Role of divalent metals in infectious disease susceptibility and outcome.

BACKGROUND: Divalent metals play important roles in maintaining metabolism and cellular growth of both eukaryotic hosts and invading microbes. Both metal deficiency and overload can result in abnormal cellular function or damage. Given its central role in host-pathogen interactions, subtle alterations of divalent metal homeostasis can occur in the course of infectious diseases which aim, from the host perspective, either to reduce the availability of respective metals to microbes or to use toxic metal accumulation to eliminate pathogens. AIMS: To provide the reader with background information and clinical data on divalent metal homeostasis in host-pathogen interactions, how this affects the course of infectious disease and whether correction of metal disturbances has shown benefit in infections. SOURCES: An in-depth analysis of PubMed articles related to the topic of this review published in English between 1970 and 2016 was performed. CONTENT: From the microbial perspective, divalent metals are essential for growth and pathogenicity and to mount effective protection against antimicrobial host responses, including toxic radical formation. Microbes have evolved multiple strategies to control their access to divalent metals. From the clinical perspective, alterations of divalent metal levels may result in increased or decreased susceptibility to infection and often occur in response to infections. However, keeping in mind the strategies underlying such alterations, for which the term 'nutritional immunity' was coined, the uncritical correction of such divalent metal imbalances may cause harm to patients. This review addresses the role of the divalent metals iron, selenium, zinc, manganese and copper in infectious diseases from a mechanistic and clinical perspective. IMPLICATIONS: We point out areas of research needed to expand our limited knowledge, hoping to improve the clinical management of patients with infections and to identify promising new targets for treatment by modulation of host or microbe divalent metal metabolism.

Multinational case-control study of risk factors for the development of late invasive pulmonary aspergillosis following kidney transplantation.

OBJECTIVES: To assess the risk factors for development of late-onset invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT). METHODS: We performed a multinational case-control study that retrospectively recruited 112 KT recipients diagnosed with IPA between 2000 and 2013. Controls were matched (1:1 ratio) by centre and date of transplantation. Immunosuppression-related events (IREs) included the occurrence of non-ventilator-associated pneumonia, tuberculosis, cytomegalovirus disease, and/or de novo malignancy. RESULTS: We identified 61 cases of late (>180 days after transplantation) IPA from 24 participating centres (accounting for 54.5% (61/112) of all cases included in the overall study). Most diagnoses (54.1% (33/61)) were established within the first 36 post-transplant months, although five cases occurred more than 10 years after transplantation. Overall mortality among cases was 47.5% (29/61). Compared with controls, cases were significantly older (p 0.010) and more likely to have pre-transplant chronic obstructive pulmonary disease (p 0.001) and a diagnosis of bloodstream infection (p 0.016) and IRE (p <0.001) within the 6 months prior to the onset of late IPA. After multivariate adjustment, previous occurrence of IRE (OR 19.26; 95% CI 2.07-179.46; p 0.009) was identified as an independent risk factor for late IPA. CONCLUSION: More than half of IPA cases after KT occur beyond the sixth month, with some of them presenting very late. Late IPA entails a poor prognosis. We identified some risk factors that could help the clinician to delimit the subgroup of KT recipients at the highest risk for late IPA.

Per-protocol investigation of a best practice exercise referral scheme.

OBJECTIVES: To investigate the effects of an exercise referral scheme (ERS) aligned to the UK best practice guidelines on a range of outcomes including those associated with key health concerns of the Scottish population. STUDY DESIGN: A longitudinal design with data collection at three time points (baseline, midway and post) during a 12-week ERS intervention was employed. METHODS: Health-related physical fitness was assessed through measurement of resting heart rate, blood pressure, FEV1:FEV6 (ratio of forced expiratory volume over one [FEV1] and six [FEV6] seconds), body mass and peak oxygen uptake (VO2 peak), whilst functional capacity was assessed through the five times sit to stand test. Psychosocial well-being and quality of life were measured using the World Health Organization Quality of Life questionnaire (WHOQOL-BREF) and the Profile of Mood State questionnaires. Growth curve analyses were used to model each outcome variable across the three time periods. RESULTS: A range of effects were obtained with significant linear improvements in physical performance tests (P < 0.001) and psychosocial assessments (P ≤ 0.002). Additionally, significant quadratic effects of time were obtained for body composition variables and physical activity levels (P < 0.001) with the greatest improvements obtained between baseline and midway assessments. CONCLUSIONS: An ERS aligned to the UK best practice guidelines can positively influence a range of health outcomes including those associated with lung function and cardiovascular fitness which are prevalent medical conditions in Scotland. In addition, results indicate that ERS can positively affect outcomes related to functional capacity as well as mental well-being and perceptions of health. The findings of the study identify the need for further investigation including consideration of the initial health status of referred clients.

