Outcome of neoadjuvant treatment for pancreatic cancer in elderly patients: comparative, observational cohort study.

BACKGROUND: Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. METHODS: This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70-74, 75 or more years) and respective treatment outcomes were compared. RESULTS: The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70-74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70-74 years, and 12 of 34 aged 75 years or more; P < 0.001). Resectability was similar among the three groups (60.0, 58.3, and 55.9 per cent respectively; P = 0.919). Trends towards shorter survival were observed in the elderly (median overall survival time 23.6, 18.0, and 17.6 months for patients aged less than 70, 70-74, and 75 or more years respectively; P = 0.090). After adjusting for co-variables, age was not a significant predictive factor. CONCLUSION: The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

Multicenter Study of the Real-World Use of Ceftaroline versus Vancomycin for Acute Bacterial Skin and Skin Structure Infections.

The objective of this study was to determine if real-world ceftaroline treatment in adults hospitalized for acute bacterial skin and skin structure infections (ABSSSI) is associated with decreased infection-related length of stay (LOSinf) compared to that with vancomycin. This was a retrospective, multicenter, cohort study from 2012 to 2017. Cox proportional hazard regression, propensity score matching, and inverse probability of treatment weighting (IPTW) were used to determine the independent effect of treatment group on LOSinf The patients were adults hospitalized with ABSSSI and treated with ceftaroline or vancomycin for ≥72 h within 120 h of diagnosis at four academic medical centers and two community hospitals in Arizona, Florida, Michigan, and West Virginia. A total of 724 patients were included (325 ceftaroline treated and 399 vancomycin treated). In general, ceftaroline-treated patients had characteristics consistent with a higher risk of poor outcomes. The unadjusted median LOSinf values were 5 (interquartile range [IQR], 3 to 7) days and 6 (IQR, 4 to 8) days in the vancomycin and ceftaroline groups, respectively (hazard ratio [HR], 0.866; 95% confidence interval [CI], 0.747 to 1.002). The Cox proportional hazard model (adjusted HR [aHR], 0.891; 95% CI, 0.748 to 1.060), propensity score-matched (aHR, 0.955; 95% CI, 0.786 to 1.159), and IPTW (aHR, 0.918; 95% CI, 0.793 to 1.063) analyses demonstrated no significant difference in LOSinf between groups. Patients treated with ceftaroline were significantly more likely to meet criteria for discharge readiness at day 3 in unadjusted and adjusted analyses. Although discharge readiness at day 3 was higher in ceftaroline-treated patients, LOSinf values were similar between treatment groups. Clinical and nonclinical factors were associated with LOSinf.

Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts.

BACKGROUND: The success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX). METHODS: BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. Mice were evaluated for human chimerism in the blood and assigned into experimental untreated or nivolumab groups based on chimerism. TNBC cell lines or tumor tissue from established CRC PDX models were implanted into both flanks of humanized mice and treatments ensued once tumors reached a volume of ~150mm3. Tumors were measured twice weekly. At end of study, immune organs and tumors were collected for immunological assessment. RESULTS: Humanized PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with anti-PD-1 exhibited increased anti-tumor human T-cell responses coupled with decreased Treg and myeloid populations that correlated with tumor growth inhibition. Combination therapies with anti-PD-1 treatment in TNBC-bearing mice reduced tumor growth in multi-drug cohorts. Finally, as observed in human colorectal patients, anti-PD-1 therapy had a strong response to a microsatellite-high CRC PDX that correlated with a higher number of human CD8+ IFNγ+ T cells in the tumor. CONCLUSION: Hu-CB-BRGS mice represent an in vivo model to study immune checkpoint blockade to human tumors. The human immune system in the mice is inherently suppressed, similar to a tumor microenvironment, and thus allows growth of human tumors. However, the suppression can be released by anti-PD-1 therapies and inhibit tumor growth of some tumors. The model offers ample access to lymph and tumor cells for in-depth immunological analysis. The tumor growth inhibition correlates with increased CD8 IFNγ+ tumor infiltrating T cells. These hu-CB-BRGS mice provide a relevant preclinical animal model to facilitate prioritization of hypothesis-driven combination immunotherapies.

