Impact of a Risk Stratification Tool on the Outcome of Liver Transplant Recipients Colonized With Carbapenem Resistant Enterobacteriaceae: an Observational Study
Conditions: Liver Transplantation, Carbapenem-Resistant Enterobacteriaceae Colonization
Sponsor: University of Bologna

 
 
Study Code: CRECOOLT 3.0 
 
 
 
Impact of a risk stratification tool on the outcome of liver 
transplant recipients colonized with carbapenem resistant 
Enterobacteriaceae: an observational study 
 

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CRECOOLT 3.0_study 
 
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Authors: 
Professor Maddalena Giannella, Doc. Matteo Rinaldi 
Department of Medical and Surgical Sciences – Alma Mater 
Studiorum University of Bologna, OU of  Infectious Diseases, 
University Hospital of Bologna, Policlinico S.Orsola-Malpighi 
Via Massarenti 11, 40138 Bologna 
Tel: 051 2143199 
Fax: 051 343500 
e-mail: maddalena.giannella@unibo.it 
Document: 
Protocol 
Version: 
1  
Release Date: 
31-08-2022 
Number of pages: 
16 
 

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PROTOCOL SIGNATURE PAGE 
 
Protocol Code: CRECOOLT 3.0 
 
 
 
 
 
 
 
 
 
 
 
     
     12/09/2022 
Maddalena Giannella 
Signature 
 
date 
 
 
 
 
 
 
 
 
 
 
 
     12/09/2022 
Matteo Rinaldi 
Signature 
 
date 
 
 
 
 
 
 
DECLARATION OF THE INVESTIGATOR: 
 
Protocol Code: CRECOOLT 3.0 
 
I declare that I have read the protocol and I agree to conduct this clinical study in accordance 
with all the requirements of the protocol and according to the Guidelines of Good Clinical 
Practice and the principles of the Declaration of Helsinki. 
 
 
 
 
 
 
 
      
 
 
 
    12/09/2022 
Maddalena Giannella 
Signature  
 
date 
(Principal Investigator) 
 
 
 

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 CONTENT INDEX 
1 
STUDY-SPECIFIC ABBREVIATIONS AND TERMS ........................................................................................ 6 
2 
INTRODUCTION ...................................................................................................................................... 7 
2.1 
BACKGROUND AND RATIONALE ......................................................................................................................... 7 
2.2 
IMPORTANCE OF THE STUDY AND ITS CLINICAL RELEVANCE .................................................................................... 10 
2.3 
PRIMARY OBJECTIVE ...................................................................................................................................... 11 
2.4 
SECONDARY OBJECTIVES ................................................................................................................................ 11 
2.5 
PRIMARY ENDPOINT ...................................................................................................................................... 11 
2.6 
SECONDARY ENDPOINTS ................................................................................................................................ 11 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 12 
3.1 
TYPE OF STUDY ............................................................................................................................................ 12 
3.2 
STUDY DESIGN ............................................................................................................................................. 12 
3.3 
MONO OR MULTICENTER STUDY ...................................................................................................................... 14 
3.3.1 
Inclusion Criteria ............................................................................................................................ 15 
3.3.2 
Exclusion Criteria ........................................................................................................................... 15 
3.3.3 
Population size of the study and statistical power ........................................................................ 15 
3.4 
GRANTS ..................................................................................................................................................... 16 
4 
DATA MANAGEMENT ........................................................................................................................... 17 
5 
ADMINISTRATIVE PROCEDURES AND DECLARATIONS .......................................................................... 18 
5.1 
INFORMED CONSENT AND CONSENT TO THE PROCESSING OF PERSONAL DATA ........................................................... 18 
5.1.1 
Methods of acquiring informed consent and consent to the processing of personal data............ 18 
5.1.2 
Cases for which the acquisition of consent to the processing of personal data is not required .... 18 
5.2 
STUDY – SPECIFIC INSURANCE ......................................................................................................................... 18 
5.3 
AMENDMENTS TO THE PROTOCOL AND CHANGES TO THE CONDUCT OF THE STUDY .................................................... 19 
5.4 
CONCLUSION OF THE STUDY ........................................................................................................................... 19 
5.5 
PUBLICATION POLICY ..................................................................................................................................... 19 
5.6 
DOCUMENTATION ARCHIVE ............................................................................................................................ 20 
5.7 
INSPECTIONS/CHECKS .................................................................................................................................... 20 
5.8 
CONTACT PERSONS ....................................................................................................................................... 20 
6 
BIBLIOGRAPHY ...................................................................................................................................... 21 