Clinical Presentation and Determinants of Mortality of Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: A Multinational Cohort Study.

The prognostic factors and optimal therapy for invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT) remain poorly studied. We included in this multinational retrospective study 112 recipients diagnosed with probable (75.0% of cases) or proven (25.0%) IPA between 2000 and 2013. The median interval from transplantation to diagnosis was 230 days. Cough, fever, and expectoration were the most common symptoms at presentation. Bilateral pulmonary involvement was observed in 63.6% of cases. Positivity rates for the galactomannan assay in serum and bronchoalveolar lavage samples were 61.3% and 57.1%, respectively. Aspergillus fumigatus was the most commonly identified species. Six- and 12-week survival rates were 68.8% and 60.7%, respectively, and 22.1% of survivors experienced graft loss. Occurrence of IPA within the first 6 months (hazard ratio [HR]: 2.29; p-value = 0.027) and bilateral involvement at diagnosis (HR: 3.00; p-value = 0.017) were independent predictors for 6-week all-cause mortality, whereas the initial use of a voriconazole-based regimen showed a protective effect (HR: 0.34; p-value = 0.007). The administration of antifungal combination therapy had no apparent impact on outcome. In conclusion, IPA entails a dismal prognosis among KT recipients. Maintaining a low clinical suspicion threshold is key to achieve a prompt diagnosis and to initiate voriconazole therapy.

Risk Factors Associated With Early Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: Results From a Multinational Matched Case-Control Study.

Risk factors for invasive pulmonary aspergillosis (IPA) after kidney transplantation have been poorly explored. We performed a multinational case-control study that included 51 kidney transplant (KT) recipients diagnosed with early (first 180 posttransplant days) IPA at 19 institutions between 2000 and 2013. Control recipients were matched (1:1 ratio) by center and date of transplantation. Overall mortality among cases was 60.8%, and 25.0% of living recipients experienced graft loss. Pretransplant diagnosis of chronic pulmonary obstructive disease (COPD; odds ratio [OR]: 9.96; 95% confidence interval [CI]: 1.09-90.58; p = 0.041) and delayed graft function (OR: 3.40; 95% CI: 1.08-10.73; p = 0.037) were identified as independent risk factors for IPA among those variables already available in the immediate peritransplant period. The development of bloodstream infection (OR: 18.76; 95% CI: 1.04-339.37; p = 0.047) and acute graft rejection (OR: 40.73, 95% CI: 3.63-456.98; p = 0.003) within the 3 mo prior to the diagnosis of IPA acted as risk factors during the subsequent period. In conclusion, pretransplant COPD, impaired graft function and the occurrence of serious posttransplant infections may be useful to identify KT recipients at the highest risk of early IPA. Future studies should explore the potential benefit of antimold prophylaxis in this group.

Multicenter study of epidemiological cutoff values and detection of resistance in Candida spp. to anidulafungin, caspofungin, and micafungin using the Sensititre YeastOne colorimetric method.

