Principles and practice of antibiotic therapy

The oral cavity and surrounding structures harbor an extremely complex array of microorganisms. As a result, when structures become acutely or chronically infected, diseases can present very differently. Surgical and pharmacologic management decisions become equally complex, depending on the source site of the infection and the areas to which it spreads. This article first reviews the various domains of the oral and maxillofacial structures, and then reviews each class of antibiotics, describing how the antibiotics are likely to be used.     

Intercultural gerontology curriculum: Principles and practice

ABSTRACT

The internationalization of universities and the aging of the global population are two current issues that converge and challenge undergraduate gerontology curriculum development in Canada. One response to this challenge is to envision an intercultural gerontology curriculum. What might this curriculum encompass? How might it be taught? An exploratory study was undertaken to address these two questions. This paper presents findings from this study based primarily on interviews with university-based stakeholders from Canada, the United States, and Europe. Thematic analysis of the interviews resulted in five themes: multiple perspectives on cultural diversity; the dynamic nature of cultural diversity and aging; flow of an intercultural curriculum; institutional culture and intercultural curricula; and principles and practice for intercultural gerontology. Framed by principles of gerontology theory and educational approaches, this paper focuses on the principles and practice suggested by study participants. Scaffolding learning, active learning strategies, experiential learning opportunities, teacher modelling, and internet-based learning are discussed as key to intercultural learning. An appendix includes a list of resources that may be useful to developing an intercultural gerontology curriculum.     

HIV-protease inhibitors alter retinoic acid synthesis

BACKGROUND: An increasing rate of highly-active antiretroviral therapy (HAART)-associated metabolic and morphological abnormalities has been reported in HIV-infected persons. Some of them resemble retinoid-related adverse events, indicating alteration(s) of retinol metabolism or of retinoic acid-mediated signalling. OBJECTIVE: To evaluate retinol levels in patients with or without HAART and to assess the effect of antiretroviral agents on retinal dehydrogenase (RALDH), a key enzyme involved in retinoic acid synthesis. DESIGN: Plasma retinol levels, measured in six patients receiving HAART and in five others with no antiretroviral therapy, were correlated with levels of serum retinol-binding proteins. We then studied the effects of seven antiretroviral agents on RALDH activity and gene expression in a kidney-derived cell line (LLCPK). RESULTS: Plasma retinol levels in patients receiving HAART were decreased in comparison with those not receiving antiretroviral drugs (51 +/- 5 versus 66 +/- 11 microg/dl; P = 0.03), whereas retinol-binding protein levels were increased (68 +/- 18 versus 45 +/- 10 mg/l; P = 0.04). RALDH activity was heightened by ritonavir (24%), indinavir (17%), saquinavir (17%), zalcitabine (14%), delavirdine (12%) and nelfinavir (10%) and decreased (22%) by DMP-450. RALDH gene expression was induced only by indinavir. CONCLUSIONS: These data indicate that certain retinoid-like adverse effects in HAART-receiving patients are not due to higher retinol levels. Enhanced RALDH activity or/and gene expression by some protease inhibitors could increase retinoic acid concentrations. Elevated retinoic acid levels might be responsible for retinoid-like or other adverse effects due to alterations in the expression of retinoic acid-responsive genes.     