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1 
STUDY-SPECIFIC ABBREVIATIONS AND TERMS 
 
OLT 
orthotopic liver transplantation 
CRE 
carbapenem resistant Enterobacterales 
SOT 
solid organ transplant 
HR 
hazard ratio 
SOFA 
Sequential organ failure assessment 
KIDGO 
Kidney Disease: Improving Global Outcomes 
AKI 
Acute kidney failure 
RRT 
Renal replacent therapy 
CMV 
Cytomegalovirus 
MV 
Mechanical ventilation 
 
  
 
  
 
  
 
  
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 

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2 
Introduction 
2.1 
Background and rationale 
    
Patients undergoing orthotopic liver transplantation (OLT) are more susceptible to acquire 
colonization with multidrug resistant Gram-negative bacteria, in particular with carbapenem 
resistant Enterobacterales (CRE), than non-solid organ transplant (SOT) recipients or 
patients with other types of SOT (1). CRE colonization, either acquired before either 
emerged after OLT, has been associated with highest risk of developing CRE infection after 
OLT (2,3) with a dramatic impact on patient survival (4). For these reasons, along with the 
improvement of infection control and antimicrobial stewardship policies, preventive strategies 
targeted to patients colonized with CRE have been suggested (5,6). However, several 
uncertainties have to be considered concerning the optimal timing for intervention, the 
correct patient stratification, and the choice of drugs. Regarding the timing for intervention, 
surgical prophylaxis is regarded as an option. However, it should be considered that of the 
overall burden of CRE carriage in OLT recipients, pre-transplant acquisition accounted for 
lower than one third of isolations in a large multicenter retrospective study (7). Furthermore, 
even when CRE carriage is present at transplantation, the colonization status is frequently 
recognized in the immediate post-operative period by results of rectal swabs done at surgery. 
Finally, current data about the efficacy of targeted prophylaxis in patients colonized with CRE 
are very limited and showed controversial results (8,9). Thus, in the majority of cases the 
unique window for preventive strategies is represented by the post-transplant course. This 
requires an active screening policy as well as the possibility of stratifying colonized patients 
according to their risk of developing CRE infection, and eventually to die, in order to target 
specific interventions in those patients who could most benefit, and to optimize essential 
resources as the new drugs. Indeed, since the availability of new drugs such as 
ceftazidime/avibactam, 
meropenem/vaborbactam 
and 
cefiderocol, 
the 
therapeutic 
management and outcome of patients colonized and/or infected with CRE has changed in 
both general population and SOT recipients (10). New drugs are associated with higher rates 
of clinical cure and patient survival, as well as with lower toxicity, compared with old 
regimens (11). However, rates of microbiological failure around 10%, consisting in persistent 
positive cultures or relapsing infections associated with development of further resistance, 

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have been reported raising concerns about the need of optimizing the use of new drugs to 
avoid the loss of their efficacy. 
To this end, we have recently carried out a large multicenter observational study aimed at 
building a prediction model to stratify patients according to their risk of developing CRE 
infection after OLT (7). The study cohort consisted of 800 OLT recipients colonized with 
CRE, 25% were colonized at OLT, and 75% acquired colonization within two weeks after 
OLT. Infection rate was of 30% and was similar between the two groups as well as the 
infection severity. All-cause 6-month mortality rate among patients who developed CRE 
infection was 58% vs. 20% among carries who did not develop infection (p<0.001). Almost all 
infections occurred within 60 days after transplant. Thus, we derived, and internally validated, 
a prediction tool able to stratify the risk of CRE infection at 30 and 60 days after OLT 
(CRECOOLT score) based on six variables easily to monitor such as CRE colonization 
detected in the 60 days prior to transplant, CRE colonization detected post-transplant, 
multisite colonization, need of prolonged (≥48 hours) mechanical ventilation, acute renal 
failure, and reintervention. Examples of the cumulative incidence of CRE infection and 
nomogram-derived prediction for a low-risk (panels a, b) and a high-risk (panels c, d) patient 
are illustrated in score was made available as app to be used at bed site.
We explored the potential clinical utility of our model using a decision-curve analysis to 
examine the “net benefit” of applying the prediction model across a range of CRE infection 
threshold probabilities (12). A theoretical risk-model guided strategy (i.e. empiric 
administration of CRE-active antibiotics) was compared against two default strategies- “treat 

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all” and “treat none” suggesting that the model-directed intervention would show net benefit 
over default strategies when the overall CRE infection risk exceeded 10%.  
 
