Synergism Between N-Formimidoyl Thienamycin and Gentamicin or Tobramycin Against Enterococci

By the time-kill curve method, the combination of N-formimidoyl thienamycin and gentamicin showed synergism against 47 of 48 strains of enterococci, whereas the combination of N-formimidoyl thienamycin and tobramycin was synergistic against 46 strains.     

In Vitro Susceptibility of Nocardia asteroides to N-Formimidoyl Thienamycin and Several Cephalosporins

The susceptibility of N. asteroides to N-formimidoyl thienamycin, cefamandole, cefoxitin, and moxalactam was determined by agar dilution. N-Formimidoyl thienamycin was the most active, inhibiting eight of nine strains at 1.56 μg/ml.     

In Vitro Evaluation of N-Formimidoyl Thienamycin (MK0787) Combined with Amikacin Against Gram-Negative Bacilli and Staphylococcus aureus

The in vitro synergistic activity of N-formimidoyl thienamycin and amikacin was determined against gentamicin-resistant enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. N-Formimidoyl thienamycin showed synergism with amikacin against 19 of the gentamicin-resistant strains, 14 of the 49 strains of S. aureus, and only 1 strain of the 46 P. aeruginosa isolates.     

Activities of New Beta-Lactam Antibiotics Against Isolates of Pseudomonas aeruginosa from Patients with Cystic Fibrosis

The in vitro activities of gentamicin, tobramycin, amikacin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, cefotaxime, ceftizoxime, cefoperazone, cefsulodin, moxalactam, ceftazidime, ceftriaxone, and N-formimidoyl thienamycin were measured against 62 isolates of Pseudomonas aeruginosa obtained from patients with cystic fibrosis. Ceftazidime and N-formimidoyl thienamycin were the most active of these agents.     

Comparative Stability of Newly Introduced β-Lactam Antibiotics to Renal Dipeptidase

Renal dipeptidase purified from swine kidney hydrolyzed N-formimidoyl thienamycin, carpetimycins A and B, and Sch29482, but not azthreonam, penicillin G, or cephaloridine.     

Comparative In Vitro Activity of New Beta-Lactam Antibiotics Against Anaerobic Bacteria

Several new beta-lactam antimicrobial agents have been introduced in the last few years. In this investigation, the in vitro activities of several recently introduced cephalosporins (cefoperazone, cefotaxime, ceftazidime, and ceftizoxime), moxalactam, and N-formimidoyl thienamycin were compared with those of cefoxitin, clindamycin, and metronidazole against 203 strains of anaerobic bacteria. At achievable serum levels, all of the antimicrobial agents were active against essentially 100% of the strains of anaerobic gram-positive cocci, Clostridium perfringens, Leptotrichia buccalis, and species of Selenomonas, Veillonella, and Eubacterium. Clindamycin, metronidazole, and N-formimidoyl thienamycin were the most active agents against the Bacteroides fragilis group, inhibiting all strains at concentrations which can be achieved in serum. Of the remaining agents tested against the B. fragilis group, cefoxitin (which required 64 μg/ml to inhibit 90% of the strains) was the most active, followed by cefoperazone (128 μg/ml), cefotaxime (128 μg/ml), moxalactam (128 μg/ml), ceftizoxime (256 μg/ml), and ceftazidime (>256 μg/ml). Important differences in cephalosporin susceptibility among species of the B. fragilis group were observed. Metronidazole and N-formimidoyl thienamycin were the most active drugs against species of clostridia other than C. perfringens; the other antibiotics displayed poor activity, although this is partly due to inclusion of a relatively large number of strains of Clostridium difficile which were very resistant to several of the cephalosporins. Only metronidazole was active against all species of Fusobacterium. Clindamycin and N-formimidoyl thienamycin displayed excellent activity against gram-positive, non-spore-forming bacilli, requiring ≤8 μg/ml to inhibit 100% of the strains. Ceftazidime, cefoperazone, and moxalactam were bactericidal for 25 strains of B. fragilis at concentrations equal or close to those required for inhibition. On the basis of its activity in vitro, N-formimidoyl thienamycin appears to be the most promising of the new beta-lactam antibiotics for the treatment of infections involving anaerobic bacteria.     

