Class of 2012 / Specific Aims: The primary aim of this study was to determine the time to appropriate therapy for all patients with candidemia and/or bacteriemia (due to either Enterococcus or Streptococcus species) during a one year period in relation to time of blood culture, time of Gram-stain result, time of PNA FISH species result, and time of final species determination result. The secondary and third aims were to compare the time to appropriate therapy based on clinician group that was notified of Gram-stain result and PNA FISH result and compare the time to appropriate therapy based on PNA FISH assay results reported during the day and night microbiology laboratory shifts. Methods: This Institutional Review Board approved project is a retrospective, chart review evaluation of the 24 hour/ 7 days a week use of PNA FISH assays with therapeutic interventions by infectious diseases pharmacists and physicians on patient outcome measures and time to appropriate therapy. All patients admitted to an academic medical center during a one year period (April 2010-March 2011) with either Enterococcus, Streptococcus, or Candida species isolated from blood were included. Main Results: A total of 168 subjects were identified with Candida species isolated from 31 subjects and Enterococcus/Streptococcus species isolated from blood in 137 subjects. Conclusions: While reporting conditions can affect interpretation and intervention rates, rapid species identification assays such as PNA FISH can be used by pharmacists to provide antimicrobial therapy recommendations based on the species identification and to decrease the time to appropriate antimicrobial therapy.

Class of 2010 Abstract / OBJECTIVES:The main purpose of this study was to review recent and good quality studies of the antimicrobial therapy of for moderate to severe (“limb threatening”) DFI. The analysis of these studies was to conclude with one or two “standard” approach to the routine management of this clinical entity. METHODS: This literature review study consisted of an evaluation of clinical trials that compare two or more active systemic antimicrobial regimens for the treatment of moderate to severe (i.e., “limb-threatening”) diabetic foot infections in human patients. Literature sources were identified primarily from OVID MEDLINE, but also included additional tertiary sources. The primary criteria for the clinical studies were: prospective, controlled, randomized and investigator blinded. Studies had to be published after the year 2003, and be available in full-text in English. RESULTS: Ultimately, only four studies were found that met the criteria for consideration. Trials differed in numerous features. All four studies were sponsored by the manufacturer of one of the comparator drugs. Three of the four were non-inferiority design. Evidence is lacking that any of the suggested regimens are superior. CONCLUSIONS: Instead of meeting our original goal of concluding that one or two regimens could be the “standard” management of DFI, we were limited to commentary on the quality and applicability of the current literature on this clinical entity. Numerous suggestions for improvement in the clinical information provided by DFI studies were offered. We eagerly anticipate the publication of the updated IDSA guideline document on DFI.

Class of 2011 Abstract / OBJECTIVES: To evaluate the appropriateness of discharge antimicrobial medications for UTI in an adult population based on therapy prescribed. METHODS: In this retrospective chart review study the appropriateness of discharge antimicrobial therapy for patients admitted to an academic medical center during 3 weeks in 2010 was assessed based on culture results, estimated renal function, reported drug allergies, route of administration, and change in UTI from in-house to discharge prescribed therapy. RESULTS: A total of 35 patients with discharge UTI antimicrobials within the study period met inclusion criteria and were evaluated. According to available urinary culture and susceptibility data, 22 of 35 (62.8%) of received an appropriate antimicrobial therapy. Based on reported gastrointestinal function, all 35 patients could take oral medications but two patients with an appropriate oral therapy option received intravenous therapy. All patients were discharged with antimicrobials that were appropriate according to patients’ reported drug allergies and only one patient received an antimicrobial agent that was inappropriately adjusted based on the patient’s estimated renal function. UTI antimicrobial therapies were the same at 24 hours prior to discharge and as the discharge antimicrobial in 100% of patient cases evaluated CONCLUSION: The antimicrobial UTI discharge therapy was evaluated for appropriateness based on urine culture results, patients’ allergies, and patients’ estimated renal function. Overall, antimicrobial therapy was only appropriate in 22 of 35 (62.8%) of patients based on the available culture results.

