Efficacy of linezolid in treatment of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.

The efficacies of orally (p.o.) dosed linezolid and intravenously (i.v.) dosed vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in rabbits with experimental aortic-valve endocarditis were investigated. After endocarditis was established with a recent clinical MRSA isolate, rabbits were dosed for 5 days with linezolid (p.o., three times a day) at either 25, 50, or 75 mg/kg of body weight or vancomycin (i.v., twice a day) at 25 mg/kg. The 25-mg/kg linezolid group had a high mortality rate and bacterial counts in the valve vegetations that were not different from those of the controls. Linezolid dosed p.o. at 50 and 75 mg/kg and i.v. vancomycin produced statistically significant reductions in bacterial counts compared to those of the untreated controls. The reduced bacterial counts and culture-negative valve rates for the animals treated with linezolid at 75 mg/kg were similar to those for the vancomycin-treated animals. Concentrations of linezolid in plasma were determined at several points in the dosing regimen. These results suggest that the efficacy of linezolid in this infection model is related to trough levels in plasma that remain above the MIC for this microorganism. At the ineffective dose of linezolid (25 mg/kg) the concentration at sacrifice was 0.045 times the MIC, whereas the concentrations of linezolid in plasma in the 50- and 75-mg/kg groups were 2 and 5 times the MIC at sacrifice, respectively. The results from this experimental model suggest that the oxazolidinone linezolid may be effective for the treatment of serious staphylococcal infections when resistance to other antimicrobials is present.

Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine.

The primary objective of this study was to compare the effects of oral linezolid with moclobemide and placebo on the pressor response to oral tyramine. Secondary objectives were to determine possible mechanisms of the effect based on changes in the pharmacokinetics of tyramine and to evaluate alternative methods for quantifying the pressor effect. Subjects received linezolid (625 mg bid orally), moclobemide (150 mg tid orally), or placebo for up to 7 days. Using the oral tyramine dose producing a >30 mmHg increase in systolic blood pressure (SBP) (PD>30), a positive pressor response was defined as a PD>30 index (pretreatment/treatment ratio of PD>30) of > or = 2. There were 8/10, 11/11, and 1/10 responders with linezolid, moclobemide, and placebo, respectively. Responses returned to baseline within 2 days of drug discontinuation. The ratio of mean greatest SBP and heart rate at the time of greatest SBP (GSBP/HR) increased linearly with tyramine dose both pretreatment and during treatment with linezolid and moclobemide. During treatment, responses to tyramine when subjects took linezolid or moclobemide were significantly different from placebo. Both drugs significantly decreased tyramine oral clearance compared with placebo. Urinary excretion of catecholamines and metabolites was consistent with MAOI activity of the drugs, but results were variable. The MAOI activity of linezolid is similar to that of moclobemide, a drug used clinically without food restrictions. Restrictions to normal dietary intake of tyramine-containing foods are not warranted when taking linezolid.

Linezolid: pharmacokinetic and pharmacodynamic evaluation of coadministration with pseudoephedrine HCl, phenylpropanolamine HCl, and dextromethorpan HBr.

Linezolid is a novel oxazolidinone antibiotic with mild reversible monoamine oxidase inhibitor (MAOI) activity. The potential for interaction with over-the-counter (OTC) medications requires quantification. The authors present data evaluating the pharmacokinetic and pharmacodynamic responses to coadministration of oral linezolid with sympathomimetics (pseudoephedrine and phenylpropanolamine) and a serotonin reuptake inhibitor (dextromethorphan). Following coadministration with linezolid, minimal but statistically significant increases were observed in pseudoephedrine and phenylpropanolamine plasma concentrations; a minimal but statistically significant decrease was observed in dextrorphan (the primary metabolite of dextromethorphan) plasma concentrations. Increased blood pressure (BP) was observed following the coadministration of linezolid with either pseudoephedrine or phenylpropanolamine; no significant effects were observed with dextromethorphan. None of these coadministered drugs had a significant effect on linezolid pharmacokinetics. Minimal numbers of adverse events were reported. Potentiation of sympathomimetic activity by linezolid was judged not to be clinically significant, but patients sensitive to the effects of increased BP due to predisposing factors should be treated cautiously. No restrictions are indicated for the coadministration of dextromethorphan and linezolid.

Efficacy of linezolid in a staphylococcal endocarditis rabbit model.

