Concentrations Of Mezlocillin Research Articles

Growth temperature regulates the induction of beta-lactamase in Pseudomonas fluorescens through modulation of the outer membrane permeation of a beta-lactam-inducing antibiotic.

The psychrotrophic bacterium, Pseudomonas fluorescens strain MFO, is more sensitive to the beta-lactam mezlocillin at a low growth temperature (i.e. 8 degrees C) than at a higher growth temperature (28 degrees C). An early effect of this antibiotic at all temperatures is bacterial filamentation, but this occurs later at 8 degrees C than at 28 degrees C, which suggests a lower permeability of the cell envelopes to mezlocillin at low growth temperature. beta-Lactamase production is later induced by mezlocillin, but the level of this induction also depends on the growth temperature, the overall induction being much less efficient at 8 degrees C. It is hypothesized that the periplasmic concentration of the drug might be too low at 8 degrees C to allow efficient beta-lactamase induction; this hypothesis was confirmed by the demonstration that beta-lactamase production is drastically enhanced in cells cultivated at 8 degrees C permeabilized for 10 min by Na-EDTA. In addition, induction kinetic curves display a marked dependence upon growth temperature. A rapid saturation was evident when mezlocillin concentrations were increased at 8 degrees C; this was not seen at 28 degrees C at up to 1000 micrograms mezlocillin ml-1. The results are discussed in terms of two different routes of drug permeation, depending on the growth temperature.

Development of a High Performance LiquidChromatographic Assay Measuring Mezlocillin inSerum or Tissue

Objective: This study evaluated the blood and uterine tissue concentration of mezlocillin, a broadspectrum penicillin. Methods: We adapted a liquid chromatographic method to measure mezlocillin in serum and tissue. Mezlocillin reference standard was diluted in water, chromatographed on a reversed phase C18 column eluted at 1.5 ml/min with acetonitrile and phosphate buffer (1:3 v:v), and detected spectrophotometrically at 210 nm. Mezlocillin was administered to 14 premenopausal women scheduled to undergo vaginal hysterectomy. Each patient received a 4 g IV infusion of the drug 30 to 60 min prior to surgery. During surgery, tissue was removed from the uterine cervix and blood was obtained for assay of mezlocillin content. Results: Chromatography of the mezlocillin standard furnished a discrete peak with a retention time of 2.4 min. The sensitivity of the assay was 0.1 µg/ml with a linear response up to 100 µg/ml. The correlation coefficient for the standard curve was 0.9997. When reference standard was diluted in pooled human serum, the assay was complicated by interfering compounds. These were removed by ether extraction. The sensitivity of the assay performed in serum was 3 µg/ml. Serum samples contained from 81.2 to 358 µg of mezlocillin/ml with an average serum concentration of 207.5 µg/ml. When serum containing a known amount of mezlocillin was homogenized for a period of time similar to that required to homogenize tissue samples, a deteatable loss of drug was observed and was applied as a correction factor to the measured tisulevels. After correction, the average tissue level was 117.2 µg/ml and ranged from 27% to 98% of the serum levels. Conclusions: The serum concentration of mezlocillin after IV infusion of 4 g was greater than that required to inhibit the majority of the most significant organisms responsible for post-hysterectomy sepsis. Although tissue levels appeared to be consistently lower than serum levels, they could be expected to provide an inhibitory effect against many of the bacterial strains that contaminate the surgical site.

Prophylactic Mezlocillin-Netilmicin Combination in Permanent Transvenous Cardiac Pacemaker Implantation: a Single-Center, Prospective, Randomized Study

A prospective, randomized study was carried out in order to assess the efficacy and safety of the mezlocillin-netilmicin combination in the prophylaxis of first permanent transvenous cardiac pacemaker implantation. Five hundred and fifty-two consecutive patients were randomly administered either 2 g mezlocillin and 200 mg netilmicin both as an i.v. bolus before implantation or 2g mezlocillin before and then 6 and 12 hours after surgery and 200 mg netilmicin before and then 12 hours after implantation. No adverse events were seen. Neither pocket nor electrode infections were observed in the 457 subjects still alive (mean follow-up: 29.2 months) or in patients who died after 1 year of follow-up (mean follow-up: 20.1 months) or before this time (mean follow-up: 4.7 months). The serum and pocket concentrations of mezlocillin and netilmicin at the end of surgery were found to be adequate to cover microorganisms that most often cause infections, including methicillin-resistant staphylococci.