Susceptibility of gram-positive cocci to various antibiotics, including cefotaxime, moxalactam, and N-formimidoyl thienamycin

The activities of cefotaxime, moxalactam, MK 0787 (N-formimidoyl thienamycin), ampicillin, oxacillin, vancomycin, and clindamycin were compared against gram-positive cocci. MK 0787 was the most active and moxalactam was the least active of these drugs, except against methicillin-resistant Staphylococcus aureus, where vancomycin was most active, and penicillin-resistant pneumococci, where cefotaxime was more active.     

Iopentol in patients with chronic renal failure: its effects on renal function and its use as glomerular filtration rate parameter.

Iopentol (mean dose 0.42 g I kg-1) was administered for abdominal aortography and pelvic angiography in 10 patients with advanced non-diabetic chronic renal failure (S-creatinine 672 +/- 259 mumol l-1, mean +/- SD). Renal glomerular function measured as creatinine clearance and plasma clearance of [99Tcm]-diethyl-enetriaminepentaacetic acid (DTPA) was unchanged by iopentol, as also was urinary excretion of the renal tubular enzymes N-acetyl-beta-glucosaminidase (NAG) and alkaline phosphatase (ALP). The elimination of iopentol from serum and urine was delayed, and detectable serum and urine concentrations were found 5 days after administration of the contrast medium. Creatine clearance was 47% higher than the corresponding renal iopentol clearance. Plasma iopentol clearance, measured as the total area under the plasma concentration curve, was 40% higher than renal iopentol clearance because of extrarenal elimination of iopentol. We conclude that abdominal aortography with iopentol can be performed without effects on renal glomerular or tubular function parameters in patients with advanced renal failure. If iopentol is used for measurement of glomerular filtration rate (GFR) in this group of patients, one should measure renal clearance, as plasma clearance overestimates GFR.     

Changes in serum and urinary myo-inositol levels in chronic glomerulonephritis

Serum and urinary myo-inositol and urinary glucose were estimated by means of gas-liquid chromatography in 54 patients with glomerulonephritis with and without renal failure, myo-inositol clearance was calculated and an index was formulated which reflected changes in glomerular filtration, tubular reabsorption and catabolism of myo-inositol by the kidney. Serum and urinary myo-inositol levels were increased in glomerulonephritis with a close correlation to the degree of renal failure. In advanced forms of glomerulonephritis, glomerular filtration, tubular reabsorption and catabolism of myo-inositol were shown to be markedly deranged. Evidence obtained showed further that a derangement of tubular reabsorption and catabolism of myo-inositol also accompany milder forms of glomerulonephritis without decreased glomerular filtration. The myo-inositol index value, especially, was increased in patients with signs of disease activity as indicated by a histological examination of the kidney tissue. The index can also be- regarded as a highly sensitive test of renal failure.Low grade glucosuria was shown to be frequently associated with glomerulonephritis with renal failure. Evidence was produced which suggested that the tubular reabsorption of myo-inositol was deranged earlier than glucose reabsorption in glomerulonephritis, although they may share a common step in the reabsorption process. The data suggest that the estimation of serum and urinary myo-inositol has advantages in the evaluation of kidney function.     

Renal Handling of β2-Microglobulin in Experimental Renal Disease

Renal extraction and urinary excretion of ¹²⁵I-labelled β₂-microglobulin was studied in rats. The effect of ischaemic renal injury, experimental pyelonephritis, and unilateral nephrectomy was investigated. The tubular secretion of o-iodohippurate (OIH) was measured for comparison. The urinary excretion was calculated as the ratio between the clearance of protein and the glomerular filtration rate. The glomerular filtration rate was estimated as clearance of polyethylene glycol (PEG 1000). The renal arteriovenous concentration difference was lower for β₂-microglobulin than for PEG 1000 in all the experimental groups. In unilateral renal disease the β₂-microglobulin excretion of the intact kidneys was similar to that of the diseased kidneys. A significant difference was noted only after ischaemic renal injury. The same was found for OIH. After removal of the intact kidneys the excretion of β₂-microglobulin increased about 10-fold in pyelonephritic animals and 2- to 30-fold in animals with ischaemic renal injury. One hour after unilateral nephrectomy in normal animals the ratio increased about 50 per cent. The tubular secretion of OIH did not change noticeably. It is concluded that the glomerular filtration is a main step in the intrarenal catabolism of β₂-microglobulin and that its urinary excretion is considerably influenced by a reduction in the functioning kidney mass.     

Renal handling of fleroxacin in rabbits, dogs, and humans.