Immune and autoimmune-related adverse events associated with immune checkpoint inhibitors in cancer therapy.

The recent development of monoclonal antibodies that disinhibit the immune system from recognizing and attacking tumor cells has revolutionized the treatment of cancer. Among these agents are drugs that specifically block cytotoxic T-lymphocyte protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) signaling, called immune checkpoint inhibitors (ICIs). While these agents are generally well tolerated, ICI therapy can lead to loss of self-tolerance and the development of autoimmunity, manifesting as immune-related adverse events (IRAEs). Although potentially linked to increased antitumor responses, the morbidity associated with IRAEs can be significant and in rare circumstances, fatal. Virtually any organ can be affected and the patients present with a broad range of signs and symptoms. Moreover, ICIs have varying IRAEs and have distinct toxicity profiles based on their mechanism of action. Fortunately, most of the IRAEs can be managed with immunosuppression and supportive care, but contingent on early recognition and prompt treatment. With increasing advances in drug development, including combination ICI therapy, these agents are becoming one of the most prescribed oncology drugs and clinicians should be knowledgeable about the recognition and management of IRAEs.

Fecal short-chain fatty acids of very-low-birth-weight preterm infants fed expressed breast milk or formula.

OBJECTIVES: In preterm infants, the metabolic responses of gastrointestinal (GI) bacteria to different diets are poorly understood despite the possible effects on GI health. Therefore, we tested the hypothesis that diet influences bacterial metabolism by measuring short-chain fatty acids (SCFAs) in stool samples from very-low-birth-weight (VLBW) preterm infants without GI disorder as surrogate biomarkers of bacterial metabolism. METHODS: Ion chromatography was used to measure fecal SCFAs (acetate, formate, propionate, butyrate, and isobutyrate), lactate, and chloride in fresh stool samples collected from 32 preterm infants (without major congenital anomalies, GI disorders, or a recent history of antibiotic administration and on full feed of either expressed maternal breast milk [EBM; n = 13] or a formula for preterm infants [Similac Special Care Formula; preterm formula, PTF; n = 19]). RESULTS: The mean birth weight was 972 g, the mean gestational age was 27 weeks, and the mean postnatal age at first stool sample was 36 days. When adjusted for gestational age, the stools of EBM infants had higher concentrations (micromoles per gram of stool) of total SCFA (128 vs 68; P = 0.002), acetate (41 vs 13; P = 0.005), propionate (15.1 vs 4.4; P = 0.003), and chloride (21,814 vs 10,652; P = 0.02). Interactions between postnatal age and diet were detected for lactate (P = 0.05), propionate (P = 0.03), and butyrate (P = 0.03). CONCLUSIONS: Diets fed to VLBW preterm infants influence fecal SCFA profiles, and hence the metabolism of the GI bacteria, and potentially the health of preterm infants. The responses of bacterial metabolism to diet are influenced with postnatal age and gestational age at birth.

The development of regorafenib and its current and potential future role in cancer therapy.

Regorafenib is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types, in preclinical and clinical studies. Preclinical data show inhibitory activity of angiogenic, stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1, 2 and 3, tyrosine-protein kinase receptor TIE-2, platelet-derived growth factor receptor ß, fibroblast growth factor receptor 1, proto-oncogene tyrosine-protein kinase receptor Ret, mast/stem cell growth factor receptor Kit, RAF proto-oncogene serine/threonine-protein kinase and wild-type and V600E mutant serine/threonine-protein kinase B-raf. Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3-weeks-on/1-week-off schedule, or 100 mg daily on a continuous schedule, with adverse effects typical of other multikinase inhibitors. Phase II studies demonstrated clinical benefit in a variety of tumor types, mostly associated with prolonged stable disease. Phase III studies include the CORRECT trial, which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies. There is still much work to be done to determine the role of regorafenib in the future of cancer therapy. This review will focus on the development of regorafenib, from early preclinical work through phase I, II and III trials, as well as highlighting the current role and potential future directions of this novel agent.

