Restricted antimicrobial prescribing in an area of highly prevalent antimicrobial resistance.

OBJECTIVE: To assess the predictive value for infection with multidrug-resistant organisms (MDROs) of reasons for empirical prescription of restricted antibiotics (rABX), in a setting with high resistance rates. METHODS: We prospectively studied all rABX prescriptions in a 550-bed tertiary teaching hospital from April 15 to June 14, 2018 and from September 1 to October 30, 2018. Prescribing physicians had to justify their decision by choosing one or more prespecified reasons. RESULTS: We reviewed 172 empirical prescriptions of rABX, which accounted for 67.2% of all rABX prescriptions. Stated reasons for empirical prescription of rABX were recent hospitalization (72.7%), escalation due to non-response to previous antimicrobials (47.7%), treatment for severe sepsis/septic shock (45.9%), escalation due to recurrence or deterioration (22.1%), prior MDRO infection (12.8%), and prior MDRO colonization (7.6%). Empirical treatment for septic shock or severe sepsis was the only significant predictor of MDRO isolation (OR=5.26, 95% CI: 1.5-18.4, P=0.009), while recent hospitalization had a high negative predictive value for MDRO (97.4%). Fourteen per cent of microbiologically documented infections were associated with MDROs resistant to the prescribed rABX. CONCLUSIONS: Empirical treatment for severe sepsis or septic shock was the only independent predictor of MDRO isolation. Recent hospitalization had a high negative predictive value for MDRO infection. The isolation of pathogens resistant to the prescribed rABX suggests that in a setting with widespread antimicrobial resistance, it could be difficult to reduce the empirical use of rABX without risking inadequate treatment.

Impact of a non-compulsory antifungal stewardship program on overuse and misuse of antifungal agents in a tertiary care hospital.

OBJECTIVES: To assess the impact of an antifungal stewardship (AFS) program on appropriate use, consumption and acquisition costs of antifungals, and on clinical outcomes (in-hospital-mortality, in-hospital-length-of-stay). METHODS: The study was conducted at a 535-bed tertiary-care hospital and had three consecutive periods. A) Observational period (10 months): all antifungal prescriptions were prospectively evaluated. B) Educational intervention to increase the awareness on proper antifungals use. C) Implementation of a non-compulsory AFS program (10 months) based on prospective audit and feedback. Interrupted time series analysis has been used to assess the impact of the intervention. RESULTS: During the pre-interventional period 198 AF prescriptions for 147 patients, have been evaluated compared to 181 prescriptions in 138 patients during the AFS period. Statistical analysis showed a significant immediate drop of inappropriate prescriptions after intervention with a significantly declining trend thereafter, and a significant drop of the total consumption of antifungals immediately after the intervention with a significant declining trend thereafter. All-cause, in-hospital- mortality was stable during the pre-intervention period with a significant declining trend after the AFS program implementation, although no immediate intervention effect could be established. Comparison of pre-and post-interventional periods showed significant reduction in acquisition costs (-26.8%, p<0.001) but no difference regarding the total number of bed-days (107,654 vs. 102,382), and mean length of hospital-stay (5.19 vs. 4.96 days, p=NS). CONCLUSIONS: The implementation of a non-compulsory AFS program resulted in significant improvement in the quality of prescriptions and reduction in antifungals consumption and acquisitions costs, without affecting the overall in-hospital-mortality and mean in-hospital-length-of-stay.

Cross-transmission of multidrug-resistant Acinetobacter baumannii clonal strains causing episodes of sepsis in a trauma intensive care unit.

OBJECTIVE: To investigate the mode of transmission of imipenem-resistant Acinetobacter baumannii strains causing episodes of sepsis. SETTING: A 7-bed trauma intensive care unit (ICU) in an orthopedic hospital in Greece. DESIGN: During a 14-week period (from January 10 to April 16, 2006), clinical specimens, along with samples taken on a weekly basis from the ICU environment and from the hands of health care workers (HCWs), were prospectively tested for imipenem-resistant A. baumannii. Pulsed-field gel electrophoresis was used to study the genetic relatedness of the isolates recovered from these specimens and samples. RESULTS: During the survey, imipenem-resistant A. baumannii was identified in 14 hospitalized patients, from whom 40 multidrug-resistant and imipenem-resistant A. baumanii isolates were recovered. These pathogens caused episodes of bacteremia and sepsis in all but one of the patients and contributed to the death of 3 patients. Samples for culture were obtained from the environment and from the hands of HCWs; 29 imipenem-resistant A. baumannii isolates were recovered from the environment, and 12 from HCWs. One predominant genotype and 2 less predominant genotypes were detected among the 81 imipenem-resistant A. baumannii isolates. All 3 of these genotypes were found among patients and HCWs and were recovered from environmental samples. INTERVENTIONS: Control measures consisted of the closure of the ICU and the transfer of the patients to other units. The ICU was disinfected, and adherence to proper hand hygiene protocol was reinforced. These same clonal isolates were not recovered from clinical or environmental samples during the month after the reopening of the ICU. CONCLUSIONS: The extensive dissemination of imipenem-resistant A. baumannii clonal strains causing episodes of bacteremia and/or sepsis resulted from modes of transmission via multiple contaminated surfaces and objects and transiently colonized HCWs' hands. Closure of the ICU and its meticulous environmental decontamination led to the successful control of the outbreak.

