The Journal of antimicrobial chemotherapy
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Nitric oxide (NO) is one of many vasoactive substances released, from a variety of cells, under conditions of endotoxaemia and sepsis. Under physiological conditions it is produced by two constitutive calcium-dependent enzymes (nitric oxide synthase; NOS) in neurones (nNOS) and endothelial cells (eNOS) and has functions ranging from neurotransmission and vasodilatation to inhibition of platelet adhesion and aggregation. Following bacterial infection, especially with Gram-negative organisms, its formation from L-arginine is enhanced due to the cytokine-mediated induction of a NOS enzyme (iNOS) in cells (e.g. cardiac myocytes, vascular smooth muscle) that do not normally have the ability to synthesize NO. ⋯ Because some of these detrimental effects are due to inhibition of eNOS, attempts have been made to examine the effects of substances with a higher selectivity for the induced form of the enzyme. In experimental animals, one of these (L-canavanine) protects endothelial cells from damage, increases survival time and restores vascular responsiveness without increasing blood pressure or peripheral vascular resistance. However, whether even this approach will be of benefit to patients with sepsis remains in doubt since studies in iNOS knock-out mice do not support the concept that eliminating this particular source of NO improves ultimate survival.
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Complement provides a critical and multifaceted defence system against infection. Following activation, complement can clear invading microorganisms by lysis or by opsonization, which promotes recognition by complement receptors on phagocytes. ⋯ The host has developed regulatory mechanisms for controlling complement activation and for protecting its own cells against complement attack. Some microorganisms have also evolved ways to avoid the opsonic and lytic action of complement.
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Cardiovascular alterations in sepsis include a decrease in vascular tone and an impairment in myocardial contractility, and occur largely as the result of the release and action of mediators of the sepsis cascade. Many mediators are involved including cytokines, particularly tumour necrosis factor and interleukin-1, and secondary mediators such as nitric oxide and oxygen free radicals. The degree of reduced vascular tone and myocardial depression have both been related to the severity of sepsis. In this article we will review current knowledge on the factors involved in the cardiovascular alterations of sepsis, the clinical implications of these alterations, and the possibilities for future treatments.
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J. Antimicrob. Chemother. · Jul 1996
ReviewIs continuous infusion of beta-lactam antibiotics worthwhile?--efficacy and pharmacokinetic considerations.
The most important pharmacodynamic parameter for beta-lactam antibiotics has been shown to be the time above the MIC, which is used as an argument to administer beta-lactam antibiotics by continuous infusion. Studies in vitro and in laboratory animals comparing efficacy of continuous and intermittent infusion of beta-lactam antibiotics generally show continuous infusion to be more efficacious. While comparative trials in humans are scarce and a significant difference was only found in subgroup analysis in one study, several case-reports support the use of continuous infusion. ⋯ Pharmacokinetic studies which have been performed in humans during continuous infusion show that serum concentrations can be predicted from total clearance or, using population pharmacokinetic modelling, the elimination rate constant as obtained during intermittent infusion. A nomogram is presented which allows calculation of the daily dose to obtain the target steady state blood concentrations suggested by the susceptibility of the infecting bacterium, usually 4 x MIC. For bacteria with a low MIC, the daily dose may be substantially lower than that used in conventional dosing regimens, while in infections which are difficult to treat as a result of more resistant bacteria, continuous infusion may be more effective than an equivalent bolus dose.
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J. Antimicrob. Chemother. · Jun 1996
ReviewThe use of corticosteroids in the management of bacterial meningitis in adults.
Despite the introduction of newer antimicrobial agents, bacterial meningitis continues to be associated with significant morbidity and mortality. Evidence from in-vitro studies, experimental animal models, and clinical studies indicate that the host inflammatory response is responsible for much of the deleterious consequences of this disease. ⋯ Although there is considerable evidence from animal models and from clinical trials in children that adjunctive antiinflammatory therapy with corticosteroids is effective in reducing inflammation and in improving long-term outcomes, similar data involving adults are largely lacking. The rationale for the use of corticosteroids in the management of bacterial meningitis, and the applicability to disease in adults, are discussed, and some recommendations for their use in this setting are made.