Finally, we have explored the risk of death using the same variables included in the 
CRECOOLT score by a multi-state model obtaining three risk groups: low, intermedium and 
high (unsubmitted data). We have then estimated the potential impact of using ceftazidime-
avibactam in each of such groups finding a significant protective role (HR 0.32) only in 
patients with intermedium or high risk of dying. 

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2.2 
Importance of the study and its clinical relevance  
 
Although CRE infection after OLT have a dramatic impact on patient survival and several 
implementations have been proposed (i.e. preventive strategies or targeted surgical 
prophylaxis), a standardized approach in colonized patients is still missing. We recently 
developed and internally validated a bed-side score to stratify the risk of CRE infection (7). 
We deem such score could be useful to select patients at high of infection as well as of poor 
outcome supporting clinicians in the therapeutic management in such difficult setting. With 
the present study we aimed at investigating the impact on outcome of the systematic 
evaluation of the risk score in OLT recipients colonized with CRE. 
 
 

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2.3 
Primary objective 
The primary objective is to investigate the impact on all-cause 90-day mortality in OLT 
recipients colonized with CRE using the CRECOOLT score for the systematic evaluation of 
CRE infection risk. 
2.4 
Secondary objectives 
Secondary objectives include:  
 
To analyse days of therapy with anti-CRE antibiotic regimens in patients with and 
without systematic evaluation of CRE infection risk, according to clinical practices.  
 
To evaluate rates of documented CRE infections and their relapses with selection of 
further resistance in patients with and without systematic evaluation of CRE infection 
risk.  
 
To evaluate the length of hospital, ICU stay and rates of hospital readmission in 
patients with and without systematic evaluation of CRE infection risk. 
2.5 
Primary endpoint 
Primary endpoint will be all-cause mortality assessed at 90 days after OLT. 
2.6 
Secondary endpoints 
Secondary endpoints will be assessed from OLT to 180 days and include: 
- 
Overall days of CRE antibiotics; 
- 
Rates of CRE infection;  
- 
Rates of CRE infection relapse;  
- 
Rates of CRE infection relapse with resistance to previously used antibiotics; 
- 
Hospital and ICU lengths of stay;  
- 
Hospital readmission for infectious complications.   
 

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3 
Investigational plan 
3.1 
Type of study 
Cross sectional study .................................. 
 
Retrospective Case-control study ................
 
Retrospective cohort study ......................... 
 
Prospective cohort study ............................. 
 
Retrospective and prospective cohort study..X 
Descriptive pilot/feasibility study ................. 
 
Qualitative study ......................................... 
 
3.2 
Study design 
All consecutive adult (≥18 years) patients undergoing OLT and found to be colonized with 
CRE within 60 days prior to or after transplantation.  
Retrospective period will be from January 2018 to December 2021. This time period has 
been established considering the introduction in the clinical use of new drugs active against 
CRE (i.e. ceftazidime-avibactam), to include both pre-COVID-19 and pandemic periods, and 
it is before developing the CRE-COOLT score. 
Prospective period will be carried out over 18-month period, starting soon after the approval 
by Ethic Committees. During this period, all patients undergoing OLT will be prospectively 
evaluated for study participation. In eligible patients who will accept to participate the 
CRECOOLT score will be systematically calculated once week, or at the occurrence of 
complications, until 60 days after OLT.  
The therapeutic management of all patients, during both retrospective and prospective 
periods, will be established by the attending physicians according with routine practice and 
not dictated by study protocol. Standard antibiotic prophylaxis according to local protocol will 
be performed during both study periods. Targeted (anti-CRE) antibiotic prophylaxis will be 
accepted, but for a duration no longer than 48 hours (see exclusion criteria). 