Colistin resistance in carbapenemase-producing Klebsiella pneumoniae bloodstream isolates: Evolution over 15 years and temporal association with colistin use by time series analysis.

Colistin is often the only available treatment option against infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp). In this study, the evolution of colistin resistance among CP-Kp and its relationship with colistin use in a tertiary-care hospital in Athens, Greece, was investigated. All CP-Kp blood isolates recovered between January 2002 and June 2016 were tested for susceptibility to colistin by agar dilution and broth microdilution methods. Data on colistin use were collected from the pharmacy database. Time series of colistin use and resistance were analysed using the Box and Jenkins method. A transfer function model was built to quantify the dynamic relationship between colistin use and resistance. Overall, 313 CP-Kp isolates were identified. The percentage colistin resistance increased from 0% in 2002 to 26.9% in 2016 (R2 = 0.5, P < 0.01). A temporal association between colistin use and resistance was observed; an increase in colistin use by 1 DDD/100 patient-days led to a 0.05 increase in the incidence rate of colistin resistance. The time lag between the effect of colistin use on subsequent variations in colistin resistance was 3 months. Colistin use and prior levels of colistin resistance could explain 69% of colistin resistance; in the remaining 31%, other factors might have played a role. The results presented here demonstrate a significant temporal association between colistin use and colistin resistance. These findings have important implications in implementing strategies to contain colistin resistance.

Characterization of clinical isolates of Pseudomonas aeruginosa heterogeneously resistant to carbapenems.

Fourteen apparently carbapenem-susceptible Pseudomonas aeruginosa clinical isolates that exhibited colonies within the inhibition zone around carbapenem discs were analysed. MICs of carbapenems were determined and the isolates were genotyped by PFGE. Population analysis, one-step selection of carbapenem-resistant mutants and growth curves of progenitors and carbapenem-resistant subpopulations were performed. Agar dilution MICs of imipenem and meropenem ranged from 0.5 to 4 mg l(-1) and from 0.25 to 2 mg l(-1), respectively. Population analysis confirmed subpopulations that grew in concentrations of up to 18 mg l(-1) and 12 mg l(-1) of imipenem and meropenem, respectively, at frequencies ranging from 6.9 x 10(-5) to 1.1 x 10(-7), suggesting that they might not be detected by standard agar dilution MIC testing. The minority subpopulations exhibited MICs for imipenem ranging from 10 to 20 mg l(-1) and for meropenem from 4 to 14 mg l(-1). The one-step 8 mg l(-1) selection of imipenem-resistant mutants test showed growth in all isolates at frequencies ranging from 3.8 x 10(-4) to 5.1 x 10(-7). Growth curves revealed a prolonged lag phase and a short exponential phase for the heterogeneous subpopulations compared with their respective native subpopulations. These findings may be indicative that the use of carbapenems can lead to selection of P. aeruginosa resistant subpopulations that subsequently cause infections and result in treatment failure.

Differences in the changes in resistance patterns to third- and fourth-generation cephalosporins and piperacillin/tazobactam among Klebsiella pneumoniae and Escherichia coli clinical isolates following a restriction policy in a Greek tertiary care hospital.