Understanding soaring bird migration through interactions and decisions at the individual level.

Many soaring bird species migrate southwards in autumn from their breeding grounds in Europe and Central Asia towards their wintering grounds. Our knowledge about interactions between migrating birds, thermal selection during migration and mechanisms that lead to flocking or convergent travel networks is still very limited. To start investigating these aspects we developed an individual-based simulation model that describes the local interactions between birds and their environment during their migratory flight, leading to emergent patterns at larger scales. The aim of our model is to identify likely decision rules with respect to thermal selection and navigation. After explaining the model, it is applied to analyse the migration of white storks (Ciconia ciconia) over part of its migration domain. A model base-run is accompanied by a sensitivity analysis. It appears that social interactions lead to the use of fewer thermals and slight increases in distance travelled. Possibilities for different model extensions and further model application are discussed.

Botulinum toxin abolishes sweating via impaired sweat gland responsiveness to exogenous acetylcholine.

BACKGROUND: Botulinum toxin A (BTX) disrupts neurotransmitter release from cholinergic nerves. The effective duration of impaired sweat secretion with BTX is longer relative to that of impaired muscle contraction, suggesting different mechanisms in these tissues. OBJECTIVES: The aim of this study was to test the hypothesis that BTX is capable of altering sweating by reducing the responsiveness of the sweat gland to acetylcholine. METHODS: BTX was injected into the dorsal forearm skin of healthy subjects at least 3 days before subsequent assessment. On the day of the experiment, intradermal microdialysis probes were placed within the BTX-treated area and in an adjacent untreated area. Incremental doses of acetylcholine were administered through the microdialysis membranes while the sweat rate (protocol 1; n = 8) or a combination of sweat rate and skin blood flow (protocol 2; n = 8) were assessed. RESULTS: A relative absence of sweating was observed at the BTX site for both protocols (protocol 1: 0.05 +/- 0.09 mg cm(-2) min(-1); protocol 2: 0.03 +/- 0.04 mg cm(-2) min(-1), both at the highest dose of acetylcholine), while the sweat rate increased appropriately at the control sites (protocol 1: 0.90 +/- 0.46 mg cm(-2) min(-1); protocol 2: 1.07 +/- 0.67 mg cm(-2) min(-1)). Cutaneous vascular conductance increased to a similar level at both the BTX and control sites. CONCLUSIONS: These results demonstrate that BTX is capable of inhibiting sweat secretion by reducing the responsiveness of the sweat gland to acetylcholine, while not altering acetylcholine-mediated cutaneous vasodilatation.

Modeling Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis.

OBJECTIVE: The goal of this investigation was to demonstrate that internuclear ophthalmoparesis (INO) can be utilized to model the effects of body temperature-induced changes on the fidelity of axonal conduction in multiple sclerosis (Uhthoff's phenomenon). METHODS: Ocular motor function was measured using infrared oculography at 10-minute intervals in patients with multiple sclerosis (MS) with INO (MS-INO; n = 8), patients with MS without INO (MS-CON; n = 8), and matched healthy controls (CON; n = 8) at normothermic baseline, during whole-body heating (increase in core temperature 0.8 degrees C as measured by an ingestible temperature probe and transabdominal telemetry), and after whole-body cooling. The versional disconjugacy index (velocity-VDI), the ratio of abducting/adducting eye movements for velocity, was calculated to assess changes in interocular disconjugacy. The first pass amplitude (FPA), the position of the adducting eye when the abducting eye achieves a centrifugal fixation target, was also computed. RESULTS: Velocity-VDI and FPA in MS-INO patients was elevated (p < 0.001) following whole body heating with respect to baseline measures, confirming a compromise in axonal electrical impulse transmission properties. Velocity-VDI and FPA in MS-INO patients was then restored to baseline values following whole-body cooling, confirming the reversible and stereotyped nature of this characteristic feature of demyelination. CONCLUSIONS: We have developed a neurophysiologic model for objectively understanding temperature-related reversible changes in axonal conduction in multiple sclerosis. Our observations corroborate the hypothesis that changes in core body temperature (heating and cooling) are associated with stereotypic decay and restoration in axonal conduction mechanisms.