Prospective randomized comparison of mezlocillin therapy alone with combined ampicillin and gentamicin therapy for patients with cholangitis

Forty-six patients with cholangitis were randomized to receive therapy with mezlocillin sodium (24 patients) or a combination of ampicillin sodium--gentamicin sulfate (22 patients). The biliary concentration of mezlocillin was 112 times higher than that of ampicillin and 778 times higher than that of gentamicin. The ratio of the concentration in serum or bile over the minimum inhibitory concentration against aerobic gram-negative bacilli (therapeutic index) was higher for mezlocillin than for either ampicillin or gentamicin. Twenty (83%) of 24 patients were cured following mezlocillin therapy compared with 9 (41%) of 22 patients after ampicillin-gentamicin therapy. The 3 patients with superinfection were in the ampicillin-gentamicin arm of the study. Fewer toxic or adverse effects occurred in association with mezlocillin treatment than with ampicillin-gentamicin treatment. Mezlocillin therapy was more effective, less toxic, and less expensive than treatment with ampicillin and gentamicin for patients with cholangitis.

Prospective Randomized Comparison of Mezlocillin Therapy Alone With Combined Ampicillin and Gentamicin Therapy for Patients With Cholangitis

• Forty-six patients with cholangitis were randomized to receive therapy with mezlocillin sodium (24 patients) or a combination of ampicillin sodium—gentamicin sulfate (22 patients). The biliary concentration of mezlocillin was 112 times higher than that of ampicillin and 778 times higher than that of gentamicin. The ratio of the concentration in serum or bile over the minimum inhibitory concentration against aerobic gram-negative bacilli (therapeutic index) was higher for mezlocillin than for either ampicillin or gentamicin. Twenty (83%) of 24 patients were cured following mezlocillin therapy compared with 9 (41%) of 22 patients after ampicillin-gentamicin therapy. The 3 patients with superinfection were in the ampicillin-gentamicin arm of the study. Fewer toxic or adverse effects occurred in association with mezlocillin treatment than with ampicillin-gentamicin treatment. Mezlocillin therapy was more effective, less toxic, and less expensive than treatment with ampicillin and gentamicin for patients with cholangitis. (<i>Arch Intern Med</i>. 1989;149:1279-1284)

The penetration of antibiotics into human pancreas.

In order to analyse the penetration of two antibiotics (mezlocillin and metronidazole) which cover the spectrum of microorganisms involved in pancreatic infection, we determined their concentration in pancreatic tissue, juice and cyst fluid in 16 patients undergoing pancreatic surgery. In addition, the external pancreatic fistula fluid of one patient was analysed for antibiotic concentration and bacterial counts during a seven-day treatment with mezlocillin, metronidazole and netilmicin (i.v.). Antibiotic concentrations were determined by HPLC between 16 and 210 (median 74) min after i.v. administration of 4 g mezlocillin and 500 mg metronidazole, respectively. The median concentration of mezlocillin was 23.2 (range: 3.1-37.4) mg/kg, 15.9 (range: 4.2-55.0) mg/l and 9.9 (range: 5.2-14.8) mg/l in pancreatic tissue, juice and cyst fluid, respectively. The median concentration of metronidazole was 5.1 (range: 1.8-13.0) mg/kg, 8.5 (range: 3.6-16.2) mg/l and 1.2 (0.9-1.4) mg/l in pancreatic tissue, juice and cyst fluid, respectively. From the fistula patient, seven different bacteria were cultured (five aerobic and two anaerobic isolates); their concentration in fistula fluid ranged from 10(5) to 10(7) CFU/ml. The bacteria sensitive for mezlocillin and metronidazole disappeared after four days of i.v. treatment, whereas the two isolates sensitive for netilmicin showed continuous growth seven days after i.v. treatment. The peak concentrations for mezlocillin, metronidazole and netilmicin in the fistula fluid were 6.8 mg/l, 5.6 mg/l and less than 0.1 mg/l, respectively.

Mezlocillin in pleural effusions — analysis by HPLC

Mezlocillin concentrations in the pleural fluid of six patients (42–76 years of age, suffering from cytologically confirmed malignant pleural effusions) were determined after intravenous infusion of 10 g mezlocillin. Serum and pleural fluid samples were withdrawn 15, 30, 45, 60 min, 2, 4, and 8 h post infusion. Detection of mezlocillin and its metabolites penicilloic acid and penilloic acid was carried out by means of high performance liquid chromatography (HPLC). Mezlocillin concentrations in serum increased up to 778 ± 270 μg/ ml after 15 min, steadily decreasing to 55 ± 50 μg/ml (8 hours post infusion) comparable to the known pharmacokinetic behaviour of mezlocillin; in the pleural effusions mezlocillin levels increased up to 100 ± 38 μg/ml after 1 h. This concentration was maintained throughout the following 7 h. Penicilloic levels ranged about 2–4% within serum, whereas levels below 1% were measured in the pleural fluid.