A rabbit endocarditis model was used to test the efficacy of oral linezolid and iv vancomycin. Twenty-four hours after catheter placement across the aortic valve, rabbits were infected with 3.5 x 10(6) cfu of Staphylococcus aureus (UC-9258). Two days after infection, control rabbits were killed, and treated rabbits were given 5 days of therapy with linezolid at 8 h intervals (tds) using either 25, 50 or 75 mg/kg/dose, or vancomycin at 12 h intervals (bd) using 25 mg/kg/dose. Linezolid at 75 and 50 mg/kg, and vancomycin significantly reduced S. aureus in aortic valve vegetations compared with the control. Linezolid at 25 mg/kg was ineffective. The efficacy of 75 and 50 mg/kg linezolid was related to maintenance of plasma drug levels near or above the linezolid MIC for UC-9258 (2 mg/L).

Linezolid--a new option for treating gram-positive infections.

The increase in serious gram-positive infections has increased the need for treatment of gram-positive infections in patients with hematologic malignancies. Common gram-positive pathogens exhibit a variety of resistance mechanisms, and this has supported the need for new antibiotics with unique modes of action and no endogenous resistance mechanism(s) directed against them. Linezolid (Zyvox), the first member of the oxazolidinone class of antibiotics to be tested clinically, is such an antibiotic. Linezolid has been shown to be effective against key gram-positive pathogens in vitro, without evidence of resistance development or cross-resistance to other antibiotics. Its efficacy and safety in the treatment of non-immunocompromised patients with hospital- and community-acquired pneumonia and skin and soft-tissue infections have been found to be comparable to commonly used present-day antibiotics. It has also been shown to be effective against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. Linezolid has a wide gram-positive spectrum of activity and is amenable to oral or parenteral administration These attributes make it potentially useful for continuing outpatient therapy that was initiated for inpatients.

Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1-infected patients.

The safety, tolerability, and antiviral activity of atevirdine (ATV), a nonnucleoside reverse transcriptase inhibitor, were studied in a phase I/II clinical trial (ACTG 187) of patients with CD4 counts < or =500/mm3. In all, 34 HIV-1-infected patients were randomized to receive ATV for 12 weeks in doses chosen to achieve one of three serum trough levels: 5 to 13 microM, 14 to 22 microM, or 23 to 31 microM. Rash was the most common adverse event, with a grade 3 or 4 rash occurring in 4 patients. No significant change from baseline in HIV-1 plasma RNA mean copy number was detected at week 4 (+0.09 log10 copies/ml; p = .30). However, some evidence indicated moderate antiviral activity at week 4, based on median changes in CD4 count (+23/mm3; p = .05), and viral peripheral blood mononuclear cell (PBMC) titer (-0.68 log10) copies/ml; p = .03). In addition, 2 of 4 patients with detectable baseline serum p24 antigen showed declines of >50%. HIV-1 resistance to ATV was detected in 41% of patients and was most commonly associated with RT mutations K103N and Y181C. In contrast, the Y181C mutation was not detected in ATV-resistant isolates obtained from patients enrolled in ACTG 199, a study of ATV given in combination with zidovudine. Under the conditions of this study, ATV failed to demonstrate significant antiretroviral activity. However, transient in vivo activity might have been obscured by rapid development of resistance coupled with inadequate sampling at early time points following initiation of ATV therapy.

Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers.

The potential pharmacokinetic drug-drug interaction between delavirdine, a nonnucleoside analogue reverse transcriptase inhibitor, and indinavir, an inhibitor of HIV protease, was evaluated in healthy volunteers. Subjects received a single 800-mg dose of indinavir sulfate on day 1 (baseline). Delavirdine mesylate 400 mg was administered three times daily on days 2 through 10. On day 9, a single 400-mg dose and on day 10 a single 600-mg dose of indinavir were given along with morning doses of delavirdine. Pharmacokinetic evaluations of indinavir were made on days 1, 9, and 10, and of delavirdine on days 8, 9, and 10. Fourteen healthy male volunteers completed the study. Single doses of indinavir had no clinically important effects on the pharmacokinetics of delavirdine. Mean indinavir Cmax values for the 400-mg and 600-mg doses administered concomitantly with delavirdine were dose proportionally lower than that observed following the 800-mg dose administered alone. Mean Tmax values were similar and ranged from 1.0 +/- 0.3/hour for indinavir 800 mg administered alone to 1.3 +/- 0.4/hour for indinavir 600 mg administered with delavirdine. These results indicate that delavirdine had no clinically important effect on the rate of indinavir absorption. In contrast, the mean indinavir AUC0-infinity, value following the 400-mg dose administered with delavirdine was only 14% lower than the baseline value determined for the 800-mg indinavir dose (25,400 +/- 6960 nM hour versus 29,600 +/- 7920 nM hour), and the mean indinavir AUC0-infinity value for the 600-mg indinavir dose administered with delavirdine (42,700 +/- 9800 nM hour) was 44% greater than the baseline value. All differences among mean AUC0-infinity values were statistically significant. Mean indinavir half-life values were slightly longer when indinavir was given in a dose with delavirdine than when indinavir was administered alone. These results suggest that delavirdine inhibits metabolism of indinavir and support the possibility of a reduction in the magnitude or frequency of indinavir dosage when given in combination with delavirdine.