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The minimum follow-up period for all enrolled patients, during both retrospective and 
prospective periods, will be of 180-days after OLT. This follow-up duration has been 
established considering that OLT recipients colonized with CRE usually develop CRE 
infection within 60 days after OLT, indeed the CRE-COOLT score has been developed and 
proposed to be used during this time period (7). Thus, primary outcome (all-cause mortality) 
will be evaluated at 90 days after OLT, while secondary outcomes (especially relapse of CRE 
infections and emergence of further resistance) will be evaluated at 180 days (see 
endpoints). 
Total duration of the study: 24 months (18 recruitment / data collection +6 follow-up).  
Start of the study: soon after the approval by Ethic Committees and “nulla osta” of General 
Manager.  
 
Definitions 
CRE is defined as any Enterobacterales displaying in vitro non-susceptibility to any of the 
carbapenems according to the criteria (Clinical and Laboratory Standards Institute or 
European Committee on Antimicrobial Susceptibility Testing) adopted at the participating 
center during the study period. EUCAST criteria (13).  
Colonization status is defined as isolation of CRE from rectal swab or other samples, other 
than blood cultures or sterile fluids, (e.g., urine, respiratory samples, superficial skin 
samples) in absence of symptoms and signs of infection. Multisite colonization is defined as 
concomitant CRE isolation from more than one of such samples.   
CRE infection is defined according to Center for Disease Control criteria (14). CRE infection 
relapse is defined as new symptoms and positive cultures yielding CRE in patients with prior 
documented clinical and microbiological response to anti-CRE antibiotic course.  
 
Study variables 
The following variables will be collected, according to normal clinical practice: demographic 
data (age and sex); comorbidities according to Charlson index; underlying liver disease, and 
severity of liver disease according to Model for End stage Liver Disease (MELD) at inclusion 
in waiting list and at OLT.  

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For graft characteristics donor age, cold ischemia time, combined transplant, culture results 
of organ donor and preservation fluid will be collected.  
Intraoperative variables will include: antibiotic prophylaxis, biliary anastomosis, bleeding with 
need of massive transfusion (≥40 units of cellular blood products), prolonged intervention (≥ 
8 hours).  
Post-OLT complications will include: re-intervention, Acute Kidney Injury (AKI) according to 
KDIGO criteria (15), renal replacement therapy (RRT), prolonged (≥48 hours) mechanical 
ventilation (MV), graft dysfunction (primary or secondary), biopsy-proven rejection, re-
transplantation, and CMV DNAemia >100,000 copies/ml.  
Management of CRE colonization will be recorded according to the following categories: no 
strategy adopted, pre-emptive strategy according to the risk stratification using the 
CRECOOLT tool, standard empirical/targeted treatment upon to clinical deterioration. All 
drugs used for these purposes will be recorded with relative administration schedules and 
onset/end dates. 
For CRE infection: clinical severity according to SOFA and septic shock criteria on the day of 
positive clinical sample collection (infection onset) will be recorded, infection source and 
presence of bloodstream infection, appropriateness of empirical therapy (defined as 
administration of at least one in vitro active drug within 24 hours from infection onset), 
targeted antibiotics with relative administration schedules and onset/end dates, source 
control, documentation of and time to microbiological clearance, clinical response at 7 days, 
and CRE infection relapse with susceptibility pattern of recurrent isolate.   
For outcome, lengths of hospital and ICU stay after OLT, number of re-hospitalization, all-
cause mortality. 
 
3.3 
Mono or multicenter study 
Monocentric .................................................
  
National multicenter .....................................
  
         International multicenter ................................ X 
 
 

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All the transplant programs belonging to the CRECOOLT study group (7) will be invited to 
participate. 
 
3.3.1 Inclusion Criteria 
 
Signature of the informed consent 
 
Age ≥ 18 years 
 
CRE colonization within 60 days prior to or after transplantation 
 
3.3.2 Exclusion Criteria 
 
Patients receiving targeted antibiotic prophylaxis (against CRE) for a period longer 
than 48 hours   
 
Patients receiving graft from a donor with cultures yielding a carbapenem-resistant 
Gram negative bacteria 
 
3.3.3 Population size of the study and statistical power 
 
Our hypothesis is that the systematic use of the CRE-COOLT score at the bedside of OLT 
recipients colonized with CRE may improve antibiotic use and outcome of patients. 
According with prior literature data, the post-OLT all-cause mortality rate in CRE carriers is 
around 30%, ranging from 20 to 58% in non-infected and CRE infected patients, respectively 
(7). Our hypothesis is to observe in the prospective period a reduction of overall mortality of 
about 15%, thus accepting a power of at least 80% and an alpha error of 5%, we calculated 
a sample size of 120 patients in both study period (retrospective/prospective). 
 