Neither breakpoints (BPs) nor epidemiological cutoff values (ECVs) have been established for Candida spp. with anidulafungin, caspofungin, and micafungin when using the Sensititre YeastOne (SYO) broth dilution colorimetric method. In addition, reference caspofungin MICs have so far proven to be unreliable. Candida species wild-type (WT) MIC distributions (for microorganisms in a species/drug combination with no detectable phenotypic resistance) were established for 6,007 Candida albicans, 186 C. dubliniensis, 3,188 C. glabrata complex, 119 C. guilliermondii, 493 C. krusei, 205 C. lusitaniae, 3,136 C. parapsilosis complex, and 1,016 C. tropicalis isolates. SYO MIC data gathered from 38 laboratories in Australia, Canada, Europe, Mexico, New Zealand, South Africa, and the United States were pooled to statistically define SYO ECVs. ECVs for anidulafungin, caspofungin, and micafungin encompassing ≥97.5% of the statistically modeled population were, respectively, 0.12, 0.25, and 0.06 µg/ml for C. albicans, 0.12, 0.25, and 0.03 µg/ml for C. glabrata complex, 4, 2, and 4 µg/ml for C. parapsilosis complex, 0.5, 0.25, and 0.06 µg/ml for C. tropicalis, 0.25, 1, and 0.25 µg/ml for C. krusei, 0.25, 1, and 0.12 µg/ml for C. lusitaniae, 4, 2, and 2 µg/ml for C. guilliermondii, and 0.25, 0.25, and 0.12 µg/ml for C. dubliniensis. Species-specific SYO ECVs for anidulafungin, caspofungin, and micafungin correctly classified 72 (88.9%), 74 (91.4%), 76 (93.8%), respectively, of 81 Candida isolates with identified fks mutations. SYO ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin, micafungin, and especially caspofungin, since testing the susceptibilities of Candida spp. to caspofungin by reference methodologies is not recommended.

Quality improvement in chronic illness care: a collaborative approach.

BACKGROUND: Despite rapid advances in the clinical and psycho-educational management of diabetes, the quality of care received by the average patient with diabetes remains lackluster. The "collaborative" approach--the Breakthrough Series (BTS; Institute for Healthcare Improvement [IHI]; Boston)--coupled with a Chronic Care Model was used in an effort to improve clinical care of diabetes in 26 health care organizations. METHODS: Descriptive and pre-post data are presented from 23 health care organizations participating in the 13-month (August 1998-September 1999) BTS to improve diabetes care. The BTS combined the system changes suggested by the chronic care model, rapid cycle improvement, and evidence-based clinical content to assist teams with change efforts. The characteristics of organizations participating in the diabetes BTS, the collaborative process and content, and results of system-level changes are described. RESULTS: Twenty-three of 26 teams completed participation. Both chart review and self-report data on care processes and clinical outcomes suggested improvement based on changes teams made in the collaborative. Many of the organizations evidencing the largest improvements were community health centers, which had the fewest resources and the most challenged populations. DISCUSSION: The initial Chronic Illness BTS was sufficiently encouraging that replication and evaluation of the BTS collaborative model is being conducted in more than 50 health care systems for diabetes, congestive heart failure, depression, and asthma. This model represents a feasible method of improving the quality of care across different health care organizations and across multiple chronic illnesses.

Continuous quality improvement for patients with back pain.

Recent evidence has changed traditional approaches to low back pain, suggesting minimal bed rest, highly selective imaging, and early return to normal activities. However, there are wide geographical variations in care, and substantial gaps between practice and evidence. This project sought to merge scientific evidence about back pain and knowledge about behavior change to help organizations improve care for back pain. Participating insurance plans, HMOs, and group practices focused on problems they themselves identified. The year-long program included quarterly meetings, coaching for rapid cycles of change, a menu of potential interventions, and recommendations for monitoring outcomes. Participants interacted through meetings, e-mail, and conference calls. Of the 22 participating organizations, 6 (27%) made major progress. Typical changes were reduced imaging, bed rest, and work loss, and increased patient education and satisfaction. Specific examples were a 30% decrease in plain x-rays, a 100% increase in use of patient education materials, and an 81% drop in prescribed bed rest. Despite the complexity of care for back pain, rapid improvements appear feasible. Several organizations had major improvements, and most experienced at least modest improvements. Key elements of successful programs included focus on a small number of clinical goals, frequent measurement of outcomes among small samples of patients, vigilance in maintaining gains; involvement of office staffs as well as physicians, and changes in standard protocols for imaging, physical therapy, and referral.