The aim of the present study was to investigate whether replacement of broad-spectrum cephalosporins (CEPs) by piperacillin/tazobactam (TZP) as first-line empirical therapy may have an effect on beta-lactam resistance among Klebsiella pneumoniae and Escherichia coli in a tertiary care hospital. Data regarding CEP and TZP consumption and resistance were collected on a bimonthly basis during an open-label 2-year (1 year observational and 1 year interventional) study. Consumption of ceftazidime was reduced by 64.5%. In contrast, consumption of the other third-generation CEPs (cefotaxime and ceftriaxone) remained almost stable, whereas an increase in consumption of TZP by 2.8-fold was observed. A significant decrease in resistance to third-generation cephalosporins among K. pneumoniae isolates was observed, and the incidence of extended-spectrum beta-lactamase-producing isolates was notably reduced. These findings were less evident among E. coli isolates. Despite the significant increase in TZP consumption, the respective resistance rates of both bacterial species examined have remained almost unchanged.

Wireless electrostimulation: a new approach in combating infection?

Electrostimulation (ES), hitherto successfully employed in wound treatment, has shown potential in antimicrobial applications, suggesting its use as synergistic to or replacement of antibiotics. The differential susceptibility of pathogens and host tissue and organs to various ES modalities might allow selective use against specific infections. The use of ES is cheaper in terms of development/testing, routine application and environmental footprint. If extensive substitution of chemical compounds is achieved, the development of resistance might be reversed through negative selection. A promising setup of ES seems to be the noncontact current transfer, due to low amperage similar to innate bioelectricity, painlessness, simple logistics and low risk for treatment-caused infection.

Recent Advances in Antiretroviral Agents: Potent Integrase Inhibitors.

Integrase strand transfer inhibitors (INSTIs) belong to a novel class of antiretroviral agents that have emerged as the new first-line treatments. Three such compounds are currently available, raltegravir, elvitegravir, dolutegravir and two more under development, bictegravir and cabotegravir. These compounds share the same mode of action but exhibit different pharmacokinetic/ pharmacodynamic properties, and drug-drug interactions. A series of studies in the past decade have established their efficacy compared to previous regimens, both in treatment- naïve and experienced patients. INSTIs have demonstrated a favorable safety profile with fewer adverse events and low rates of virological failure. Emergence of resistance to these agents, however, is a worrying concern, particularly for elvitegravir and raltegravir that display a lower genetic barrier than dolutegravir. On-going trials aim at establishing INSTIs as part of dual-drug HIV treatments or even monotherapy. New long-acting, injectable formulations are under investigation for treatment or prevention.

Pharmacokinetics of cefepime in bile and gall bladder tissue after prophylactic administration in patients with extrahepatic biliary diseases.

The purpose of this study was to determine the cefepime concentrations in serum, bile and gall bladder tissue after administration of a single dose in patients with extrahepatic biliary diseases for pre-operative antimicrobial prophylaxis. During a 3-year period (1999-2002), 30 patients aged above 18 years with extrahepatic biliary diseases (acute and chronic cholecystitis and symptomatic cholelithiasis) were included in the study. Cefepime concentrations were determined by the agar microbiological diffusion method. A significant correlation between serum and gall bladder tissue concentrations of cefepime with the sampling interval was observed (r2 = 0.771, P<0.0001), whereas no correlation between serum and bile fluid concentrations of the drug was noted. In patients with non-functioning gall bladder, very low tissue levels of cefepime were detected. During the time of surgery, serum and gall bladder tissue concentrations of cefepime exceeded the minimum inhibitory concentration for 90% of the organisms (MIC90) for most common pathogens. Cefepime has the required pharmacokinetic properties to be considered for pre-operative antimicrobial prophylaxis in patients undergoing biliary tract surgery.

Prevalence of infection by HTLV-I/II among pregnant women and high-risk groups in the Peloponnese peninsula, Greece.

Although screening for human T-cell lymphotropic virus types I and II (HTLV-I/II) antibodies in volunteer blood donors has been systematic in Greece since 1995, the epidemiology and the determinants of HTLV-I/II infection are not well defined among population groups. During 1997-2005, the prevalence of HTLV-I/II infection was investigated in a sample of 2016 pregnant women, 102 multitransfused haematologic and oncologic patients, 93 thalassaemic patients and 57 intravenous drug users originating from four geographic areas of Pelopennese peninsula, Greece. One recipient of HTLV-I infected blood and the relatives of a woman died from adult T-cell leukaemia/lymphoma (ATTL) related to HTLV-I have also been tested. The subjects were initially screened by an enzyme immunoassay whereas Western blot, INNO-LIA HTLV, polymerase chain reaction and nucleotide sequencing confirmed the infection. One thalassaemic patient had proved HTLV-I infection giving an overall prevalence of 11 per 1000. In the recipient of the infected blood and in two of the five relatives of the woman died from ATTL, HTLV-I infection was also detected. In none of the pregnant women, multitransfused patients and intravenous drug users HTLV-I/II infection was confirmed. These data suggest that HTLV-I is present in Greece among populations at high-risk. However, they would not support the need for HTLV-I/II antenatal screening in Greece.

