Inhibition of Adhesion and Invasion of \u3cem\u3ePseudomonas aeruginosa\u3c/em\u3e to Lung Epithelial Cells: A Model of Cystic Fibrosis Infection

Over their life time, CF patients experience multiple infections by various pneumoniacausing bacteria [6]. With more patients surviving to adulthood, chronic infections with Pseudomonas aeruginosa are coming to the forefront as a leading cause of death [7]. Problems presented by infected CF lung are multi-dimensional; the electrolyte balance and pH of the fluids are abnormal. The mucus is thick and of an alternative composition compared to normal lung and may contribute to colonization with Pseudomonas aeruginosa [2, 3, 5]. As such, research is multi-pronged and includes gene therapy to correct the defective protein, amelioration of inflammatory response and thinning of alveolar surface fluids [8, 9]. Significantly, Pseudomonas bacteria colonize the CF lung far easier than normal lung. Normal lung tissue has several naturally occurring defenses that work in concert with commonly prescribed antibiotics for recovery from lung infections [4, 10]. The CF patient appears to lack these natural defenses [1, 7].https://digitalcommons.chapman.edu/pharmacy_books/1009/thumbnail.jp

In Vitro Antibiofilm Efficacies of Different Antibiotic Combinations with Zinc Sulfate against \u3cem\u3ePseudomonas aeruginosa\u3c/em\u3e Recovered from Hospitalized Patients with Urinary Tract Infection

Urinary tract infections (UTIs) are a serious healthcare dilemma influencing millions of patients every year and represent the second most frequent type of body infection. Pseudomonas aeruginosa is a multidrug-resistant pathogen causing numerous chronic biofilm-associated infections including urinary tract, nosocomial, and medical devices-related infections. In the present study, the biofilm of P. aeruginosa CCIN34519, recovered from inpatients with UTIs, was established on polystyrene substratum and scanning electron microscopy (SEM) and was utilized for visualization of the biofilm. A previously described in vitro system for real-time monitoring of biofilm growth/inhibition was utilized to assess the antimicrobial effects of ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ertapenem, ceftriaxone, gentamicin, and tobramycin as single antibiotics as well as in combinations with zinc sulfate (2.5 mM) against P. aeruginosa CCIN34519 biofilm. Meanwhile, minimum inhibitory concentrations (MICs) at 24 h and mutant prevention concentrations (MPCs) at 96 h were determined for the aforementioned antibiotics. The real-time monitoring data revealed diverse responses of P. aeruginosa CCIN34519 biofilm to the tested antibiotic-zinc sulfate combinations with potential synergisms in cases of fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, and norfloxacin) and carbapenem (ertapenem) as demonstrated by reduced MIC and MPC values. Conversely, considerable antagonisms were observed with cephalosporin (ceftriaxone) and aminoglycosides (gentamicin, and tobramycin) as shown by substantially increased MICs and MPCs values. Further deliberate in vivo investigations for the promising synergisms are required to evaluate their therapeutic potentials for treatment of UTIs caused by P. aeruginosa biofilms as well as for developing preventive strategies

Comparative Pharmacodynamics of Ceftobiprole, Daptomycin, Linezolid, Telavancin, Tigecycline, and Vancomycin in the Treatment of Methicillin Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e: A Monte Carlo Simulation Analysis