Descriptive statistics will be obtained for all the variables assessed in the study population. 
Mean and standard deviation will be used for normally distributed continuous variables, 
median and interquartile ranges for skewed distributions, proportions for categorical 
variables. Comparison between retrospective and prospective periods will be done, 
differences will be tested with parametric or nonparametric tests for quantitative variables 
according with their distribution, and with Pearson’s Chi-square or Fisher’s exact test, as 
appropriate, for categorical variables.  

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To assess the impact of a systematic use of CRE-COOLT score on all-cause 90-day 
mortality, univariate and multivariate Cox regression analysis will be carried out. Statistical 
significance will be represented by a p value of <0.05. 
 
3.4 
Grants 
Are there any funding for the study? 
No  ................................................................... 
  
Yes, with internal grants ................................... 
  
Yes, by institutional third parties ...................... 
  
Yes, from private third parties ............................ X 
 
 
The study was submitted to Pfizer Global Medical Grants and received a positive evaluation 
(Pfizer Grant 75038507). Access to funds is subject to the submission of the final version of 
the protocol with the relative favorable opinion of the Ethics Committee on the Pfizer Global 
Medical Grants system, no later than 10/30/2022, and to an agreement between our center 
of affiliation ( Department of Medical and Surgical Sciences of the University of Bologna) and 
Pfizer to be reached within the next 3 months. 

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4 
Data management 
 
Pseudonymized data will be collected using a pre-established electronic case report form 
(eCRF) and managed using REDCap capture tool hosted by Alma Mater University of 
Bologna (16). Data sources will be clinical charts and hospital electronic records. 
During all the study period, the principal investigator will inform investigators about the status 
of patient enrolment, follow-up, and data collection by newsletter periodically.  
At the end of the enrolment and follow-up period, the principal investigator will be responsible 
for reviewing all collected data for integrity and accuracy. Queries will be generated and sent 
to the local investigators. The database will be locked after fulfilment of all the queries. 

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5 
Administrative procedures and declarations 
5.1 
Informed consent and consent to the processing of personal data 
The study protocol, any protocol amendment, informed consent, consent to the processing of 
personal data and any other information for patients must be approved by the Ethics 
Committee. 
To participate in the study, each patient must provide written informed consent as well as 
consent to the processing of their personal data.  
5.1.1 Methods of acquiring informed consent and consent to the processing of 
personal data 
Informed consent will be obtained by local investigators in collaboration with the attending 
physicians. For the retrospective cohort, it will be obtained during the standard scheduled 
follow-up visits. For the prospective cohort, informed consent will be administered to the 
patients during the evaluation visit for enrolment. Only patients who will provide informed 
consent will be enrolled.  
 
5.1.2 Cases for which the acquisition of consent to the processing of personal 
data is not required 
For the retrospective cohort, if patients will be unable to give the consent (deceased or lost at 
follow-up), data will be collected, in order to avoid a significant reduction in the sample size 
generating potential bias on results according to Italian regulatory dispositions (art. 110, 
comma 1 d.lgs. 196/2003 and in accordance with the Provision containing the requirements 
relating to the processing of particular categories of data, pursuant to art. 21, paragraph 1 of 
Legislative Decree 10 August 2018, n. 101 issued by the Guarantor Authority for the 
protection of personal data (provv. n.146/2019). It will be mandatory to provide information 
about the study to all enrolled patients if reachable in a second time (Reg. UE 2016/679).  
5.2 
Study – specific insurance 
Considering the nature of the study, a specific insurance is considered unnecessary.  