Purpose: Use of ampicillin in outpatient parenteral antimicrobial therapy (OPAT) has historically been complicated by frequent dosing and short beyond use dates. However historic stability data relied on inaccurate testing methods. The purpose of this study is to evaluate the stability of ampicillin using high-pressure liquid chromatography (HPLC), the gold standard, in a real-world OPAT dosing model using continuous infusion at room temperature over 24 hours immediately following preparation compared to batches stored under refrigeration for 24 hours, 72 hours, and 7 days. Methods: An HPLC method was developed and validated as stability – indicating according to guidance in USP general Chapter . Method development included linearity, precision, accuracy, repeatability and forced degradation. Four batches were prepared using 4 different lots from 2 different manufacturers for each storage condition (immediate, 24 hours, 72 hours, and 7 days). Three 2-gram vials were each reconstituted with 10 mL of sterile water for injection (SWFI) and added to 250 mL of normal saline by a licensed pharmacist and stored in a laboratory refrigerator (2 – 8oC). A pump system was used to continuously circulate the solutions through medical grade tubing at room temperature. One milliliter aliquots were removed from each batch at time 0, 4 hours, 8 hours, 12 hours and 24 hours and analyzed for ampicillin concentration using the aforementioned HPLC method. The samples were filtered prior to analysis using a 0.22-micron syringe filter and analyzed in triplicates along with freshly prepared calibration samples (24 – 12 mg/mL). Peak area was used to determine percent recovery for each sample. Results: Each batch was assayed for initial concentration (20.34 – 21.50 mg/mL) upon preparation, and percent recovery was compared to that initial concentration thereafter. Acceptable recovery was defined as 90 – 110% of initial concentration. On the day of product preparation (immediate use), the average percent recovery over 24 hours was 96.4%. The other average percent recoveries were as follows: 95.8% (24-hour storage), 94.6% (72-hour storage) and 90.3% (7-day storage). These data represent the average percent recovery for all time points during the 24 hours sampling (n = 60 for each experiment). When evaluating individual time points, the percent recovery remained above 90% for all batches and time points except for the 7-day storage experiment. Under 7-day storage conditions, the percent recovery fell below 90% after 4 hours of circulation through the medical grade tubing. Furthermore, 95% confidence interval for percent recovery for ampicillin in the samples stayed within 90 – 110% of the initial concentration for the duration of the experiment for all test groups except 7-day storage. Conclusions and Relevance: Ampicillin can be prepared and stored in a refrigerator for up to 72-hours prior to continuously infusing at room temperature over 24 hours with less than a 10% loss of potency over the dosing period. This model supports twice weekly OPAT delivery of ampicillin.

Yes / Microbial keratitis can arise from penetrating injuries to the cornea. Corneal trauma promotes bacterial attachment and biofilm growth, which decrease the effectiveness of antimicrobials against microbial keratitis. Improved therapeutic efficacy can be achieved by reducing microbial burden prior to antimicrobial therapy. This paper assesses a highly-branched poly(N-isopropyl acrylamide) with vancomycin end groups (HB-PNIPAM-van), for reducing bacterial attachment and biofilm formation. The polymer lacked antimicrobial activity against Staphylococcus aureus, but significantly inhibited biofilm formation (p = 0.0008) on plastic. Furthermore, pre-incubation of S. aureus cells with HB-PNIPAM-van reduced cell attachment by 50% and application of HB-PNIPAM-van to infected ex vivo rabbit corneas caused a 1-log reduction in bacterial recovery, compared to controls (p = 0.002). In conclusion, HB-PNIPAM-van may be a useful adjunct to antimicrobial therapy in the treatment of corneal infections. / Medical Research Council and the Department of Biotechnology, India under grant number, MR/N50188/2.

