| Abstract |
Study 1: Antimicrobial resistance and antibiotic consumption in the University
Hospital of Heraklion
Objective: to study the most common isolates, their main resistance patterns, the
consumption of antibiotics, as well as related timely trends in the university hospital of
Heraklion.
Methods: During a 15-month period (January 2009 through March 2010), microorganisms
isolated in the hospital per sample and their respective resistance patterns were recorded
on a daily basis. Aggregate data concerning antibiotic consumption were analyzed for two
different time periods, 2004-06 and 2008-09. Antibiotic consumption was classified
according to the J01 group of the Anatomical Therapeutic Chemical 2006 of the World
Health Organization. Results were compared to other studies from the literature.
Results: 6364 non duplicate isolates were recorded and 4705 (73.9%) were nosocomial, of
which 39.1% were isolated in medical departments, 26.6% in surgical departments, 17.8%
in the ICU and 16.5% in pediatric departments. The most commonly isolated
microorganisms were coagulase-negative staphylococci (CNS, 18.4% of total), E. coli
(16.0%), Enterococcus spp (11.1%), K. pneumoniae (8.5%) and P. aeruginosa (7.4%). CNS
were the most common microorganisms in blood cultures (46.6% of positive blood
cultures), E. coli was the most common microorganism cultured from urine (54.4%), and
from the lower respiratory tract the most common isolates were A. baumannii (19.9%), P.
aeruginosa (13.5%), K. pneumoniae (11.1%) and S. aureus (10.6%). Compared to previous
years, most resistance rates were similar or decreasing, with the exclusion of K.
pneumoniae isolates which presented a clear increase in resistance to all tested antibiotics
(56.7% production of ESBL, 42.2% resistance to imipenem, 51.7% to fluoroquinolones,
7.1% to colistin). Increasing resistance to fluoroquinolones was also observed among E.
coli isolates, whereas A. baumannii were overall resistant to carbapenems (82.9%), with
isolates from the ICU, Internal Medicine, Hematology, Nephrology and Neurosurgery
departments being increasingly resistant compared to previous years. Resistance patterns
of P. aeruginosa were steady compared to previous years (19.8% to imipenem, 12.4% to
fluoroquinolones, 7.2% to gentamicin) and similar to rates presented in the literature.
Resistance rates of gram-positive microrganisms, particularly vancomycin-resistant
enterococci (5%),, methicillin-resistant S. aureus (39.1%) and methicillin-resistant CNS
(66.1%), were lower in 2009 compared to previous years and were also similar or lower
than rates reported in the literature. In the ICU, the most common blood isolates were CNS
(isolated in 53.7% of blood cultures), while A. baumannii (25.6%) and K. pneumoniae
(13.2%) prevailed in lower respiratory tract samples. High resistance rates were observed
among K. pneumoniae and A. baumannii isolates, whereas resistance rates of staphylococci,
enterococci, E. coli and P. aeruginosa were similar or lower compared to the literature.
Concerning antibiotic consumption, cephalosporins were the most commonly
prescribed antibiotics in the hospital (20% of total consumption,), followed by
fluoroquinolones (15%) and b-lactam/inhibitor combinations (13%). Total antibiotic
consumption had a 73% increase in 2009 compared to 1998 and mainly involved
extended spectrum antibiotic groups. Compared to most studies, there is similar or lower
consumption of b-lactams, but a significantly higher consumption of cephalosporins,
carbapenems and new antibiotics such as macrolides, fluoroquinolones, glycopeptides,
linezolid, polymyxins, daptomycin and tigecycline. Total antibiotic consumption in the ICU
was significantly higher compared to the hospital overall and the literature.
Conclusions: this study highlights the most important areas for improvement: high
resistance rates among the most commonly isolated gram-negative microorganisms and
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an increasing consumption of extended spectrum and of novel, last resort antibiotics,
accompanied by a decrease in consumption of narrow-spectrum antibiotics. In the ICU,
enhancement of infection control interventions, as well as antimicrobial stewardship are
required due to high resistance rates among K. pneumoniae and A. baumannii isolates and
increased antibiotic consumption.
Study 2: Infections by pandrug-resistant gram-negative bacteria: clinical profile,
therapeutic management, and outcome in a series of 21 patients
Objective: to describe and analyze the clinical characteristics, therapeutic management and
outcome of infections due to pandrug-resistant (PDR) gram-negative bacteria which
occurred over a 2-year period in the University Hospital of Heraklion.
Methods: observational case series study of infections due to PDR gram-negative bacteria
from April 2006 through April 2008 in the university hospital of Heraklion. Isolated A.
baumannii, K. pneumoniae and P. aeruginosa strains were considered PDR if they were
resistant to all classes of antibiotics used for empirical treatment.
Results: A total of 21 patients infected by 23 PDR gram-negative bacteria were recorded.