What would the world be like without animals for food, fiber, and labor? Are we morally obligated to do without them?

Numerous animal rights and animal liberation theorists have concluded that nonhuman animals have moral standing and noninterference rights. Therefore, they say that humans are morally obligated to stop using animals for food, fiber, labor, and research. I disagree with that conclusion for at least 2 reasons. First, it has been suggested that food production models are possible using large herbivores that might actually cause less harm (kill) to animals than a vegan food production model. This is because intensive crop production used to produce food for a vegan diet kills (harms) far more animals of the field than extensive agriculture (pasture production). So, a combined food production system that includes crops and pasture harvested by large herbivores to be used for human food may kill fewer animals than would a vegan-crop model. Second, pragmatically, it is improbable that all peoples of the world could ever be convinced that they must give up animals. In fact, it may be unethical to try to do that, because in poor countries, these animals are essential to the survival of the human populations. But what about the richer nations? Maybe they will or should be convinced to do without animals because of the moral strength of the animal rights and animal liberation theories. However, I believe that there are far too many obstacles for that to happen. What then are we morally obligated to do about animals? I suggest that animals do have moral standing, and that we are morally obligated to recognize their unique species-specific natures and treat them accordingly. That would mean treating animals according to their physical and behavioral needs or telos. That, I believe, is the most likely outcome of the conversation about animal rights.

Infective endocarditis caused by USA300 methicillin-resistant Staphylococcus aureus (MRSA).

We report seven cases of infective endocarditis caused by USA300 methicillin-resistant Staphylococcus aureus (MRSA) at an urban, tertiary care, academic institution. Five strains were community associated and two were healthcare associated. All patients were injection drug users. Staphylococcus aureus isolates were characterised as USA300-type MRSA using pulsed-field gel electrophoresis. Five cases were right-sided endocarditis and two cases were left-sided. The mean length of in-hospital antimicrobial therapy was 23 days and the mean length of total antibiotic therapy was 55 days. Complications included heart failure resulting in valve replacement in one patient as well as death in that patient. As USA300 strains of MRSA continue to increase in prevalence, clinicians must be aware of the increasing spectrum of illness in considering management and prevention strategies.

Epidemiology and outcomes of community-associated methicillin-resistant Staphylococcus aureus infection.

Over a 2-year period (2003 to 2005) patients with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and community-acquired methicillin-susceptible Staphylococcus aureus (CA-MSSA) infections were prospectively identified. Patients infected with CA-MRSA (n = 102 patients) and CA-MSSA (n = 102 patients) had median ages of 46 and 53 years, respectively; the most common sites of infection in the two groups were skin/soft tissue (80 and 93%, respectively), respiratory tract (13 and 6%, respectively), and blood (4 and 1%, respectively). Fourteen percent of patients with CA-MRSA infections and 3% of patients with CA-MSSA infections had household contacts with similar infections (P < 0.01). Among the CA-MRSA isolates, the pulsed-field gel electrophoresis (PFGE) groups detected were USA300 (49%) and USA100 (13%), with 27 PFGE groups overall; 71% of the isolates were staphylococcal chromosome cassette mec (SCCmec) type IV, 29% were SCCmec type II, and 54% had the Panton-Valentine leucocidin (PVL) gene. Among the CA-MSSA isolates there were 33 PFGE groups, with isolates of the USA200 group comprising 11%, isolates of the USA600 group comprising 11%, isolates of the USA100 group comprising 10%, and isolates of the PVL type comprising 10%. Forty-six and 18% of the patients infected with CA-MRSA and CA-MSSA, respectively, were hospitalized (P < 0.001). Fifty percent of the patients received antibiotic therapy alone, 5% received surgery alone, 30% received antibiotics and surgery, 3% received other therapy, and 12% received no treatment. The median durations of antibiotic therapy were 12 and 10 days in the CA-MRSA- and CA-MSSA-infected patients, respectively; 48 and 56% of the patients in the two groups received adequate antimicrobial therapy, respectively (P < 0.001). The clinical success rates of the initial therapy in the two groups were 61 and 84%, respectively (P < 0.001); recurrences were more common in the CA-MRSA group (recurrences were detected in 18 and 6% of the patients in the two groups, respectively [P < 0.001]). CA-MRSA was an independent predictor of clinical failure in multivariate analysis (odds ratio, 3.4; 95% confidence interval, 1.7 to 6.9). In the community setting, the molecular characteristics of the S. aureus strains were heterogeneous. CA-MRSA infections were associated with a more adverse impact on outcome than CA-MSSA infections.