Serum inhibitory titers and serum bactericidal titers for human subjects receiving multiple doses of the antibacterial oxazolidinones eperezolid and linezolid.

In Phase I trials subjects received multiple doses of eperezolid (PNU-100592; formerly U-100592) and linezolid (PNU-100766; formerly U-100766), and steady-state samples were drawn at the projected peak and trough timepoints. Serum inhibitory titer and serum bactericidal titer values were determined using single strains of Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Serum inhibitory titer values generally correlated with drug concentration in serum and inherent organism susceptibility. Against S. aureus and E. faecalis sera from patients dosed with either drug were generally inhibitory at the peak timepoint, but at trough only linezolid exhibited a persistent effect. No bactericidal activity was seen for either drug against S. aureus or E. faecalis. The sera from patients dosed with either drug exhibited inhibition of S. pneumoniae at peak and trough. Bactericidal activity was seen against S. pneumoniae for both drugs at peak time and at trough for many of the sera for patients on the higher dose regimens. The results demonstrated that the sera from most human subjects dosed with eperezolid or linezolid were inhibitory to S. aureus and E. faecalis and S. pneumoniae and that many of the samples exhibited bactericidal activity for S. pneumoniae.

Absorption of clindamycin after intravaginal application of clindamycin phosphate 2% cream.

In recent clinical studies, clindamycin phosphate cream administered intravaginally has been shown to be efficacious in the treatment of bacterial vaginosis (BV). In support of the safety profile for this dosage form, a study assessing the systemic absorption of clindamycin was undertaken in five BV patients and six healthy volunteers who were dosed with 5 mL (100 mg) clindamycin phosphate 2% cream intravaginally once daily in the evening for 7 days. Two weeks later, a single 100 mg dose of clindamycin phosphate sterile solution was administered as a 4 min iv infusion. Serial blood samples were collected on days 1, 4, and 7 after dosing with the cream and over a 16 h period after the iv treatment. Clindamycin concentrations in serum samples were assayed by capillary gas chromatography. After treatment with the cream, steady-state serum clindamycin concentrations were reached by 24 h in all but one subject in each group. Mean absolute bioavailability was 2.7%-4.3% in the BV group and 2.7%-4.7% in the healthy group. These results indicate that systemic exposure to clindamycin from intravaginal administration of clindamycin phosphate cream is minimal.

Use of recombinant soluble CD4 Pseudomonas exotoxin, a novel immunotoxin, for treatment of persons infected with human immunodeficiency virus.

Single and multiple doses of sCD4-PE40, a soluble recombinant fusion toxin selectively toxic to gp120-expressing cells, were evaluated in persons infected with human immunodeficiency virus type 1 (HIV-1). Seventeen of 24 patients who completed a single-dose safety trial were given either 1, 5, 10, or 15 micrograms/kg of sCD4-PE40 by intravenous bolus once a month for 2 months, then weekly for 6 weeks. The weekly maximally tolerated dose was 10 micrograms/kg. The major toxicity was a transient dose-dependent elevation in hepatic aminotransferases peaking 48 h after infusion. Anti-Pseudomonas exotoxin antibody developed in 58% of recipients, and sera from 13 of 17 showed neutralizing activity against sCD4-PE40. No consistent changes in immunologic or virologic markers were observed. Weekly infusions of < or = 10 micrograms/kg of sCD4-PE40 are generally well tolerated, but additional studies correlating optimal dosing and frequency of administration with efficacy will be needed to define the role of this novel agent in the management of HIV-1-infected patients.

Failure of short-term CD4-PE40 infusions to reduce virus load in human immunodeficiency virus-infected persons.