The renal handling of fleroxacin was studied by renal clearance and stop-flow techniques in rabbits and dogs and by analyzing the pharmacokinetics with and without probenecid in humans. In rabbits the excretion ratios (fleroxacin intrinsic renal clearance/glomerular filtration rate) were greater than unity (2.01) without probenecid and were decreased to a value below unity (0.680) with probenecid. In dogs, on the other hand, the excretion ratios were less than unity (0.608 and 0.456) both without and with probenecid, and so were not affected by probenecid. This fact suggested that fleroxacin was excreted into urine by both glomerular filtration and renal tubular secretion in rabbits, but only by glomerular filtration in dogs, accompanied by partial renal tubular reabsorption in both species; these mechanisms were also supported by stop-flow experiments. In humans probenecid treatment induced increases in the elimination half-life and area under the serum concentration-time curve and decreases in apparent serum clearance, renal clearance, and urinary recovery of fleroxacin. The excretion ratio without probenecid was 1.13, which was significantly decreased to 0.750 with probenecid. These results indicated that both renal tubular secretion and reabsorption contributed to renal excretion of fleroxacin in humans. The contribution of tubular secretion was species dependent and was extensive in rabbits, minimal in dogs, and moderate in humans. Renal tubular reabsorption was commonly found in every species. The long elimination half-life of fleroxacin in humans might be explained by its small total serum clearance and small renal clearance, which are attributed to less tubular secretion and more tubular reabsorption.     

Factors Influencing the Handling of Insulin by the Isolated Rat Kidney

The renal handling of immunoreactive insulin was studied in the isolated perfused normothermic rat kidney to determine (a) the relative contributions of glomerular clearance and peritubular clearance to the renal clearance of insulin under different conditions, (b) what metabolic factors influence the ability of tubular cells to remove insulin from the glomerular filtrate and the peritubular circulation, and (c) whether the same factors influence the luminal and contraluminal uptake of insulin.     

Clinical Pharmacokinetics and Safety of High Doses of Ceforanide (BL-S786R) and Cefazolin

The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t_½, 2.8 h), plasma clearance (Cl_p, 48 ml/min per 1.73 m²), and renal clearance (Cl^0−12h_r, 47 ml/min per 1.73 m²; tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t_½ (1.9 h), area under the plasma concentration-time curve, Cl_r (60 ml/min per 1.73 m²; tubular secretion, 80%, and glomerular filtration, 20%), or Cl_p (75 ml/min per 1.73 m²) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 μg/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.     

Comparative In Vitro Activities of N-Formimidoyl Thienamycin and Moxalactam Against Nonfermentative Aerobic Gram-Negative Rods

N-Formimidoyl thienamycin was the most active drug against strains of Pseudomonas aeruginosa with a 90% minimum inhibitory concentration of 1.25 mug/ml. With the exception of P. maltophilia, thienamycin was as active or more active than moxalactam against other species of pseudomonads and against other genera of nonfermenters.     

Synergistic Effect of N-Formimidoyl Thienamycin with Gentamicin and Amikacin Against Streptococcus faecalis

The in vitro activities of N-formimidoyl thienamycin alone and in combination with amikacin and gentamicin were tested against 10 strains of Streptococcus faecalis. Synergy was demonstrated in 35% of the combinations tested by the microtiter checkerboard technique; 50% were found to be synergistic with time killing curves.     

Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds

Introduction

The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal clearance (ARC), using exogenous marker compounds.

Methods

This prospective, observational pharmacokinetic (PK) study was performed in a university-affiliated, tertiary-level, adult intensive care unit (ICU). Patients aged less than or equal to 60 years, manifesting a systemic inflammatory response, with an expected ICU length of stay more than 24 hours, no evidence of acute renal impairment (plasma creatinine concentration <120 μmol/L) and no history of chronic kidney disease or renal replacement therapy were eligible for inclusion. The following study markers were administered concurrently: sinistrin 2,500 mg (Inutest; Laevosan, Linz, Austria), p-aminohippuric acid (PAH) 440 mg (4% p-aminohippuric acid sodium salt; CFM Oskar Tropitzsch, Marktredwitz, Germany), rac-pindolol 5 or 15 mg (Barbloc; Alphapharm, Millers Point, NSW, Australia) and fluconazole 100 mg (Diflucan; Pfizer Australia Pty Ltd, West Ryde, NSW, Australia). Plasma concentrations were then measured at 5, 10, 15, 30, 60 and 120 minutes and 4, 6, 12 and 24 hours post-administration. Non-compartmental PK analysis was used to quantify GFR, tubular secretion and tubular reabsorption.