Background and Objectives: Tendencies in Drug Use (DU) of highly toxic drugs-such as aminoglycosides and vancomycin and level of Rational Drug Use (RDU) is unknown in Lithuania. Our goal was to evaluate the first experiences in serum concentration measurements (Sc) of vancomycin & gentamicin, monitor patients receiving these antimicrobials and explore the practicality of using defined daily dose (DDD) in measuring their consumption tendencies. Design: DU study based on hospital pharmacy and hospital administrative databases; consumption in DDD per 100 occupied bed daily (100OBD) during 2004-6 and highest consumers of aminoclycosides and vancomycin in 2006. Evaluation of Sc in 2006. Monitoring assessment of 17 patients over 7 months. Data were processed with SPSS 16.0 using descriptive and comparative statistics for nonparametric values (Mann-Whitney test). Main outcomes measures: Annual consumptions of gentamicin, amikacin, tobramycin and vancomycin according to DDD/100OBD; intensity of gentamicin & vancomycin monitoring (as per number of DDDs) and proportions of abnormal Sc; Evaluation of the rationality level of antimicrobial’s therapy in a cohort of 17 patients. Results: Mean (±SE) DDD/100OBD values of gentamicin (240mg) were 3.67±0.69 (median 1.31; CI95% 2.29-5.06) in 2004; 4.53±1.87 (median 0.86; CI 95% 0.79-8.27) in 2005, and 4.24±0.82 (median 1.05; CI95%2.60-5.88) in 2006. Mean (±SE) DDD/100OBD values of amikacin (1000mg) were 0.55±0.17 (median 1.22; CI95% 0.23-0... [to full text] / Toksiškų vaistų, tokių kaip aminoglikozidų ir vankomicino, bei racionalus vaistų vartojimo tendencijos Lietuvoje dar nėra pakankamai žinomos. Mūsų darbo tikslas buvo nustatyti ir įvertinti aminoglikozidų ir vankomicino suvartojimo KMU klinikose tendencijas , gentamicino ir vankomicino koncentracijas kraujo serume (KKS), bei įvertinti 17 stebėtų pacientų gydymo šiais antibiotikais atvejus. Vaistų suvartojimo duomenys buvo gauti iš ligoninės vaistinės ir jos administracijos. Apskaičiuotos DDD šimtui lovadienių per paskutinius trejus metus (2004 – 2006), nustatyti daugiausia 2006 metais aminoglikozidų ir vankomicino suvartoję KMU klinikų skyriai. Įvertintos 2006 m. antibiotikų KKS. 17 pacientų, gavę šiuos antibiotikus, buvo stebimi 7 mėnesius. Duomenų statistinė analizė buvo atlikta naudojant SPSS 16.0 statistinę duomenų apdorojimo programą, kokybinių duomenų įvertinimui atliktas Mann-Whitney testas neparametriniams kriterijams. Vidutinis gentamicino (240mg) suvartojimas 2004m. (±SE) DDD/100OBD buvo 3.67±0.69 (median 1.31; CI95% 2.29-5.06); 2005m. 4.53±1.87 (median 0.86; CI 95% 0.79-8.27); 2006m. 4.24±0.82 (median 1.05; CI95%2.60-5.88). Amikacino (1000mg) buvo 0.55±0.17 (median 1.22; CI95% 0.23-0.88) 2004m.; 2005m. 0.44±0.13 (median 1.03; CI 95% 0.18-0.69), ir 0.52±0.13 (median 1.08; CI95%0.27-0.78) 2006m. Tobramicino (240mg) buvo 0.03±0.02 (median 0.14; CI95% 0.00-0.07) 2004m, 0.006±0.003 (median 0.03; CI95% 0.00-0.01) 2005m. Vancomicino (2000mg) buvo 0.55±0.17... [toliau žr. visą tekstą]

The primary clinical characteristics of cystic fibrosis (CF) are malnutrition caused by malabsorption secondary to pancreatic insufficiency, chronic pulmonary infections, and male infertility. The major cause of morbidity and mortality are bronchiectasis and obstructive pulmonary disease. Lung disease in CF is manifested by this chronic lung disease progression, with intermittent episodes of acute worsening of symptoms called pulmonary exacerbations. Once the patient has stabilized, and if suitable care can be arranged, these interventions are often transitioned to the home. This review summarizes important points pertinent to the use of intravenous and inhaled antimicrobials that may be encountered by prescribers, nurses, technicians, and case managers in the home health setting. Appropriate dosing, indications, adverse drug reactions, monitoring parameters, and practicality of both intravenous and inhaled antimicrobials are discussed.

What is known and objective: Amphotericin is the preferred treatment for pulmonary histoplasmosis during pregnancy. The long half-life of amphotericin supports less than daily administration. Case summary: A 28-year-old pregnant woman diagnosed with recurrent pulmonary histoplasmosis was initiated on liposomal amphotericin 250 mg (4 mg/kg) intravenously daily. After 2 weeks, the patient was discharged and successfully received 250 mg thrice weekly at a hospital-associated outpatient infusion centre. After 6 weeks of outpatient treatment, a chest X-ray demonstrated no remaining disease and therapy was discontinued. What is new and conclusion: Administration of thrice-weekly liposomal amphotericin in a hospital-associated, outpatient infusion centre may be a promising option for stepdown treatment in patients unable to take itraconazole.