A 2.5-Mb contig constructed from Angus, Longhorn and horned Hereford DNA spanning the polled interval on bovine chromosome 1.

The polled locus has been mapped by genetic linkage analysis to the proximal region of bovine chromosome 1. As an intermediate step in our efforts to identify the polled locus and the underlying causative mutation for the polled phenotype, we have constructed a BAC-based physical map of the interval containing the polled locus. Clones containing genes and markers in the critical interval were isolated from the TAMBT (constructed from Angus and Longhorn genomic DNA) and CHORI-240 (constructed from horned Hereford genomic DNA) BAC libraries and ordered based on fingerprinting and the presence or absence of 80 STS markers. A single contig spanning 2.5 Mb was assembled. Comparison of the physical order of STSs to the corresponding region of human chromosome 21 revealed the same order of genes within the polled critical interval. This contig of overlapping BAC clones from horned and polled breeds is a useful resource for SNP discovery and characterization of positional candidate genes.

Heat stress enhances arterial baroreflex control of muscle sympathetic nerve activity via increased sensitivity of burst gating, not burst area, in humans.

The relationship between muscle sympathetic nerve activity (MSNA) and diastolic blood pressure has been used to describe two sites for arterial baroreflex control of MSNA. By determining both the likelihood of occurrence for sympathetic bursts and the area of each burst for a given diastolic blood pressure, both a 'gating' and an 'area' control site has been described in normothermic humans. Assessing the effect of heat stress on these mechanisms will improve the understanding of baroreflex control of arterial blood pressure under this thermal condition. Therefore, the purpose of this study was to test the hypothesis that heat stress enhances arterial baroreflex control of burst gating and area. In 10 normotensive subjects (age, 32+/-2 years; mean+/-s.e.m.), MSNA (peroneal) was assessed using standard microneurographic techniques. Five minute periods of data were examined during normothermic and whole-body heating conditions. The burst incidence (i.e. number of sympathetic bursts per 100 cardiac cycles) and the area of each burst were determined for each cardiac cycle and were placed into 3 mmHg intervals of diastolic blood pressure. During normotheric conditions, there was a moderate, negative relationship between burst incidence and diastolic blood pressure (slope=-2.49+/-0.38; r(2)=0.73+/-0.06; mean+/-s.e.m.), while area per burst relative to diastolic blood pressure exhibited a less strong relationship (slope=-1.13+/-0.46; r(2)=0.45+/-0.09). During whole-body heating there was an increase in the slope of the relationship between burst incidence and diastolic blood pressure (slope=-4.69+/-0.44; r(2)=0.84+/-0.03) compared to normothermia (P<0.05), while the relationship between area per burst and diastolic blood pressure was unchanged (slope=-0.92+/-0.29; r(2)=0.41+/-0.08) (P=0.50). The primary finding of this investigation is that, at rest, whole-body heating enhanced arterial baroreflex control of MSNA through increased sensitivity of a 'gating' mechanism, as indicated by an increase in the slope of the relationship between burst incidence and diastolic blood pressure. This occurrence is likely to afford protection against potential decreases in arterial blood pressure in an effort to preserve orthostatic tolerance during heat stress.