Outpatient parenteral antibiotic therapy: Principles and practice

Outpatient parenteral antimicrobial therapy (OPAT) refers to the administration of a parenteral antimicrobial in a non inpatient or ambulatory setting with the explicit aim of facilitating admission avoidance or early discharge. Whilst OPAT has predominantly been the domain of the infection specialist, the internal medicine specialist has a key role in service development and delivery as a component of broader ambulatory care initiatives such as “hospital at home”. Main drivers for OPAT are patient welfare, reduction of risk of health care associated infection and cost-effective use of hospital resources. The safe practice of OPAT is dependent on a team approach with careful patient selection and antimicrobial management with programmed and adaptable clinical monitoring and assessment of outcome. Gram-positive infections, including cellulitis, bone and joint infection, bacteraemia and endocarditis are key infections potentially amenable to OPAT whilst resistant Gram-negative infections are of increasing importance. Ceftriaxone, teicoplanin, daptomycin and ertapenem lend themselves well to OPAT due to daily (or less frequent) bolus administration, although any antimicrobial may be administered if the patient is trained to administer and/or an appropriate infusion device is employed. Clinical experience from NHS Greater Glasgow and Clyde is presented to illustrate the key principles of OPAT as practised in the UK. Increasingly complex patients with multiple medical needs, the relative scarcity of inpatient resources and the broader challenge of ambulatory care and “hospital at home” will ensure the internal medicine specialist will have a key role in the future development of OPAT.     

Principles and practice of antibiotic therapy of diabetic foot infections

Foot infections are a common and serious problem in diabetic patients. They usually occur as a consequence of a skin ulceration, which initially is colonized with normal flora, and later infected with pathogens. Infection is defined clinically by evidence of inflammation, and appropriate cultures can determine the microbial etiology. Aerobic gram-positive cocci are the most important pathogens; in chronic, complex or previously treated wounds, gram-negative bacilli and anaerobes may join in a polymicrobial infection. In all diabetic foot infections a primary consideration is whether or not surgical intervention is required, e.g. for undrained pus, wound debridement or revascularization. Antibiotic regimens are usually selected empirically initially, then modified if needed based on results of culture and sensitivity tests and the patient's clinical response. Initial therapy, especially in serious infections, may need to be broad-spectrum, but definitive therapy can often be more targeted. Severe infections usually require intravenous therapy initially, but milder cases can be treated with oral agents. Treatment duration ranges from 1-2 weeks (for mild soft tissue infection) to more than 6 weeks (for osteomyelitis). The choice of a specific agent should be based on the usual microbiology of these infections, data from published clinical trials, the severity of the patient's infection, and the culture results. Extension of infection into underlying bone can be difficult to diagnose and may require imaging tests, e.g. magnetic resonance scans. Cure of osteomyelitis usually requires resection of infected bone, but can be accomplished with prolonged antibiotic therapy. Various non-antimicrobial adjunct therapies may sometimes be helpful. Published in 2000 by John Wiley & Sons, Ltd.     

Phase 1 single dose studies to optimize the pharmacokinetics of DG17, a novel HIV-protease inhibitor pro-drug, using sodium bicarbonate and ritonavir

DG17 is an orally available prodrug of DG35 (a novel HIV protease inhibitor with variable pharmacokinetics). These studies aimed to optimize DG17 pharmacokinetics by gastric acid neutralization and ritonavir pharmacoenhancement. Both studies were conducted using a randomized, cross-over design in which 6 healthy individuals were administered a single dose of 100mg or 200mg DG17, half with the study intervention (sodium bicarbonate solution in the first study, low dose ritonavir in the second). After a one week washout period, each subject was then administered a second dose of DG17, with the study intervention only administered to the other half. Cmax and AUC increases with gastric acid neutralization were greatest in those with the lowest absorption of DG17 alone. All doses were subsequently given with sodium bicarbonate solution in the second study. Low-dose ritonavir co-administration with DG17 increased DG35 C(max) (median 1437 versus 100 ng/ml, p=0.028) and AUC (median 6975 versus 154ng/ml*hr, p=0.028) compared with DG17 without ritonavir. Plasma DG35 exceeded the IC(90) for HIV for > or = 12 hours following a single DG17/ritonavir dose. No significant adverse events occurred. Single dose DG17 is safe and best administered in a manner preventing gastric acid degradation and with low-dose ritonavir.     