Bronchial stump buttressing with an intercostal muscle flap in diabetic patients.

BACKGROUND: The development of a bronchopleural fistula (BPF) is a devastating complication after lung resection. Diabetic patients exhibit a high propensity for postpneumonectomy complications, particularly BPF. This study evaluated the use of an intercostal muscle flap to reinforce the bronchus in high-risk diabetic patients after pneumonectomy. METHODS: From February 2002 to December 2005, 70 patients with established diabetes mellitus undergoing pneumonectomy were prospectively enrolled in this study. Patients were randomized to have their bronchial stump reinforced with an intercostal muscle flap or to a conventional resection. A univariable statistical analysis was performed to assess differences in perioperative variables and in outcomes of interest. A multivariable logistic regression analysis was also performed to evaluate the association of BPF development with a number of confounding variables, including intercostal muscle flap usage. RESULTS: Randomization ensured that groups were equally distributed. Mean follow-up was 18 +/- 9.2 months. The group that received an intercostal muscle flap had a lower incidence of BPF development (0% versus 8.8%; p = 0.02) and of empyema (0% versus 7.4%; p = 0.05) compared with the group that received conventional pneumonectomy. CONCLUSIONS: The low incidence of BPF and empyema observed in patients who received an intercostal muscle flap suggest that bronchial stump reinforcement with this technique is a highly effective method for the prevention of BPF in high-risk diabetic patients.

Detection of a novel variant bla(CTX-M-3) extended spectrum beta-lactamase gene in a community-acquired Escherichia coli isolate.

A highly cefotaxime- and cefepime-resistant but ceftazidime-sensitive Escherichia coli isolate was recovered from a community-acquired urinary infection of a Greek patient. Susceptibility testing, transfer assays, plasmid analysis as well as PCR and sequencing techniques were used to investigate the underlying mechanism of resistance. The isolate carried a new variant of the bla(CTX-M-3) gene that possessed a T instead of A at nt position 663. Cefotaxime resistance was transferable and carried on a 60 kb plasmid. The bla(CTX-M-3) variant was located downstream of an ISEcp1B element. The emergence of this new derivative indicates further evolution of the worldwide-distributed bla(CTX-M-3) gene.

In vivo effect of carbon dioxide laser-skin resurfacing and mechanical abrasion on the skin's microbial flora in an animal model.

BACKGROUND: Although beam-scanning carbon dioxide (CO2) lasers have provided a highly efficient tool for esthetic skin rejuvenation there has been no comprehensive animal studies looking into microbial skin changes following CO2 laser skin resurfacing. OBJECTIVE: To evaluate the in vivo effects of CO2 laser skin resurfacing in an experimental rat model in comparison with mechanical abrasion on the skin microbial flora. METHODS: Four separate cutaneous sections of the right dorsal surface of 10 Wistar rats were treated with a CO2 laser, operating at 18 W and delivering a radiant energy of 5.76 J/cm2, while mechanical abrasions of the skin were created on four sections of the left dorsal surface using a scalpel. Samples for culture and biopsies were obtained from the skin surfaces of the rats on day 1 of application of the CO2 laser or mechanical abrasion, as well as 10, 30, and 90 days after the procedure. The presence of four microorganisms (staphylococci, streptococci, diphtheroids, and yeasts) was evaluated as a microbe index for the skin flora, and colony counts were obtained using standard microbiological methods. RESULTS: Skin biopsy specimens, following CO2 laser treatment, initially showed epidermal and papillary dermal necrosis and later a re-epithelization of the epidermis as well as the generation of new collagen on the upper papillary dermis. The reduction in microbial counts on day 1 of the CO2 laser-inflicted wound was statistically significant for staphylococci and diphtheroids compared with the baseline counts (p=.004 and p<.001, respectively), and for staphylococci, diphtheroids, and yeasts compared with the scalpel-inflicted wound on the same day (p=0.029, p<.001, and p=.030, respectively). CONCLUSIONS: Skin resurfacing using CO2 lasers considerably reduces microbial counts of most microorganisms in comparison with either normal skin flora or a scalpel-inflicted wound. This might contribute to the positive clinical outcome of laser skin resurfacing.