Citations

Cyclosporine induces hypertension and wide-spread vasoconstriction after transplantation in addition to reducing kidney function. We studied hemodynamic, renal, and hormonal effects of monotherapy with nifedipine XL (n = 37) in liver transplant recipients within a year after transplant (median, 4.4 months). Systemic hemodynamics were determined with thoracic electrical bioimpedance. Blood pressure before therapy was 172 +/- 4/108 +/- 2 mm Hg. Sixty-four percent of recipients achieved blood pressures less than 140/90 mm Hg mediated by a fall in systemic vascular resistance index (2427 +/- 245 dyne.s.cm-5.m-2 in responders versus 2905 +/- 281 in nonresponders, P < .01). Despite the fall in systemic vascular resistance, glomerular filtration rates were not changed during nifedipine therapy, as measured by both creatinine and iothalamate clearances. Urinary prostacyclin (6-ketoprostaglandin F1 alpha) was suppressed below normal from 2468 +/- 323 ng/d before transplant to 1103 +/- 99 ng/d (P < .01) after transplant and did not change during nifedipine therapy. Urinary thromboxane B2 and plasma renin activity also fell after transplant and remained low during nifedipine. These data demonstrate that nifedipine can reverse systemic vasoconstriction associated with hypertension after transplantation. Systemic effects were not transmitted to the kidney sufficiently to improve glomerular filtration rate or reverse hormonal changes within the kidney. Hence, vascular and functional regulation of the kidney was dissociated from the systemic circulation during nifedipine administration after transplantation.

Functional values of LogSD of the ventilation distribution (σV̇) have been reported previously, but functional values of LogSD of the perfusion distribution (σq̇) and the coefficient of correlation between ventilation and perfusion (ρ) have not been measured in humans. Here, we report values for σV̇, σq̇, and ρ obtained from wash-in data for three gases, helium and two soluble gases, acetylene and dimethyl ether. Normal subjects inspired gas containing the test gases, and the concentrations of the gases at end-expiration during the first 10 breaths were measured with the subjects at rest and at increasing levels of exercise. The regional distribution of ventilation and perfusion was described by a bivariate log-normal distribution with parameters σV̇, σq̇, and ρ, and these parameters were evaluated by matching the values of expired gas concentrations calculated for this distribution to the measured values. Values of cardiac output and LogSD ventilation/perfusion (V̇a/Q̇) were obtained. At rest, σq̇ is high (1.08 ± 0.12). With the onset of ventilation, σq̇ decreases to 0.85 ± 0.09 but remains higher than σV̇ (0.43 ± 0.09) at all exercise levels. Rho increases to 0.87 ± 0.07, and the value of LogSD V̇a/Q̇ for light and moderate exercise is primarily the result of the difference between the magnitudes of σq̇ and σV̇. With known values for the parameters, the bivariate distribution describes the comprehensive distribution of ventilation and perfusion that underlies the distribution of the V̇a/Q̇ ratio.

The efficacy of cefazolin or cefpirome alone or combined with rifampin was compared with that of vancomycin alone or combined with rifampin in an experimental model of methicillin-resistant, beta-lactamase-producing, coagulase-negative staphylococcal endocarditis. Phenotypically, the mecA gene-positive strain used in vivo did not exhibit methicillin resistance by the agar dilution or disk susceptibility method but was resistant in vitro (oxacillin MIC, 64 micrograms/ml) by the microtiter dilution method with 2% NaCl supplementation. Macrodilution broth susceptibilities of standard inocula failed to demonstrate cross-resistance of staphylococci to cefazolin (MIC, 8 micrograms/ml) or cefpirome (MIC, 4 micrograms/ml). In vivo, vancomycin and cefpirome had similar activities, and both regimens were more effective than was cefazolin alone. While the MIC of rifampin was low (0.031 micrograms/ml), monotherapy with rifampin resulted in a bimodal distribution of outcomes due to the expected emergence of resistant mutants. The results in vitro of time-kill synergy studies using rifampin in combination with cefazolin or cefpirome varied with the antimicrobial concentrations tested and did not reliably predict activities in vivo of rifampin-beta-lactam combination therapies. Cefpirome, but not cefazolin or vancomycin, in combination with rifampin was synergistic in vivo. Cefpirome in combination with rifampin was more effective than was cefazolin in combination with rifampin. Both cephalosporin-rifampin regimens were significantly more effective than was cephalosporin or vancomycin monotherapy and were as effective as vancomycin combined with rifampin. These data support further evaluation of rifampin-beta-lactam combinations as possible alternative therapies to vancomycin-containing regimens for selected methicillin-resistant coagulase-negative staphylococcal infections.