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5.3 
Amendments to the protocol and changes to the conduct of the study 
If during the enrolment period, the principal and local investigators will agree that any 
deviation from the original protocol is needed to reach the predefined sample size and/or to 
avoid bias in the assessment of outcomes, the protocol will be revised and an amendment 
will be submitted to Ethic Committees.  
5.4 
Conclusion of the study 
After the lock of database, preliminary results will be shared with all the investigators in order 
to plan publication and other dissemination activities. These results will be used to 
communicate to local Ethic Committees the conclusion of the study. 
5.5 
Publication policy 
Preliminary results will be revised by all the investigators in order to refine statical analysis, 
and to plan publication and other dissemination activities (presentation of results at 
International Congresses of Infectious Diseases and Transplant Societies).  
For authorship, Recommendations for the Conduct, Reporting, Editing and Publication of 
Scholarly Work in Medical Journals (ICMJE Recommendations) will be followed. The ICMJE 
recommends that authorship be based on the following criteria: 
- 
Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
- 
Drafting the work or revising it critically for important intellectual content; AND 
- 
Final approval of the version to be published; AND 
- 
Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
According to the rules of good scientific practice, the principal investigator can claim the 
position of last author if he/she is not already first author. In the case of several research 
project leaders, they should agree on the last authorship among themselves at an early 
stage; in this context, shared first and last authorships should also be considered. As a 
rule, the "corresponding author" should be the research project leader with primary 

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responsibility. The middle group of co-authors will be included according to contribution 
to the manuscript as per the ICMJE recommendations. The CRECOOLT working group 
will be included as co-author in all manuscripts and communications. In the CRECOOLT 
group all the investigators and the attending physicians who contributed to patient 
enrolment and data acquisition should be acknowledged.     
5.6 
Documentation archive 
The principal investigator is responsible for the archiviation and conservation of the essential 
documents of the study, before, during and after the study conduction, according to the 
Italian law and good clinical practice.  
Patient data will be gathered pseudo-anonymously, included subjects will be identified by a 
number/code. Principal and local investigators will keep the original data of the patient and 
his personal informed consent in a safe place. 
5.7 
Inspections/checks 
If a regolatory authority will request an ispection, the principal investigator will soon inform 
the Ethic Committee.  
5.8 
Contact persons 
Contacts (telephone numbers and emails) of the involved physicians are reported in the 
Investigator Folder for the local center. 

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6 
Bibliography 
 
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transplant patients. J Antimicrob Chemother. 29 gennaio 2021;76(Suppl 1):i27–39. 
2. Freire MP, Oshiro ICVS, Pierrotti LC, Bonazzi PR, de Oliveira LM, Song ATW, et al. Carbapenem-
Resistant Enterobacteriaceae Acquired Before Liver Transplantation: Impact on Recipient Outcomes. 
Transplantation. aprile 2017;101(4):811–20. 
3. Giannella M, Bartoletti M, Campoli C, Rinaldi M, Coladonato S, Pascale R, et al. The impact of 
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6. Pouch SM, Satlin MJ. Carbapenem-resistant Enterobacteriaceae in special populations: Solid organ 
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7. Giannella M, Freire M, Rinaldi M, Abdala E, Rubin A, Mularoni A, et al. Development of a Risk 
Prediction Model for Carbapenem-resistant Enterobacteriaceae Infection After Liver Transplantation: A 
Multinational Cohort Study. Clin Infect Dis Off Publ Infect Dis Soc Am. 16 agosto 2021;73(4):e955–66. 
8. Freire MP, Song ATW, Oshiro ICV, Andraus W, D’Albuquerque LAC, Abdala E. Surgical site 
infection after liver transplantation in the era of multidrug-resistant bacteria: what new risks should be 
considered? Diagn Microbiol Infect Dis. gennaio 2021;99(1):115220. 
9. Taimur S, Pouch SM, Zubizarreta N, Mazumdar M, Rana M, Patel G, et al. Impact of pre-transplant 
carbapenem-resistant Enterobacterales colonization and/or infection on solid organ transplant 
outcomes. Clin Transplant. aprile 2021;35(4):e14239. 
10. Tumbarello M, Raffaelli F, Giannella M, Mantengoli E, Mularoni A, Venditti M, et al. Ceftazidime-
Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A 
Retrospective Observational Multicenter Study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2 novembre 
2021;73(9):1664–76. 
11. Karaiskos I, Lagou S, Pontikis K, Rapti V, Poulakou G. The “Old” and the “New” Antibiotics for 
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