Most urinary tract infections in humans and dogs are caused by uropathogenic strains of , and increasing antimicrobial resistance among these pathogens has created a need for a novel approach to therapy. Bacterial iron uptake and metabolism are potential targets for novel antimicrobial therapy, as iron is a limiting factor in . growth during infection. As a trivalent metal of similar atomic size to iron (III), gallium can interact with a wide variety of biomolecules that normally contain or interact with iron. Gallium compounds disrupt bacterial iron metabolism, are known to accumulate at sites of infection and inflammation in mammals, exert antimicrobial activity against multiple bacterial pathogens in vitro, and may be good candidates as novel antimicrobial drugs. We assessed the suitability of orally administered gallium maltolate as a potential new antimicrobial therapy for urinary tract infections by evaluating its distribution into the bladder, its activity against uropathogenic . in vitro, and its pharmacokinetics and efficacy in a mouse cystitis model. Using a novel application of synchrotron-based analytical methods, we confirmed the distribution of gallium to the bladder mucosa and characterized the relationship between iron and gallium distribution in the bladder. In vitro experiments with human and canine uropathogenic . isolates demonstrated that gallium maltolate exerts antimicrobial effects in a time-dependent, bacteriostatic manner. Minimum inhibitory concentrations ranged from 0.144 µmol/mL to >9.20 µmol/mL with a median of 1.15 µmol/mL. Isolates resistant to ampicillin, ciprofloxacin, or with decreased susceptibility to cephalothin were susceptible to the antimicrobial activity of gallium maltolate, suggesting that resistance to conventional antimicrobials does not predict resistance to gallium maltolate. Pharmacokinetic studies in healthy mice and in a mouse model of urinary tract infection confirmed that gallium is absorbed into systemic circulation after oral administration of gallium maltolate. Gallium is slowly eliminated from the body, with a trend toward longer terminal half-lives in blood and bladder for infected mice relative to healthy mice. This study did not reveal any statistically significant effect of infection status on maximum blood gallium concentrations (4.46 nmol/mL, 95% confidence interval 2.75 nmol/mL – 6.18 nmol/mL and 4.80 nmol/mL, 95% confidence interval 2.53 nmol/mL – 7.06 nmol/mL in healthy and infected mice, respectively) or total gallium exposure in blood and kidney as represented by area under the concentration vs. time curves. Gallium exposure in the bladder was significantly greater for mice with urinary tract infections than for healthy mice. The investigation of gallium distribution within tissues represented a novel application of synchrotron-based analytical techniques to antimicrobial pharmacokinetics. Prior to analysing tissue samples, a library of x-ray absorption spectra was assembled for gallium compounds in both the hard and soft x-ray ranges. The suitability of hard x-ray fluorescence imaging and scanning and transmission x-ray microscopy for localizing and speciating trace elements in tissues was subsequently assessed. Of these methods, only hard x-ray microprobe analysis was well-suited to the analysis and was successfully used for this application. This approach confirmed that gallium arrives at the bladder mucosa after oral administration of gallium maltolate. Furthermore, comparison of iron and gallium distribution within the bladder mucosa indicated that these elements are similarly but not identically distributed and that they do not significantly inhibit one another’s distribution. This finding suggests that gallium may be distributed in part via pathways that do not involve iron. Despite the favorable distribution characteristics of gallium and the persistence of gallium in target tissues following the oral administration of gallium maltolate, its efficacy in a mouse model of urinary tract infection was disappointing. In this study, no statistically significant difference was detected between gallium maltolate, ciprofloxacin and sham treatments in their ability to eliminate bacteria in the urinary tracts. The failure of ciprofloxacin treatment to render bladder tissue culture-negative for an organism that is classified as ciprofloxacin-susceptible in vitro is consistent with observations from other research groups. The similar lack of efficacy observed for gallium maltolate may be related to the large gap between minimum inhibitory concentrations observed in vitro and gallium concentrations observed in tissues from treated mice, but may also be related to the small study size if the effect size of gallium maltolate treatment is small. Given the magnitude of the difference between tissue concentrations and minimum inhibitory concentrations, it may not be possible to increase the dose sufficiently to achieve therapeutic concentrations without causing toxicity. While the results of these experiments suggest that orally administered gallium maltolate may not be a reasonable antimicrobial drug candidate for treating urinary tract infections caused by uropathogenic . , it may be useful for other applications. Other bacterial pathogens may be more susceptible to the antimicrobial effects of gallium maltolate, and local or topical administration could produce much higher concentrations than we observed following oral administration. Continued development of the synchrotron-based analytical techniques used in these experiments could provide new and important opportunities to investigate antimicrobial distribution and metabolism within cells and tissues, particularly for metal-based drugs.