Results of in vitro time-kill synergy studies using subinhibitory, inhibitory, or suprainhibitory concentrations of bactericidal agents were compared with treatment outcomes of experimental infective endocarditis due to a methicillin-susceptible strain of Staphylococcus aureus. For rifampin-cephalosporin combinations, in vitro synergy testing using recommended fractions of the MIC failed to predict antagonism in vivo while concentrations above the MIC corresponded with antagonism in vivo.

The effects of treatment with broad-spectrum parenterally administered cephalosporins and cefuroxime, cefazolin, or nafcillin were compared in an experimental model of Staphylococcus aureus infective endocarditis, and the results in vivo were compared with the activities of the study drugs in vitro. After 3 days of treatment, all antimicrobial agents tested were more effective than no treatment in reducing the number of surviving bacteria in cardiac valve vegetations. Nafcillin was the most effective agent studied and was significantly more active than was ceftizoxime, ceftriaxone, cefotaxime, cefoperazone, cefuroxime, or cefazolin (P < or = 0.05). Cefpirome and ceftazidime were the most effective broad-spectrum cephalosporins. The outcome of treatment with cefpirome or ceftazidime was similar to that of treatment with nafcillin and significantly better than that of treatment with ceftizoxime or cefotaxime (P < or = 0.05). Treatment outcome correlated closely with the MICs of the antimicrobial agents for the study strain with the exception of ceftazidime, which was significantly more active in vivo in comparison with other agents than predicted by its MIC (P < or = 0.0003). When ceftazidime was excluded as an outlier, treatment outcome correlated with the MICs of the remaining study drugs (Spearman's correlation coefficient, 0.95; P < or = 0.0004), as well as with the estimated percentage of time during which the concentration of total drug (correlation coefficient, -0.85; P < or = 0.007) or free drug (correlation coefficient, -0.90; P < or = 0.003) exceeded the MIC. A consideration of total or free drug concentrations in relation to MICs did not significantly improve the correlation with outcome observed with the MICs alone.

We studied the efficacy of continuous intravenous infusion of ampicillin compared with that of intermittent administration of ampicillin alone or in combination with gentamicin for the therapy of highly aminoglycoside-resistant enterococcal experimental endocarditis. Rabbits were infected with a gentamicin-susceptible (MIC, 256 micrograms/ml) strain of Enterococcus faecalis or a strain of E. faecalis which was highly resistant to gentamicin in vitro (MIC, greater than 2,000 micrograms/ml). Administration of ampicillin by continuous intravenous infusion did not significantly enhance the killing of enterococci in vivo compared with that by intermittent administration of ampicillin for either the aminoglycoside-susceptible or the aminoglycoside-resistant strain. In combination with gentamicin, there were no significant differences in efficacies obtained with intermittent versus continuous intravenous infusion of ampicillin therapy for experimental endocarditis caused by either strain of E. faecalis.

Cilofungin has potent in vitro activity against Candida albicans, but previous in vivo models using twice daily intermittent dosing regimens have not consistently demonstrated in vivo efficacy. Because of the pharmacokinetics of cilofungin in rabbits, it has been suggested that administration by continuous intravenous infusion might be more effective. We compared the in vivo efficacy of continuous intravenous infusion of cilofungin with that of amphotericin B in a rabbit model of disseminated candidiasis. Cilofungin prepared as previously described in phosphate-buffered 33% polyethylene glycol was lethal to infected rabbits in this model, as was phosphate-buffered 33% polyethylene glycol alone. In contrast, cilofungin in 26% polyethylene glycol and sterile water administered by continuous intravenous infusion was tolerated by rabbits, was significantly more effective than amphotericin therapy in reducing candida colony counts in kidney tissue, and was as effective as amphotericin therapy in lung and spleen tissue and in cardiac valvular vegetations. The dosage regimen and diluent used in some previous studies may have adversely affected outcome of treatment with cilofungin.