Reducing adverse drug events: lessons from a breakthrough series collaborative.

BACKGROUND: In January 1996, 38 hospitals and health care organizations (for a total of 40 hospitals) in the United States came together in an Institute for Healthcare Improvement (IHI; Boston) Breakthrough Series collaborative to reduce adverse drug events-injuries related to the use or nonuse of medications. METHODS: The participants were taught the Model for Improvement, a method for rapid-cycle change and evaluation, and were then coached on how to identify their own problem areas and develop changes in practice for rapid-cycle testing. These changes could be implementation of one or more known medication error prevention practices or new practices developed. RESULTS: During a 15-month period the 40 hospitals conducted a total of 739 tests of changes. Process changes accounted for 63% of the cycles; the remainder consisted of preliminary data gathering, consensus-building, or education cycles. Eight types of changes were implemented by seven or more hospitals, with a success rate of 70%. These changes included non-punitive reporting, ensuring documentation of allergy information, standardizing medication administration times, and implementing chemotherapy protocols. DISCUSSION: Success in making significant changes was associated with strong leadership, effective processes, and appropriate choice of intervention. Successful teams were able to define, clearly state, and relentlessly pursue their aims, and then chose practical interventions and moved early into changing a process. They did not spend months collecting data before beginning a change. Changes that were most successful were those that attempted to change processes, not people. Health care organizations committed to patient safety need not regard current performance limits as inevitable.

Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients.

PURPOSE: To study the influence of large-volume high-calorie protein, fat, and carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous meal on the oral bioavailability of indinavir in HIV-infected subjects. METHODS: Seven male HIV-infected subjects received caloric meal treatments and control meals in a randomized crossover fashion and the viscosity meal as a final treatment. The total volume of each meal treatment was 500 mL and the caloric meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry from one hour before to four hours after drug and caloric meal administration. A single Crixivan (indinavir sulfate) dose equivalent to 600 mg indinavir was administrated orally with 100 mL of water immediately following meal administration. Indinavir plasma concentrations were obtained using reverse-phase HPLC. RESULTS: All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC0-infinity decreased by 68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal treatments versus fasted control, respectively (p < 0.05). The mean Cmax was significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean tmax was significantly delayed from I hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments, respectively. The elimination half-life of indinavir determined in the fasted state was decreased in HIV-infected subjects as compared to the reported half-life in normal healthy subjects. CONCLUSIONS: Reductions in indinavir plasma concentrations compared to drug administration in the fasted state are most severe with the high-calorie protein meal. This is consistent with an influence of elevated gastric pH on drug precipitation. Significant drug plasma concentration reductions observed with administration of the other meals in the absence of appreciably elevated gastric pH profile indicate that other factors are playing a role in the meal effects. The similarity in indinavir plasma profiles with protein and carbohydrate versus fat and viscosity suggests that the latter meals may reduce the impact of drug precipitation compared to the former meals.

HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications.

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test.

OBJECTIVE: The steady-state kinetics of delavirdine and desisopropyldelavirdine were evaluated in human immunodeficiency virus-positive patients after escalating oral doses and after repeated oral administrations at the same dose level. STUDY DESIGN: Patients (n = 8 males) were given escalating oral doses of delavirdine mesylate, in a sequential fashion, over 14 days for phases 1 (200 mg every 8 hours), 2 (300 mg every 8 hours), and 3 (400 mg every 8 hours). Control patients (n = 4 males) were given 300 mg oral doses of drug every 8 hours for all three phases. Hepatic CYP3A activity was evaluated with the erythromycin breath test (ERMBT). RESULTS: In the escalating-dose group, delavirdine displayed nonlinear kinetics as indicated by the decreasing oral clearance, maximum steady-state plasma concentration/minimum steady-state plasma concentration ratio, and log-linear terminal rate constant, as well as by increasing half-life at higher doses; the ratio of desisopropyl-delavirdine formation clearance to elimination clearance was also reduced. In the control group, the kinetics of delavirdine and desisopropyl-delavirdine were unchanged. Plasma protein binding was linear for delavirdine in the escalating-dose and control groups; on average, the fraction unbound was about 2.3% and 2.0%, respectively. Hepatic CYP3A activity was markedly reduced after short- and long-term exposure to all doses of delavirdine mesylate. Delavirdine could maximally inhibit 70% to 75% of predose ERMBT values, with an IC50 of about 0.9 mumol/L. CONCLUSION: Delavirdine is a potent and reversible inhibitor of hepatic CYP3A; it is also a substrate for this CYP450 isoform. It is likely that delavirdine will exhibit drug-drug interactions when coadministered with other CYP3A substrates.