Background/Objectives: Appropriate initial treatment choices for methicillin resistant Staphylococcus aureus (MRSA) infections are very critical. The aim of this study was to compare the ability of Ceftobiprole, Daptomycin, Linezolid, Telavancin, Tigecycline, and Vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) target against clinical MRSA isolates. Methods: Monte Carlo Simulations were performed to simulate the PK/PD indices of the investigated antimicrobials. Population Pharmacokinetic data and Pharmacodynamic indices were integrated into Monte Carlo Simulation routine with 10,000 iterations. Probability of target attainment (PTA) was estimated at MIC values ranging from 0.03-32 μg/ml to define the PK/PD susceptibility breakpoints. Cumulative fraction of response (CFR) was computed using MIC data from the Canadian National Ward (CAN-Ward) study collected in 2007, 2008 and 2009. Results: Analysis of the simulation results suggested the breakpoints of 8μg/ml for Ceftobiprole, 0.12 μg/ml for Daptomycin and Tigecycline, 0.5 μg/ml for Telavancin and 1 μg/ml for Linezolid and Vancomycin. The estimated CFR were 100, 66.5, 84, 89.1, 98.2, 60, 97.5 % for Ceft obiprole, Daptomycin (4mg/kg/day), Daptomycin (6mg/kg/day), Linezolid, Telavancin, Tigecycline, Vancomycin (2gm/day) and Vancomycin (3gm/day), respectively. Conclusions: Ceftobiprole and Telavancin have the highest probability of achieving favorable outcome against MRSA infections. The susceptibility results suggested a further reduction of the vancomycin breakpoint to 1 μg/ml

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

Regardless of its etiology, chronic kidney disease (CKD) is characterized by proteinuria, serum creatinine retention, glomerulosclerosis (GS), and tubulointerstitial damage. Notably, the last one has been correlated more closely with the evolution to kidney failure than the extent of glomerular injury. Tubulointerstitial inflammation comprises the activation of tubular epithelial cells, which release inflammatory mediators and chemokines promoting the influx of leukocytes in the renal parenchyma and the activation/proliferation of resident fibroblasts, leading to excessive production of extracellular matrix (EM), fibrosis, and renal function loss. Therefore, inflammation exerts a key role in the pathogenesis of CKD, although the mechanisms by which this process is activated and perpetuated, even when the initial insult is not immune-mediated, such as in the hypertensive nephrosclerosis, in the diabetic nephropathy, and in the crystal-induced renal disease, remain unclear. This chapter provides an overview on inflammation and CKD development not related to autoimmunity or caused by presence of foreign antigens. Cellular and molecular mechanisms involved in different pathways and its potential therapeutic targets to detain the progression of inflammation and fibrosis in CKD are also presented ahead as a contribution in this book

Application of Pharmacokinetics/Pharmacodynamics (PK/PD) in Designing Effective Antibiotic Treatment Regimens

Designing antibiotic dosing regimens is often not optimal and the dose-response relationship for most antibiotics is not well-known1. Both Pharmacokinetics (PK) and Pharmacodynamics (PD) are characteristics of antimicrobial agents that should be considered in the development of effective antibiotic therapy. By linking the concentration time profile at the site of action to the drug effect (PK/PD), the effect of varying dosage regimens against pathogens could be simulated enabling the identification of effective dosage strategies. It is known that inadequate antibiotic dosing could not only lead to a therapeutic failure, but also to the development of bacterial resistance. Importantly, the evolution of resistance in pathogenic bacteria combined with the decreasing interest from the pharmaceutical industry in developing new antibiotics has created a major public health problem3. Therefore, the activities to maintain the effects of existing antibiotics and prolong their useful life span have a high priority.https://digitalcommons.chapman.edu/pharmacy_books/1007/thumbnail.jp

Early and Late Outcome of Premature Newborns with History of Neonatal Intensive Care Units Admission at 6 Years Old in Zanjan, Northwestern Iran