The mean APACHE II score on admission was 18.8, the mean Charlson comorbidity index
was 2.9, and 20 (95.2%) patients had previous ICU hospitalization. All patients had recent
exposure to multiple antibiotics (median, 6 antibiotic groups). Infections occurred on a
mean of 41.5 days after admission. The mean length of stay after infection was 54.6 days
and 5 (23.8%) patients died due to the infection. Treatment was mainly based on a
colistin-containing regimen (47.6%) or tigecycline (33.3%). Although clinical and
demographic characteristics were similar between the two groups, all 7 patients treated
with tigecycline had total resolution of the infection and a significantly shorter length of
hospital stay after infection.
Conclusions: patients who suffered an infection by a PDR gram-negative organism were
characterized by severe underlying diseases, significant comorbidity, long hospital stay
and previous exposure to multiple antimicrobials and invasive devices. The prolongation
of hospitalization after PDR infection was notable, but mortality was not as high as
expected. Administration of tigecycline was associated with successful treatment and
decreased length of hospital stay. Prudent use of tigecycline is needed to preserve it as an
option for successful treatment of infections caused by PDR microrganisms.
Study 3: Evolution of multidrug resistance in Klebsiella pneumoniae isolates in
hospitals of Crete
Background: KPC-2-producing Klebsiella pneumoniae sequence type (ST)-258 has been
rapidly expanding and is often associated with serious infectious carrying a high mortality,
necessitating the use of last-line antibiotics including colistin and tigecycline.
Objective: To describe the genetic determinants of acquired resistance in carbapenemresistant
K. pneumoniae isolates and to assess the evolution of resistance through time, in
hospitals of Crete.
Methods: Randomly selected, single-patient carbapenem-resistant K. pneumoniae strains
recovered during 2 periods, 2010 and 2013/14, in three hospitals of Crete (University
Hospital of Heraklion, Venizelio General Hospital and General Hospital Rethymnon) were
collected and analyzed. Phenotypic, molecular and whole genome analysis were
performed, in order to define the molecular mechanisms of acquired resistance.
Furthermore, resistance patterns between the 2 time periods were compared.
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Results: Among 34 collected strains (11 in 2010 and 23 in 2013/14), six were panresistant
in 2013/14. All KPC-KP isolates produced the KPC-2 carbapenemase which is considered
endemic in Greece. All isolates but one belonged to ST258. Notable higher resistance rates
to colistin and tigecycline were detected in 2013/14 compared to 2010. Resistance to
colistin is associated with mutations in mgrB, while resistance to tigecycline is associated
to ramR or to absence of the RamRA operon. A high diversity of multiple resistance genes
that were detected, indicate complex transmission dynamics.
Conclusions: This study reports the genetic determinants of antibiotic resistance to betalactam
and non-beta-lactam antibiotics among clinical isolates of K. pneumoniae from
hospitals of Crete. Molecular resistance mechanisms as well as the emergence of panresistant
strains are described. Comparison between 2 time periods showed that the
outbreak strain evolves and disseminates rapidly. In addition, core genome-MLST is
shown as a promising tool for molecular fingerprinting of KPC-KP ST258. Interventions
are needed to withstand further transmission of this phenotype, which holds grave
implications for the healthcare system.
Study 4: Application of international guidelines for the control of a nosocomial
outbreak: The example of an outbreak due to pandrug resistant Acinetobacter
baumannii
Background: The emergence and spread of pandrug-resistant (PDR) pathogens in hospitals
is of great concern, with severe potential consequences for the healthcare system and
patient outcomes.
Objective: This study reports the effectiveness of a bundle of interventions applied for the
management of an outbreak due to PDR A. baumannii (PDR-AB) in a tertiary-care hospital
in Crete. The microbiological, molecular and clinical characteristics of the epidemic strain
are also described.
Methods: The outbreak evolved in 3 phases from February through October 2014,
according to applied interventions. Molecular and genomic analysis of the outbreak strains
was performed, and clinical characteristics of patients were retrospectively retrieved. As
PDR-AB spread continued despite initial measures, a bundle of interventions according to
ESCMID recommendations was applied. These included enhanced hand hygiene, patient
isolation, environmental and patient screening cultures, chlorhexidine bathing, alert codes,
pre-emptive contact precautions in the ICU, continuous staff education, thorough
environmental cleaning, and structural modifications.
Results: PDR-AB was identified in 39 patients, of which 22 were in the ICU. Rep-PCR
analysis revealed that the outbreak was due to clonal dissemination. Full genome
sequencing revealed the antimicrobial resistance gene content. Carbapenem-resistance
was correlated with an intrinsic blaOXA-66 copy and the acquired blaOXA-23 gene. The
outbreak was contained only after implementation of the extensive bundle of
interventions. Mortality among the PDR-AB infected patients was 57.1%.
Conclusions: This study illustrates that only the application of an extensive bundle of
measures according to international recommendations enabled containment of the PDRAB
outbreak.
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