Antifungal agents in the 1990s. Current status and future developments.

Significant advances in antifungal therapy have occurred in the last decade. Most of these advances have been tied to the introduction of the triazoles, itraconazole and fluconazole. Itraconazole has proved efficacious for the treatment of subacute to chronic infections with the endemic mycoses and other opportunistic filamentous fungi, including Aspergillus spp. Fluconazole is now routinely used for mucocutaneous and systemic candidiasis, and its use for coccidioidal meningitis has obviated the need for intrathecal amphotericin B in most patients. Large, well controlled trials in AIDS patients with cryptococcal meningitis have shown the benefit of induction therapy with amphotericin B and flucytosine, followed by consolidation and life-long maintenance therapy with fluconazole. Concomitant with the increased use of these well tolerated, effective oral triazole agents has come the emergence of drug resistance in AIDS patients and shifts in the species of yeasts causing infection in hospitalised patients. Amphotericin B remains the drug of choice for many fungal infections, especially those that are life-threatening. Lipid-containing formulations of amphotericin B have recently been approved: these preparations significantly reduce the risk of amphotericin B-induced nephrotoxicity. Several new fungicidal agents are currently in early trials. With the increasing number of available antifungal drugs, future studies will help define the appropriate niche for each and the possible benefit of therapy with combinations of drugs.

Alterations in gastric acidity in patients infected with human immunodeficiency virus.

In a randomized crossover trial, gastric acidity and gastric microbial colonization in 19 men infected with human immunodeficiency virus (HIV) (of whom nine had AIDS) were assessed. Gastric acidity was assessed during a baseline period and following pentagastrin or glutamic acid administration. Only two (22.2%) of the nine patients with AIDS and none of the non-AIDS patients were hypochlorhydric, as determined by maximal acid output. However, 60% and 67% of patients in the HIV-infected and AIDS groups, respectively, had persistently elevated gastric pH values during the baseline period. Both pentagastrin and glutamic acid significantly increased gastric acidity. Gastric colonization with Candida albicans and gram-positive mouth flora was common. Overall, this study demonstrates that many HIV-infected patients have elevated gastric pH values that may lead to alteration in drug absorption. The large degree of intrasubject and intersubject variability observed in gastric pH suggests that, unfortunately, one cannot predict which patients will have elevated gastric pH values.

Check-off logs for routine equipment maintenance.

The regulatory requirement for appropriate routine instrument maintenance documentation is approached by laboratories in numerous ways. Standard operating procedures (SOPs) may refer to maintenance listed in instrument manuals, may indicate "periodic" performance of an action, or may indicate specific tasks to be performed at certain frequencies. The Quality Assurance Unit (QAU) task of assuring the performance of these indicated maintenance tasks can be extremely laborious if these records are merged with other analysis records. Further, the lack of written maintenance schedules often leads to omission of infrequently performed tasks. We recommend creation of routine maintenance check-off logs for instruments with tasks grouped by frequency of expected performance. Usage of such logs should result in better laboratory compliance with SOPs and the compliance can be readily monitored by QAU or by regulatory agencies.

Quality auditing of chromatographic data.

We have developed a method for consistent, in-depth audit of the integrity of chromatographic records. The approach includes definition of the analyte, the method of analyte sample preparation and analysis, and the analyte concentration range. Acceptance criteria (if any) defined in the protocol or method are compared to the data. Run parameters are compared to those specified in the methodology. Certification of the standard is verified and the limit of quantitation for each run is identified and compared to data. Reasons for data discard and/or reassay are examined. If calculation software is not validated, representative calculations are recomputed and chromatograms are examined for attributability. These parameters are examined in addition to other Good Laboratory practice considerations such as sample identity, sample integrity, and transcription accuracy.

