utilization is an area of uncertainty requiring additional investigations aimed at better understanding dose optimization, duration of therapy, use of combination treatment, aerosolized antibiotics and the integration of rapid diagnostics as a guide for treatment . Recent advancements in laboratory techniques allow for the rapid identification of the infecting pathogen and antibiotic susceptibility testing that may guide fine-tuning of empirically selected regimens, facilitate de-escalation of unnecessary antimicrobials and support infection control decisions . To combat the issue of escalating antimicrobial resistance and IEAT, combination antimicrobial regimens have become increasing recommended for empiric and definitive therapy, especially for carbapenemase-producing K. pneumoniae . There is also moderate to limited evidence in support of combination therapy for treating carbapenemase-producing A. baumannii infections, including pneumonia and bacteraemia . One major issue in the spread of Gram-negative MDR bacteria is the overuse of carbapenems for empirical therapy that creates selective pressure for development of carbapenem resistance. Recently there has been a reappraisal of old compounds and a number of new drugs that will be important in the treatment of selected MDR pathogens and allow intensivists the possibility for “sparing” carbapenems. By definition, extended spectrum β-lactamases (ESBLs) are inhibited by β-lactamase inhibitors (BLBLIs) such as clavulanate and tazobactam. Because of this characteristic, β-lactam/β-lactamase inhibitors have been evaluated in several observational studies as carbapenem-sparing therapy for ESBL-producing bacterial infection. The MERINO trial was designed to help resolve the controversy of carbapenem vs piperacillin–tazobactam in the treatment of ESBL infections. The results make clear that piperacillin–tazobactam should no longer be considered an alternative to meropenem for empirical or definitive treatment of bloodstream infection due to ESBL infections .
Moreover, the presence of severe influenza continues to result in appreciable mortality especially among patients with compromised cardiopulmonary status and has been reported as a risk factor for invasive pulmonary aspergillosis and secondary bacterial infection with MDR pathogens even in non-immunocompromised patients .
Catheter and device-related infections represent a significant part of hospital-acquired infections, mostly due to the formation of biofilms. Hand hygiene and skin antisepsis for catheter insertion and handling remain the milestones of prevention of catheter colonisation . Superiority of skin disinfection with chlorhexidine–alcohol was further potentiated with a new randomised controlled trial in 16 intensive care units, from Japan . In the latter, both 0.5% and 1.0% alcohol chlorhexidine gluconate were superior to 10% aqueous povidone iodine for the prevention of intravascular catheter colonisation. In a high volume burn unit in the USA, a sustained reduction of central-line-associated bloodstream infection (CLABSI) rates from 15.5 per 1000 central-line days to zero over 3 years became feasible, with the implementation of a rigorous program translating research into practice including among others chlorhexidine bathing, chlorhexidine dressings and use of alcohol-impregnated caps .
Novel insights into biofilms will in the near future enable targeting of mature biofilms with short-course catheter locks for catheter salvage, with antibiotic adjuvants or enzymes (DispersinB, DNaseI) or cations chelators (EDTA), or molecules that directly target persister cells (sugars, ADEP4, antimicrobial peptides, etc.) . As another glimpse into the future, phage therapy and passive immunization could improve our ability to treat biofilm-forming bacteria . Direct molecular detection of pathogens in blood is anticipated as a breakthrough in microbiological diagnosis of severe infections. A multicentre, open-label, cluster-randomised crossover trial (EVAMICA) showed that the addition of direct molecular detection of pathogens in the blood with a commercial test to standard care improved microbiological diagnosis in patients with severe sepsis and shortened the time to start a species-specific antimicrobial therapy . Finally, therapeutic drug monitoring (TDM) provides a shift to refined dosing strategies for antimicrobials, compared to standard dosing, which is warranted to enhance the probability of achieving adequate drug exposure and clinical success .
The 10 most remarkable rules for antifungal stewardship programmes in ICU
Restrict or avoid antifungal prophylaxis particularly with fluconazole
Differentiate infection from colonisation and do not treat colonisation
Use non-culture-based diagnostics for early detection of IC (BDG, CAGTA, PCR)
Limit the use of empirical therapy just based on risk factors
Promote early pre-emptive antifungal treatment based on risk factors, (heavy) colonisation and biomarkers
Get treatment right the first time with adequate drugs, mainly echinocandins
Have adequate source control within 48 h (catheter removal, appropriate drainage, surgical control)
Use an adequate dose: low dose is associated with resistance
De-escalate whenever possible (if possible, within 5 days) from echinocandins to azoles
Stop early useless therapy and check duration of therapy (no more than 7–10 days for pre-emptive)
Compliance with ethical standards
Conflicts of interest
Dr. Bassetti has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, Bayer, Basilea, Cidara, Gilead, Menarini, MSD, Paratek, Pfizer, The Medicine Company, Tetraphase and Vifor. The other authors declare no conflict of interest.
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