How to Cite This Article: Sadeghzadeh M, Khoshnevisasl P, Parvaneh M, Mousavinasab N. Early and Late outcome of Premature Newborns with history of NICU Admission at 6 years old in Zanjan, Iran. Iran J Child Neurol. Spring 2016; 10(2):67-73.ObjectivePremature birth is an important factor for mortality and morbidity of neonates. This study was designed to evaluate the outcome of preterm neonates who needed neonatal intensive care (NICU) hospitalization after 6 yr at their entrance to the school.Materials & MethodsThis cross sectional study was conducted on premature neonates consecutively hospitalized in NICU of Valie Asr Hospital (the Academic Pediatric Hospital, Zanjan, Northwestern Iran) from September 2001 to September 2003. All children with a history of prematurity and NICU treatment were evaluated at their entrance to the school. Demographic findings, clinical examinations, IQ test, hearing and visual acuity exams were recorded.ResultsFrom 179 neonates, 78 (43.6%) survived and were discharged from hospital. Fifty-four of them were available and entered first grade in primary school. Only one case had severe mental retardation. One case had severe retinopathy of prematurity (ROP). Hearing abnormality was not detected in any case. There was no significant relation between IQ score, visual as well as hearing findings and gestational age.ConclusionWe did not find significant disability in the outcome of surviving infants. This could be explained by the high mortality rate of neonates during hospitalization. References1. Fakher M, Shaaban W, Abdel Monein A, Hassan Z, Moustafa Fikry M. Statistical Study of Preterm Infants Admitted to NICU in Fawzy Moaz Hospital For Children. Alex J Pediatr 2005; 19 (1):155-8.2. Fauth de Araújo B, Zatti H, Madi JM, Coelho MB, Olmi FB, Canabarro CT. Analysis of neonatal morbidity and mortality in late-preterm newborn infants. Jornal de Pediatria 2012 ; 88 (3): 259-266.3. Stephens BE, Vohr BR. Neurodevelopmental outcome of the premature infant. Pediatr Clin North Am 2009; 56 (3):631-46.4. Horbar JD, Carpenter JH, Badger GJ, Kenny MJ, Soll RF, Morrow KA, Buzas JS. Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics 2012;129 (6): 1019-26.5. Melamed N, Klinger G, Tenenbaum-Gavish K, Herscovici T, Linder N, Hod M, Yogev Y, Short-term Neonatal Outcome in Low-Risk, Spontaneous, Singleton, Late Preterm Deliveries. Obstetr Gynecol 2009 ; 114 ( 2): 253-260.6. Larroque B, Ancel PY, Marret S, Marchand L, AndréM, Arnaud C, Pierrat V, RozéJC, Messer J, Thiriez G, Burguet A, Picaud JC, Bréart G, Kaminski M, EPIPAGE Study group. Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet 2008; 371(9615): 813.7. Sajedi F, Vameghi R, Mohseni Bandpei MA, Alizad V, Hemmati Gorgani S, Shahshahani Pour S. Motor developmental delay in 7500 iranian infants: prevalence and risk factors. Iran J Child Neurol 2009; 3(3):43-50.8. Allen MC. Neurodevelopmental outcomes of preterm infants. Curr Opin Neurol 2008 ;21(2):123-8.9. Beaino G, Khoshnood B, Kaminski M, Marret S, Pierrat V, Vieux R, Thiriez G, Matis J, Picaud JC, RozéJC, Alberge C, Larroque B, Bréart G, Ancel PY, EPIPAGE Study Group. Predictors of the risk of cognitive deficiency in very preterm infants: the EPIPAGE prospective cohort. Acta Paediatr 2011;100 (3): 370.10. Mikkola K, Ritari N, Tommiska V, Salokorpi T,Lehtonen L, Tammela O, Pa¨a¨kko¨nen L, Olsen P, Korkman M, Fellman V, for the Finnish ELBW Cohort Study Group. Neurodevelopmental Outcome at 5 Years of Age of a National Cohort of Extremely Low Birth Weight Infants Who Were Born in 1996–1997. Pediatrics 2005;116:1391.11. Mercier CE, Dunn MS, Ferrelli KR, Howard DB, Soll RF. Neurodevelopmental Outcome of Extremely Low Birth Weight Infants from the Vermont Oxford Network: 1998–2003. Neonatology 2010; 97: 329–338.12. Neubauer AP, Voss W, Kattner E. Outcome of extremely low birth weight survivors at school age: the influence of perinatal parameters on neurodevelopment. Eur J Pediatr 2008; 167(1):87-95.13. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126(3):443-56.14. Khan MR, Maheshwari pK, Shamim H, Ahmed S, Ali SR. Morbidity pattern of sick hospitalized preterm infants in Karachi, Pakistan. J Pak Med Assoc 2012; 62 (4): 386- 388.15. Navaei F, Aliabady B, Moghtaderi J, Moghtaderi M, Kelishadi R. Early outcome of preterm infants with birth weight of 1500 g or less and gestational age of 30 weeks or less in Isfahan city, Iran. World J Pediatr 2010; 6 ( 3): 228-232.16. Arafa MA, Alshehri MA, Predictors of neonatal mortality in the intensive care unit in Abha, Saudi Arabia. Saudi Med J 2003; 24 (12): 1374-1376.17. Atalay D, Salihoğlu Ö, Can E, Beşkardeş A, Hatipoğlu S. Short-Term Outcomes of Very Low Birth Weight Infants Born at a Tertiary Care Hospital, Istanbul, Turkey. Iran J Pediatr 2013; 23(2): 205-211.18. Mathews TJ, MacDorman MF. Infant Mortality Statistics From the 2007 Period Linked Birth/Infant Death Data Set. National Vital Statistics Reports. 2011;59(6).19. Natarajan G, Shankaran S, Laptook AR, Pappas A, Bann CM, McDonald SA, et al. Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2013 ;98(6):F473-9.20. Tommiska V – Heinonenk Ikonen S – pokelu ML-Renlund M/Virtanen M-fellman V. A national short –term followup study of extremely LBW infants born in Finland in 1996-1997. Pediatrics 2001; 107 (1):1-9.21. Ahmadpour M, Zahedpasha Y, Khafri S, Pishnamazi N. Short-term outcome of premature neonates admitted to NICU & newborn services at Amirkola children hospital in 2010. IJN 2012; 3( 3,4): 10.22. Calisici E, Eras Z, Oncel MY, Oguz SS, Gokce IK, Dilmen U. Neurodevelopmental outcomes of premature infants with severe intraventricular hemorrhage. J Matern Fetal Neonatal Med 2014 ; 14:1-6.23. Santos IS, Matijasevich A, Domingues MR, Barros AJD, Victora CG, Barros FC. Late preterm birth is a risk factor for growth faltering in early childhood: a cohort study; BMC Pediatrics 2009; 9:71.24. Leversen KT, Sommerfelt K, Rønnestad A, Kaaresen PI, Farstad T, Skranes J, et al. Prediction of neurodevelopmental and sensory outcome at 5 years in Norwegian children born extremely preterm. Pediatrics 2011;127(3):e630.25. Christian P, Murray-Kolb LE, Tielsch JM, Katz J, LeClerq SC, Khatry SK. Associations between preterm birth, small-for gestational age, and neonatal morbidity and cognitive function among school-age children in Nepal. BMC Pediatrics 2014;14:58.26. Synnes AR, Anson S, Arkesteijn A, Butt A, Grunau RE, Rogers M, Whitfield MF. School entry age outcomes for infants with birth weight≤800 grams. J Pediatr. 2010;157(6):989.27. van Baar AL, Vermaas J, Knots E, de Kleine MJ, Soons P. Functioning at school age of moderately preterm children born at 32 to 36 weeks’ gestational age. Pediatrics 2009; 124(1): 251.28. Johnson S, Fawke J, Hennessy E, Rowell V, Thomas S, Wolke D, Marlow N. Neurodevelopmental disability through 11 years of age in children born before 26 weeks of gestation. Pediatrics 2009;124(2):e249.29. Kerstjens JM, de Winter AF, Bocca-Tjeertes IF, ten Vergert EM, Reijneveld SA, Bos AF. Developmental delay in moderately preterm-born children at school entry. J Pediatr 2011; 159(1):92.30. Soleimani F, Kazemnejad A,Vameghi R. Risk factor profiles of adverse neuromotor outcome in infants. Iran J Child Neurol 2010; 4 (4): 25-31