The safety, immunologic, and antiviral effects of a recombinant biologic product that combines the second and third domains of the CD4 molecule and Pseudomonas exotoxin A (PE40) were evaluated in 21 human immunodeficiency virus (HIV)-infected subjects in a phase III open-label dose-ranging study. Subjects with CD4+ lymphocyte counts of 100-500/mm3 received CD4-PE40 at 40, 80, or 160 micrograms/m2 by infusion three to seven times over 10 days. At the maximum tolerated dose (80 micrograms/m2), peak CD4-PE40 levels were 65-130 ng/mL with a serum half-life of 3.6 +/- 1.5 h. Toxicity, primarily increased hepatic transaminases, was dose-related and reversible. HIV DNA proviral levels in peripheral blood mononuclear cells and plasma HIV RNA remained stable during and after CD4-PE40 infusions. The relative resistance of clinical isolates of HIV, limits of the tolerated dose, and the immunogenicity and short half-life of the protein may explain the lack of in vivo antiviral effect of CD4-PE40.

Comparison of oral cefpodoxime proxetil and penicillin V potassium in the treatment of group A streptococcal pharyngitis/tonsillitis. The Cefpodoxime Pharyngitis Study Group.

Ninety-three patients with a diagnosis of acute pharyngitis/tonsillitis due to Streptococcus pyogenes were randomly assigned to receive 100 mg of cefpodoxime proxetil orally with food every 12 hours or 250 mg of penicillin V potassium orally on an empty stomach every six hours. Treatment efficacy was evaluated in 30 cefpodoxime-treated and 33 penicillin-treated patients. After 10 days of treatment, S pyogenes was eradicated from the throat culture in 29 of the 30 cefpodoxime-treated patients and in 30 of the 33 penicillin-treated patients. Twenty days after treatment termination, infection recurred in one patient of each treatment group. Clinical cure or improvement was found in 97% of the patients in each group. Adverse medical events occurred in nine of the 48 cefpodoxime-treated patients and in four of the 45 penicillin-treated patients; these were probably related to the study drug in seven and two patients, respectively. The most common adverse events were nausea (in three cefpodoxime and one penicillin patient) and diarrhea (in three and two). No patient showed colitis related to Clostridium difficile. No clinically significant abnormal laboratory test results were found in either treatment group. It is concluded that cefpodoxime proxetil is as effective and safe as penicillin V potassium in the treatment of pharyngitis due to S pyogenes.

Multiple-dose, double-blind, placebo controlled intravenous tolerance and pharmacokinetic study of trospectomycin sulfate (U-63, 366F) in healthy male volunteers.

Trospectomycin sulfate is a novel aminocyclitol antibiotic. This study evaluated the tolerance and the pharmacokinetics of multiple, intravenous doses of trospectomycin (TRO) in healthy male volunteers. Three groups of 10 volunteers were studied. Eight volunteers in each group were studied in a parallel design to receive trospectomycin (Group 1 = 250 mg, Group 2 = 500 mg, Group 3 = 750 mg) while 2 volunteers received placebo (normal saline). Drug doses were administered in 30 ml volumes over 30 min every 8 h for 7 days (i.e. 21 total doses). Evaluations of vital signs, side effects, and safety laboratory tests were made at regular intervals during the study. The most frequent medical events observed in the volunteers receiving trospectomycin were perioral/facial paresthesias (54%), pain at the i.v. infusion site (46%), dizziness/lightheadedness (58%), and GI symptoms (38%). A statistically significant dose response relationship was observed for the incidence of perioral/facial paresthesias and pain at the i.v. infusion site (i.e., increased incidence with increased dose). All the medical events were mild or moderate in severity and reversible following drug discontinuation. In the 500 and 750 mg trospectomycin groups, standing systolic blood pressure decreased significantly with the first dose of study drug. Elevated levels of SGPT were observed in 9 volunteers (1 in placebo, 3 in 250 mg, 1 in 500 mg, and 4 in 750 mg dose groups). This study demonstrates that multiple intravenous trospectomycin doses up to 750 mg are reasonably well tolerated in healthy male volunteers. The concentration of trospectomycin in serum, measured with a sensitive HPLC assay, was less than 3 mcg/ml at 8 h postinfusion for all dose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric emptying and the pharmacokinetics of the cephalosporin antibiotic, cefpodoxime proxetil.