Ciprofloxacin or rifampin was significantly (P less than 0.05) more effective than vancomycin or the combination of vancomycin plus gentamicin for the treatment of Staphylococcus epidermidis experimental endocarditis. There were no significant differences in efficacy among any of the combinations of antimicrobial agents that included ciprofloxacin or rifampin. One animal treated with rifampin alone and one treated with the combination of vancomycin, rifampin, and gentamicin were found to be infected with rifampin-resistant strains of S. epidermidis during therapy. Resistant subpopulations of S. epidermidis were not detected during therapy with any other antimicrobial agent used alone or in combination. Ciprofloxacin alone or in combination with rifampin was effective therapy against S. epidermidis experimental endocarditis.

Background— The American Heart Association published updated guidelines for infective endocarditis (IE) prevention in 2007 that markedly restricted the use of antibiotic prophylaxis in certain at-risk patients undergoing dental and other invasive procedures. The incidence of IE caused by viridans group streptococci (VGS) in the United States after publication of the 2007 American Heart Association guidelines has not been reported. Methods and Results— We performed a population-based review of all definite or possible cases of VGS-IE using the Rochester Epidemiology Project of Olmsted County, Minnesota. Patient demographics and microbiological data were collected for all VGS-IE cases diagnosed from January 1, 1999, through December 31, 2010. We also examined the Nationwide Inpatient Sample hospital discharge database to determine the number of VGS-IE cases included between 1999 and 2009. We identified 22 cases with VGS-IE in Olmsted County over the 12-year study period. Rates of incidence (per 100 000 person-years) during time intervals of 1999–2002, 2003–2006, and 2007–2010 were 3.19 (95% confidence interval, 1.20–5.17), 2.48 (95% confidence interval, 0.85–4.10), and 0.77 (95% confidence interval, 0.00–1.64), respectively ( P =0.061 from Poisson regression). The number of hospital discharges with a VGS-IE diagnosis in the Nationwide Inpatient Sample database during 1999–2002, 2003–2006, and 2007–2009 ranged between 15 318 to 15 938, 16 214 to 17 433, and 14 728 to 15 479, respectively. Conclusions— On the basis of data complete through 2010, there has been no perceivable increase in the incidence of VGS-IE in Olmsted County, Minnesota, since the publication of the 2007 American Heart Association endocarditis prevention guidelines.

Abstract—Hypercholesterolemia (HC) is often associated with impaired peripheral and coronary vascular responses to endothelium-dependent vasodilators, which are probably due to low bioavailability of nitric oxide. To examine the effect of HC on renal vascular and tubular function, 22 domestic pigs were studied after being fed a 12-week normal (n=11) or HC (n=11) diet. Renal regional perfusion and intratubular contrast media concentration in each nephron segment (representing fluid reabsorption) were quantified in vivo with electron-beam computed tomography before and after a suprarenal infusion of either acetylcholine (6 pigs of each diet) or sodium nitroprusside (SNP; 5 pigs of each diet). An increase in cortical perfusion, observed in normal pigs with acetylcholine (+35±6%,P=0.002) and SNP (+12±4%,P=0.005), was blunted in the HC group (+8.8±4.0,P=0.01, and −4.6±4.0%,P=0.1, respectively,P=0.003 andP=0.005 compared with normal) as was an increase in medullary perfusion (+58±21 in normal versus +24±11% in HC,P=0.04). A decrease in the intratubular contrast media concentration in the distal tubule and collecting duct of normal pigs was observed in all tubular segments (and was significantly enhanced in the proximal tubule and Henle’s loop) in the HC group, which was associated with increased sodium excretion. The tubular and renal excretory responses to SNP were similar between the groups. In conclusion, early experimental HC in the pig attenuates renal perfusion response to both endothelium-dependent and -independent vasodilators possibly because of decreased bioavailability or decreased vascular responsiveness to nitric oxide. This vascular impairment may play a role in maladjusted renovascular responses and contribute to renal damage in later stages of atherosclerosis.