Exogenous nitric oxide inhibits sympathetically mediated vasoconstriction in human skin.

Two experiments were performed to identify whether nitric oxide (NO) inhibits sympathetically mediated vasoconstriction in human skin. In eight subjects increasing doses of sodium nitroprusside (SNP; 8.4 x 10(-6)-8.4 x 10(-3)m) were administered via intradermal microdialysis. At each dose of SNP, cutaneous vasoconstrictor responsiveness was assessed during a 3 min whole-body cold stress. The relative reduction in forearm cutaneous vascular conductance (CVC) during the cold stress was significantly attenuated for SNP doses greater than 8.4 x 10(-4)m (control: 63.0 +/- 4.1%, SNP 8.4 x 10(-6)m: 57.1 +/- 4.7%, SNP 8.4 x 10(-5)m: 57.0 +/- 3.6%, SNP 8.4 x 10(-4)m: 44.5 +/- 5.4% and SNP 8.4 x 10(-3)m: 28.8 +/- 7.9%). The second experiment was performed to identify whether this response was due to NO attenuating sympathetically mediated vasoconstriction or due to a non-specific effect of an elevated CVC secondary to SNP administration. In seven subjects forearm CVC during a whole-body cold stress was assessed at two sites: at a site dilated via microdialysis administration of SNP and at a site dilated with isoproterenol (ISO). CVC was not different between sites prior to (SNP: 0.42 +/- 0.11; ISO: 0.46 +/- 0.11 AU mmHg(-1) (AU, arbitrary units), P > 0.05) or following drug infusion (SNP: 1.36 +/- 0.21; ISO: 1.27 +/- 0.23 AU mmHg(-1), P > 0.05). The reduction in CVC during the subsequent cold stress was significantly less at the SNP site (38.1 +/- 6.2%) relative to the ISO site (65.0 +/- 5.5%; P= 0.007). These data suggest NO is capable of inhibiting sympathetically mediated vasoconstriction in the cutaneous vasculature.

Defining a middle ground for philosophers and production: bioethics.

From the perspective of most animal scientists and producers, animal agriculture has become increasingly contentious over the last 10 to 20 years. Furthermore, our critics seem to be extremists whose views are biased and unreasonable. But guess what? The critics say the same thing about animal producers and scientists (us). So where is the middle ground and how do we get there? Should we even worry about trying to define the middle ground? Are these contentious issues a fad that will go away? Are these "extremist" critics so far outside reason that they will be ignored by society? Ignoring "them" is not likely to work because we have seen society changing its mind (developing a new social ethic) with regard to farm animals, in part because of what these critics are saying. As a result, it is vitally important for us to know and understand what is happening and why. For example, there isn't just one voice among the critics. There is actually a spectrum of opinion among the group which conventional agriculturalists usually call their critics. The WCC-204 committee generally agrees that the key to finding the middle ground between what is perceived as a polarized set of issues between "us" (animal scientists and producers) and "them" (philosopher critics) is for both sides to learn about the reasons why each side says what they do. Only then can all parties rationally begin to identify where the middle ground lies.

Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases.

This review outlines some of the many factors a clinician must consider when selecting an antimicrobial dosing regimen for the treatment of infection. Integration of the principles of antimicrobial pharmacology and the pharmacokinetic parameters of an individual patient provides the most comprehensive assessment of the interactions between pathogen, host, and antibiotic. For each class of agent, appreciation of the different approaches to maximize microbial killing will allow for optimal clinical efficacy and reduction in risk of development of resistance while avoiding excessive exposure and minimizing risk of toxicity. Disease states with special considerations for antimicrobial use are reviewed, as are situations in which pathophysiologic changes may alter the pharmacokinetic handling of antimicrobial agents.