The effects of gastric motility on the pharmacokinetics of cefpodoxime proxetil, an oral, broad spectrum, third-generation cephalosporin antibiotic were evaluated in 12 healthy subjects. In this open-label, crossover trial, each subject took a 200 mg dose (two 100 mg film-coated tablets) in each study period. There was an initial fasting period followed by a control period and then either a propantheline or metoclopramide period. Gastric motility was measured using [99mTc]-labeled sulfur colloid in oatmeal in the control, propantheline and metoclopramide periods. Treatment with propantheline or metoclopramide was given 30 min before dosing with the antibiotic and the radioisotope. Serial images with a gamma counter were made every 15 min for 2 h. Gastric emptying time was faster than control with metoclopramide, but generally slower with propantheline than control. The mean peak plasma concentration, mean area under plasma concentration time curve and mean half-life of cefpodoxime proxetil were similar in all groups as compared to control. The mean time to peak plasma concentration was delayed in the propantheline period and peak plasma concentrations were greater at all sampling times at six hours after dosing. This study utilized the gastric nuclear scan with modification of gastric motility by metoclopramide and propantheline and with simultaneous determination of the disposition of cefpodoxime proxetil to understand the absorption of the drug.

The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil.

The effects of alteration of gastric pH and food on the pharmacokinetics of 200 mg doses of cefpodoxime proxetil tablets were studied in two separate randomized, open label, crossover studies in healthy subjects. In the pH study (n = 17 subjects), there was a lead-in period done under fasting conditions, followed by randomization to a four-way crossover of pentagastrin (6 micrograms/kg, subcutaneously), ranitidine (150 mg orally, 10 and 2 hours before dosing with the antibiotic), sodium bicarbonate (12.6 gm), or aluminum hydroxide (120 cc). Gastric pH was determined by nasogastric aspirates before and 10 minutes after the intervention, just before the antibiotic was given. Peak plasma concentrations (Cmax) and area under plasma concentration-time curve (AUC) were highest in fasting and pentagastrin periods and were 35% to 50% lower for all of the other periods (p less than 0.0001). Gastric pH and Cmax and AUC were inversely related (r = 0.66 and r = 0.62; p less than 0.0001 for both). In the food study (n = 16 subjects), there were two lead-in periods, one done while subjects were fasting and one while they were normal diet, followed by randomization to a four-way crossover of either high or low protein diets, or high or low fat diets. There were six meals in each diet. Dosing with the antibiotic was done at the midpoint of the fourth meal. Cmax and AUC were 22% to 34% higher for all diets than for the fasting period (p less than 0.0001), whereas the time to Cmax was unchanged. These studies demonstrated that absorption of cefpodoxime proxetil is best at low gastric pH or in the presence of food, which suggests that the role of gastrointestinal function on the pharmacokinetic profile is complex.

Postoperative discitis. Diagnosis and management.

Postoperative discitis (POD) continues to be a diagnostic challenge and its management remains variable. This article raises the following questions and presents new observations. What is the current role of the CT scan in POD? Is a uniform pathogen involved and is there a basis for the duration of intravenous antibiotics? What is the expected long-term functional result? In a retrospective analysis of 12 consecutive patients with POD followed for an average of 29 months (17-42 months), the CT scan was extremely sensitive in showing a pathogen was present. The CT scan was misread in over one-third of the cases. Gram-positive cocci were the only organisms cultured (10 of 13 cultures, 8 of 12 patients). The erythrocyte sedimentation rate (ESR) invariably fell predictably to normal within 90 days when patients were treated with IV antibiotics for more than 40 days. Most patients were clinically improved and subjectively better at follow-up examination. No correlation existed between the patient's subjective result and preexisting medical conditions, the type of antibiotic, or the length of treatment, the ESR, or the follow-up roentgenograms.

Disseminated histoplasmosis, invasive pulmonary aspergillosis, and other opportunistic infections in a homosexual patient with acquired immune deficiency syndrome.

A homosexual man with the acquired immune deficiency syndrome had an unusually wide array of opportunistic infections. Despite antibiotic treatment over a period of two and a half years, the patient died. Perianal herpetic ulcers, oral candidiasis, cytomegalovirus infection, and disseminated infections with both Histoplasma capsulatum and Mycobacterium avium-intracellulare were diagnosed during illness. An autopsy revealed invasive pulmonary aspergillosis and a cerebellar lesion caused by cytomegalovirus. The latter was probably responsible for the patient's gait disturbance.