The role of plasmids in opsonin-independent staphylococcus aureus-leukocyte interactions

The opsonin-independent phagocytic and bactericidal activity of human polymorphonuclear leukocytes stimulated by two Staphylococcus aureus strains and their variants with differing plasmid patterns was investigated. Interactions between staphylococci and phagocytes were evaluated by chemiluminescence and intracellular killing tests. The results obtained indicate that the presence or absence of certain plasmids can modify staphylococcal phagocytosis and their susceptibility to intracellular killing. Pretreatment of the strains investigated with subinhibitory concentrations of mezlocillin and ofloxacin (10% MIC) influenced these parameters, too.

Behaviour of TEM-1 beta-lactamase as a resistance mechanism to ampicillin, mezlocillin and azlocillin in Escherichia coli.

Escherichia coli isolates which synthesised the extremely common 'TEM-1' plasmid mediated beta-lactamase were more resistant to the alpha-aminopenicillins, ampicillin, mezlocillin and azlocillin, than were strains which lacked this enzyme. However, many TEM-1+ isolates remained sensitive to therapeutic concentrations of mezlocillin (less than 64 mg/l), whereas virtually none was susceptible to such levels of ampicillin or azlocillin. Transconjugants of E. coli K12 into which we introduced various TEM-1 coding plasmids similarly acquired lower levels of resistance to mezlocillin than to ampicillin and azlocillin. Those which expressed relatively small amounts of enzyme remained sensitive to 64 mg/l of mezlocillin, whereas they were substantially resistant (MIC greater than 64 mg/l) to the other alpha-aminopenicillins. These data suggested that the enzyme afforded weaker protection against mezlocillin than against azlocillin and ampicillin and we attempted to relate this finding to its hydrolytic activity. Extracted TEM-1 beta-lactamase hydrolysed high concentrations of mezlocillin more rapidly than ampicillin and azlocillin; however, mezlocillin was calculated to be the weakest substrate at the low concentrations which are likely to be obtainable in the bacterial cell. These data may partly account for the residual activity of mezlocillin against enzyme producers, but target and permeability factors probably also contribute.

Pharmacokinetics of mezlocillin in patients with hepatobiliary dysfunction.

The pharmacokinetics of mezlocillin were investigated in 26 patients with alcoholic liver disease. Serum concentrations of mezlocillin were measured following intravenous administration of 3 g doses over 30 min. The mean peak serum concentration (+/- standard deviation) of mezlocillin at the end of infusion was 138.8 +/- 55.7 mg/l and the mean terminal half-life (T 1/2 beta) was 2.10 +/- 0.9 h. The 24 h urinary recovery of mezlocillin was 35.4 +/- 12.4% of the administered dose. Serum clearance was found to be inversely correlated with alkaline phosphatase and with total bilirubin. The T 1/2 beta was related to the following clinical measurements: age, SGOT and prothrombin time. This relationship suggests it may be prudent to adjust the dosage and the dosage interval of mezlocillin in patients with hepatobiliary dysfunction.

Concentrations of mezlocillin in the serum, heart valves, muscle and subcutaneous tissue of patients undergoing open-heart surgery.

4 g mezlocillin as a five-minute intravenous bolus were given preoperatively to 31 adult patients undergoing open-heart surgery. Mezlocillin serum levels declined from 42.8 mg/l at 1-2 h after injection to less than 1 mg/l at 6-8 h after application. Concentrations in muscle and subcutaneous tissue varied between 18 micrograms/g and less than 1 microgram/g. Mezlocillin levels in heart valves were higher than those in muscle and subcutaneous tissue, thus suggesting rapid diffusion of mezlocillin.

Mezlocillin concentrations in human aqueous humour after intravenous and subconjunctival administration.

27 patients received either 4 g intravenous infusion 1-3 h or 100 mg subconjunctival application of mezlocillin 1-12 h before cataract extraction. After intravenous administration the mean aqueous humour concentration of mezlocillin was 2.9 micrograms/ml after 2 h. The subconjunctival dose produced a mean aqueous humour concentration of 23 and 2.6 micrograms/ml after 3 and 12 h, respectively. These levels are above the minimum inhibitory concentration of mezlocillin for sensitive organisms.

Excretion of azlocillin and mezlocillin by the normal pancreas and in acute pancreatitis in dogs and rats.