Results

Twenty patients were included in the study. Marker administration was well tolerated, with no adverse events reported. Sinistrin clearance as a marker of GFR was significantly elevated (mean, 180 (95% confidence interval (CI), 141 to 219) ml/min) and correlated well with creatinine clearance (r =0.70, P <0.01). Net tubular secretion of PAH, a marker of tubular anion secretion, was also elevated (mean, 428 (95% CI, 306 to 550) ml/min), as was net tubular reabsorption of fluconazole (mean, 135 (95% CI, 100 to 169) ml/min). Net tubular secretion of (S)- and (R)-pinodolol, a marker of tubular cation secretion, was impaired.

Conclusions

In critically ill patients at risk of ARC, significant alterations in glomerular filtration, renal tubular secretion and tubular reabsorption are apparent. This has implications for accurate dosing of renally eliminated drugs.     

In Vitro Comparison of N-Formimidoyl Thienamycin, Piperacillin, Cefotaxime, and Cefoperazone

The antibacterial activity of N-formimidoyl thienamycin was compared with those of cefotaxime, cefoperazone, and piperacillin against 536 clinical aerobic isolates.     

In Vitro Activity of Thienamycin

The in vitro activity of thienamycin was tested against 135 aerobic and anaerobic bacteria. The compound was highly active against resistant gram-negative bacilli and penicillin-resistant Straphylococcus aureus. The antianaerobic spectrum of the drug seemed to be comparable to that of metronidazole.     

Pharmacokinetics and tolerance of N-formimidoyl thienamycin (MK0787) in humans.

The pharmacokinetics of intravenously administered N-formimidoyl thienamycin (MK0787) were studied in 14 healthy male subjects in a single-dose study, in which the volunteers received N-formimidoyl thienamycin with and without probenecid, and in a multiple-dose study, in which the subjects were given 250 or 500 mg every 8 h for 10 doses. High dose-related plasma concentrations of N-formimidoyl thienamycin were achieved; co-administration with probenecid resulted in only minor increases in these concentrations. No accumulation in plasma was seen after multiple doses. The plasma half-life of N-formimidoyl thienamycin was slightly less than 1 h and did not increase significantly with the coadministration of probenecid. The urinary recovery of N-formimidoyl thienamycin varied between 6.0 and 38.4% of the dose with a marked intersubject variability. Variations in individual subjects were small, however, when the urinary recoveries after repeated doses were compared. These results were in agreement with previous animal studies showing a renal metabolism of N-formimidoyl thienamycin. Probenecid administration resulted in a marked decrease in N-formimidoyl thienamycin urinary recovery. In vitro experiments showed that the decay of N-formimidoyl thienamycin in spiked pretreatment urine samples was 2 to 5%/h with more rapid degradation at acidic than at basic pH.     

Reversal of postischemic acute renal failure with a selective endothelinA receptor antagonist in the rat.

Studies were designed to examine the effect of a selective endothelinA (ETA) receptor antagonist, BQ123, on severe postischemic acute renal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in uninephectomized, chronically instrumented rats by 45-min renal artery occlusion. BQ123 (0.1 mg/kg.min) or vehicle was infused intravenously for 3 h on the day after ischemia. Measurements before infusion (24 h control) showed a 98% decrease in glomerular filtration rate (GFR), increase in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicle-treated rats died in 4 d because of continuous deterioration of renal function, resulting in an increase of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ123 significantly improved survival rate (75%) by markedly improving tubular reabsorption of Na+ and moderately increasing GFR and K+ excretion. Plasma K+ returned to basal levels by the 5th d after ischemia. Improved tubular function was followed by gradual recovery in GFR and urinary concentrating mechanism. Additional data from renal clearance studies in rats with moderate ARF (30-min ischemia) and in normal rats with intact kidneys showed that ETA receptor blockade increases Na+ reabsorption and has no effect on renal hemodynamics. These results indicate that in the rat, the ETA receptor subtype mediates tubular epithelial function, and it plays a significant role in the pathogenesis of ischemia-induced ARF. Treatment with the selective ETA receptor antagonist reverses deteriorating tubular function in established ARF, an effect of possible therapeutic significance.