Antibacterial activity of sucralfate versus aluminum chloride in simulated gastric fluid.

Studies have previously demonstrated that sucralfate possesses intrinsic antibacterial activity. This study was designed to indirectly assess whether aluminum is the active antibacterial component of sucralfate and to further evaluate factors that may influence this agent's antibacterial activity. Utilizing an in vitro model, the antibacterial activity of sucralfate, an equivalent quantity of aluminum in the form of aluminum chloride, and a control were compared. In addition, the influences of bacterial species (Enterobacter cloacae and Pseudomonas aeruginosa), time (0-24 h) and environmental pH (3,5,7) on the agents' antibacterial activities were evaluated. Equivalent quantities of aluminum, as either sucralfate or aluminum chloride, were added to two of three flasks containing approximately 10(5) cfu/ml of bacteria in pH-adjusted simulated gastric fluid. The third flask served as a control. Samples were obtained over 24 h, diluted and subcultured onto agar plates. The experiments demonstrated that bacterial growth was influenced by pH, time and treatment (aluminum chloride or sucralfate). Regardless of pH or bacterial species, bacterial death occurred within 20 min following the addition of aluminum chloride. In contrast, bacterial death following the addition of sucralfate was more variable and appeared to be pH dependent. In conclusion, sucralfate and aluminum chloride both possess antibacterial activity, even at pH values that normally support bacterial growth in gastric fluid. Although differences in the antibacterial activity of the two agents may in part be related to drug-induced changes in pH, these differences also support data suggesting that aluminum release from sucralfate is incomplete and is dependent on pH.

In vitro analysis of the interaction between sucralfate and ketoconazole.

In healthy volunteers, the bioavailability of ketoconazole is significantly decreased during simultaneous administration with sucralfate. In an effort to address this problem, we examined the interaction between sucralfate and ketoconazole in aqueous solutions and in simulated gastric fluid (SGF) at various initial pHs (1, 2, 3, and 6) in the presence or absence of glutamic acid hydrochloride (GA). Samples from each solution were taken 30 min and 2 h after the addition of ketoconazole to evaluate the solubility of ketoconazole over the usual time period of maximal absorption of ketoconazole in humans. The addition of GA to SGF leads to an increase in solution acidity, while the pHs of SGF at a pH of 1, 2, or 3 are markedly increased by the addition of sucralfate. There is a net decrease in acidity from initial pHs for the pH 1, 2, and 3 solutions when GA and sucralfate are combined. The concentration of ketoconazole in SGF at pHs of 1, 2, 3, 4, and 6 was evaluated in order to assess the pH-dependent solubility properties of the drug in the absence of other interacting species. Regardless of the initial pH, combinations of GA plus ketoconazole showed high concentrations of ketoconazole (approximately 100%) in solution. In contrast, significant decreases in the concentration of soluble ketoconazole were observed when sucralfate was mixed with ketoconazole, and, in some cases, soluble ketoconazole was not detectable. The addition of GA to a mixture of sucralfate and ketoconazole leads to a significant increase in the concentration of solubilized ketoconazole. Nonetheless, important sucralfate-ketoconazole interactions are still observed. After 2 h, approximately 35% of the maximal ketoconazole concentration remained in solution. Comparison of the ketoconazole concentrations at different pHs with the predicted concentrations of the three protonation species of ketoconazole [H2(ketoconazole)(2+), H(ketoconazole)(+), or ketoconazole] showed no correlation. Therefore, the decrease in ketoconazole solubility is not simply a reflection of pH perturbation associated with the dissolution of sucralfate. The observed data are most consistent with a model that has H2(ketoconazole)(2+) or H(ketoconazole)(+) forming an electrostatic interaction with the sucralfate polyanion. The findings of this study suggest that the coadministration of sucralfate with other azole antifungal agents should be investigated.