A High-Throughput In Vitro Model Illustrating Potential Microbiologocal Interactions During Treatment of \u3cem\u3ePseudomonas aeroginosa\u3c/em\u3e Biofilm Associated Infections

Objective: Amend a real-time, high-throughput method of bacterial growth detection for use as a model of biofilm response to co-administered pharmaceuticals during the treatment of devise associated infections. Background: Biofilms are the root etiology for chronic infections, particularly in regard to infections in patients with implanted medical devices. Calcium channel blockers (CCBs) are used for control of hypertension and angina and are commonly prescribed to elderly patients. We address potential interference of commonly prescribed CCBs with levofloxacin for treatment of Pseudomonas aeruginosa biofilms. Methods: Inoculum of 1–3×106CFU∕mL in the log phase were seeded into each well of a polystyrene plate. Biofilms developed over 6h at 37°C, was washed and medium containing various CCBs plus levofloxacin was added to the biofilm. OD measurements were obtained at 1h intervals over 90h at 37°C. Changes in turbidity were kinetically measured with a vertical photometer with a wide-band filter. Results: Mibefradil and diltiazem appear to be strongly antagonistic toward levofloxacin where both of them decrease antibiofilm effect of levofloxacin and they encourage the selection of resistant mutants from biofilm. Discussion: Implanted medical devices are quite common and are subjected to biofilm infections. Increasing multi-drug resistance underscores the need to conserve current antibiotics by judicious use. This necessitates consideration of evidence regarding antagonistic or synergistic activity of commonly prescribed drugs of different classes toward commonly used antibiotics. The combinations described here show vital and previously unreported effects of some CCBs when co-prescribed with levofloxacin on Pseudomonas aeruginosa biofilm

Calli Essential Oils Synergize with Lawsone against Multidrug Resistant Pathogens.

The fast development of multi-drug resistant (MDR) organisms increasingly threatens global health and well-being. Plant natural products have been known for centuries as alternative medicines that can possess pharmacological characteristics, including antimicrobial activities. The antimicrobial activities of essential oil (Calli oil) extracted from the Calligonum comosum plant by hydro-steam distillation was tested either alone or when combined with lawsone, a henna plant naphthoquinone, against MDR microbes. Lawsone showed significant antimicrobial activities against MDR pathogens in the range of 200-300 µg/mL. Furthermore, Calli oil showed significant antimicrobial activities against MDR bacteria in the range of 180-200 µg/mL, Candida at 220-240 µg/mL and spore-forming Rhizopus fungus at 250 µg/mL. Calli oil's inhibition effect on Rhizopus, the major cause of the lethal infection mucormycosis, stands for 72 h, followed by an extended irreversible white sporulation effect. The combination of Calli oil with lawsone enhanced the antimicrobial activities of each individual alone by at least three-fold, while incorporation of both natural products in a liposome reduced their toxicity by four- to eight-fold, while maintaining the augmented efficacy of the combination treatment. We map the antimicrobial activity of Calli oil to its major component, a benzaldehyde derivative. The findings from this study demonstrate that formulations containing essential oils have the potential in the future to overcome antimicrobial resistance

Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling of Anti-Neoplastic Agents

Development of tumor resistance to chemotherapeutics is related to inherent tumor variations regarding sensitivity to chemotherapeutics and to sub-optimal dosing regimens, including variation in patient pharmacokinetics that result in suboptimal exposure of tumor cells to anti-neoplastic drugs [1, 2]. The rate and extent of drug efficacy depends on the extent of drug exposure at the tumor site and the time above the effective concentration [3]. In vitro models that incorporate these pharmacokinetic and pharmacodynamic (PK/PD) principles to optimize therapeutic response may be considered the method of choice for optimizing dosing schedules before translating data from static assays to animals and clinical trials [4, 5]. The hollow fiber bioreactor was recently used to evaluate pharmacokinetic/pharmacodynamic (PK/PD) effects of gemcitibine in lung and breast cancers and to model HIV treatments [4-6].https://digitalcommons.chapman.edu/pharmacy_books/1008/thumbnail.jp