Principles of modern antibiotic therapy in general practice and the clinic

It is reported on the principles of modern therapy with antibiotics and here above all is referred to the differences in the antibiotic treatment in practice and clinic. Issuing from the infections usually occurring in practice with the spectre of causative agents known in many cases the therapeutic possibilities are discussed also taking into consideration economic points of view. In contrast to this in infections in the clinic, so-called nosocomial diseases, changing situations are present, which need a therapy on the basis of the antibiogramme. In these cases partly also combination therapies for the enlargement of the spectre of action and for the increase of the antibacterial activity are used.     

Intravenous proton pump inhibitor use in hospital practice

AIM: North American studies suggest that intravenous proton pump inhibitors are used inappropriately in hospital practice, but little is known of prescribing patterns in Europe. Our aim was to examine intravenous proton pump inhibitors prescribing in a single university teaching hospital. METHODS: Observational study of 101 consecutive hospital patients administered intravenous proton pump inhibitors over a 3-month period in a single hospital in Dublin, Ireland. Demographic, clinical, biochemical, haematological, endoscopic and follow-up data were collected and analysed. RESULTS: Sixty-five percent (65 of 101) of the patients had no objective evidence of gastrointestinal blood loss and 85 were haemodynamically stable before treatment. Two patients underwent endoscopic haemostasis before IV administration. The remaining 99 were treated for ulcer prophylaxis, presumed gastrointestinal haemorrhage, unrelated gastrointestinal conditions or for unknown reasons. Relatively senior nonconsultant staff prescribed intravenous therapy in most cases. Only six patients in the study were deemed to have received intravenous therapy for an appropriate indication. CONCLUSIONS: Intravenous proton pump inhibitors use in hospital practice is usually inappropriate. It may be that other valid indications exist within hospital practice, but these might reasonably be evaluated in randomized trials that would assess the risks and costs of intravenous treatments as well as their benefits.     

HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D

BACKGROUND: A high prevalence of bone demineralization occurs in people living with HIV/AIDS. The contribution of HIV itself and its treatment is still unclear. Protease inhibitors (PIs) are potent inhibitors of the cytochrome p450 enzyme system. Three cytochrome p450 mixed function oxygenases control serum levels of 1,25-dihydroxyvitamin D (1,25(OH) D ), which is responsible for vitamin D actions in target tissues including bone. The 25- and 1alpha-hydroxylases regulate 1,25(OH) D synthesis and 24-hydroxylase 1,25(OH) D catabolism. OBJECTIVE: To assess whether HIV-protease inhibitors (ritonavir, indinavir, nelfinavir) impair the activity of the main enzymes involved in 1,25(OH) D homeostasis. DESIGN AND METHODS: Studies were conducted in the human hepatocyte (H3B)- and monocyte (THP-1) cell lines, expressing 25-hydroxylase and 1alpha-hydroxylase, respectively. The 24-hydroxylase expression was induced in macrophages by exposure to 1,25(OH) D. Conversion rates of vitamin D to 25-hydroxyvitamin D [25(OH)D ]; 25(OH)D to 1,25(OH) D or 24,25(OH) D, and 1,25(OH) D degradation were quantified in untreated and HIV-PI-treated cells after C -cartridge extraction and high-performance liquid chromatography purification of 25(OH)D - 24,25(OH) D - and 1,25(OH) D fractions. RESULTS: The PIs impair hepatocyte 25(OH)D - and macrophage 1,25(OH) D synthesis in a reversible, dose-dependent manner. Furthermore, PIs inhibit 1,25(OH) D -degradation in macrophages with lower potency than that elicited on 1alpha-hydroxylase. Thus, reduced macrophage 1,25(OH) D production is the net effect of PIs action. CONCLUSIONS: In intact cells, HIV-PIs markedly suppress the activities of 25- and 1alpha-hydroxylase, which are critical in 1,25(OH) D synthesis, while exerting mild inhibition of 24-hydroxylase, responsible for 1,25(OH) D catabolism. If PIs elicit a similar potency in inhibiting these critical steps for 1,25(OH) D homeostasis, defective 1,25(OH) D production could contribute to the bone demineralization in HIV patients.