Introdução: estudos de farmacocinética/farmacodinâmica (FC/FD) observaram que a probabilidade de alcançar o alvo FC/FD é maior quando a dose do beta-lactâmico é otimizada. Porém, poucos estudos demonstraram que a otimização de dose resulta em melhores desfechos clínicos. Métodos: Fatores associados com mortalidade em 30 dias foram avaliados em 100 pacientes com bacteremia por enterobactérias tratados com cefepime, piperacilina-tazobactam ou meropenem em um estudo de coorte prospectivo. Posologia dos antibióticos foi classificada em otimizada, apropriada e potencialmente inapropriada. Resultados: Cinquenta e dois (52%) episódios foram causados por E. coli, seguidos por K. pneumoniae (10%). Dezesseis (16%) episódios foram causados por isolados resistentes à cefepime e não houve nenhum caso de resistência à carbapenêmicos. A maioria dos isolados apresentou concentrações inibitórias mínimas (CIMs) baixas para as drogas prescritas (≤0.5, ≤1.0, ≤1/4 mg/L, para meropenem, cefepime e piperacilina-tazobactam respectivamente). Cefepime foi o antimicrobiano mais frequentemente prescrito para tratamento empírico e definitivo. Terapia otimizada foi observada em 42% dos pacientes e terapia adequada em 58%. A mortalidade em 30 dias foi 37%. Escore de Pitt, Charlson e apresentação com sepse severa foram independentemente associados à mortalidade. Não houve diferença em mortalidade entre os pacientes que receberam terapia otimizada e terapia adequada. Conclusões: os resultados mostram que a otimização das doses de cefepime, piperacilina-tazobactam e meropenem não teve impacto em mortalidade Em pacientes recebendo terapia empírica apropriada para bacteremias por Enterobacteriaceae. Este achado pode ser devido aos baixos valores de CIM apresentados pelas bactéria. Comorbidades e a severidade da apresentação são fatores associados à pior evolução. / Background: Pharmacokinetic/pharmacodynamic (PK/PD) studies have shown that the probability of PK/PD target attainment is higher when optimized dosage regimes of beta-lactams are employed, but few studies have shown clinical benefit of such strategy. Methods: We investigated the effect of dosage regimes in 30-day mortality in 100 patients with Enterobacteriaceae bloodstream infections (BSIs) receiving appropriate empirical therapy with cefepime, piperacillin-tazobactam or meropenem. Posology of antibiotic was classified as optimized, adequate and possibly inadequate. Results: Most isolates presented relatively low MIC for the prescribed drugs (≤0.5, ≤1.0, ≤1/4 μg/mL, for meropenem, cefepime and piperacillin-tazobactam respectively). Cefepime was the most common prescribed drug for empirical and main therapy. Optimized posology was prescribed in 42% of patients and adequate in 58%. The overall 30-day mortality was 27.0%. Charlson score, Pitt score and presentation with severe sepsis were independently associated with the 30-day mortality. Patients receiving optimized dosage regime presented no distinct 30-day mortality of those with adequate ones (25.0% versus 28.3%, P=0.89), even after inclusion in multivariate model. Conclusion: Our results suggest that dosage regime optimization of cefepime, piperacillin-tazobactam and meropenem may have no effect on mortality when infecting bacteria with low MICs for these drugs. In patients receiving appropriate empirical therapy for Enterobacteriaceae BSI, baseline comorbidity is an independent predictor of death and the severity of BSI presentation is also significantly associated with this outcome is such patients. Studies in population with higher MIC heterogeneity are required to evaluate the role of optimized doses in clinical setting.