Dogs and rats were studied to evaluate the excretion of two new acyl-ureidopenicillins, azlocillin and mezlocillin, in the pancreatic fluid. After intravenous administration of 55 mg X kg-1 of either drug, an extremely low concentration (less than 3.0 micrograms X ml-1) of both antibiotics was measured in pancreatic juice of conscious dogs. In rats, both azlocillin and mezlocillin were excreted by the pancreas in bactericidal concentrations (greater than 10 micrograms X ml-1) during the first 15 min following their injection. In anesthetized dogs and rats in which acute pancreatitis was induced by injection of sodium taurocholate into the main pancreatic duct, the tissue concentration of mezlocillin (55 mg X kg-1 i.v.) was significantly higher than in the pancreatic tissue of control animals. In both instances, bactericidal concentrations of mezlocillin were measured in the pancreatic tissue. During the first 30 min following its injection, the concentration of mezlocillin was about five times higher in inflammed pancreatic tissue than in the normal pancreas (dogs: 44 +/- 14 vs. 5 +/- 3 micrograms X g-1 tissue; rats: 67 +/- 10 vs. 13 +/- 2 micrograms X g-1). These data indicate that (1) azlocillin and mezlocillin are excreted in bactericidal concentrations by the normal pancreas only in rats but not in dogs, and (2) in both species, bactericidal concentrations of mezlocillin can be observed in the normal pancreatic tissue and in acute pancreatitis; its concentration being significantly higher in acute pancreatitis than in controls.

Penetration of mezlocillin and oxacillin into the glandular and adipose tissue of the breast after simultaneous intravenous infusion. A pharmacokinetic study

The concentrations of mezlocillin and oxacillin were measured after simultaneous intravenous infusion of 4 and 2 g respectively in serum, fat and mammary gland tissue of 35 patients. The maximum mean concentrations of mezlocillin were measured in serum with 281 micrograms/ml and in fat with 38 micrograms/g after the end of the infusion and in the mammary gland with 52.3 micrograms/g after 90 minutes. Mezlocillin concentrations of less than or equal to 2.0 micrograms/ml and g respectively were found after 6-8 hours after the end of the infusion. The maximum mean concentrations of oxacillin were measured in the serum with 107.8 micrograms/ml also after the end of the infusion, declining to levels less than or equal to 2.0 micrograms/ml within 6 hours. Measurable oxacillin-concentrations could not be found in the fat and in the tissue of mammary gland with the chosen dose. The clinical relevance of the results is discussed.

In-vitro synergism between mezlocillin and isoxazolyl penicillins against beta-lactamase-producing Gram-negative organisms.

Forty beta-lactamase producing Gram-negative organisms were tested with mezlocillin plus an isoxazolyl penicillin for synergy. With standard chequerboard techniques, the combination showed enhanced activity, when compared to either drug alone, against 30 strains. Eighteen of these 30 strains showed synergism at concentrations of mezlocillin and isoxazolyl penicillins which were attainable in the serum (7 strains of Morganella morganii, 8 strains of Eschericia coli and 3 strains of Serratia marcescens).

Mezlocillin kinetics in hepatic insufficiency.

To establish elimination kinetics of mezlocillin in patients with hepatic insufficiency, we gave eight normal subjects and four patients with hepatic insufficiency and normal renal function a single 3-gm dose of mezlocillin by intravenous infusion. Subjects with hepatic insufficiency all had serum bilirubins levels of above 3 mg/dl, prothrombin times more than 2 sec longer than control, and creatinine clearances above 60 ml/min. Mezlocillin concentrations were determined by microbiologic assay. Kinetic analysis was by model-independent methods. Elimination half-life was 0.96 hr for subjects with normal liver function and 2.62 hr for patients with hepatic insufficiency. Mean total body clearance for normal subjects was 247 ml/min, while in patients with hepatic insufficiency it was 125.4 ml/min. We conclude that hepatic insufficiency prolongs mezlocillin elimination and suggest that therapeutic guidelines be set up.

Interaction of mezlocillin and cefoxitin against Proteus morganii in the granuloma pouch model.

The interaction of cefoxitin and mezlocillin was studied in rats using the granuloma pouch technique. Proteus morganii strains against which cefoxitin and penicillins exhibited antagonistic antibacterial activity were selected for infection of the pouches. Animals were treated with cefoxitin and/or mezlocillin, and bacterial counts, drug levels and beta-lactamase production in the pouch exudate monitored. A significant decrease in bacterial counts was seen after administration of mezlocillin and cefoxitin in combination but not after the drugs administered alone. Drug concentrations of mezlocillin and/or cefoxitin corresponded directly to the rate of induction of beta-lactamase activity. Although both beta-lactam antibiotics induce beta-lactamase activity, administered in combination in vivo they appear to protect each other from being inactivated thus resulting in synergistic antibacterial activity.

Pharmacokinetics and antibacterial efficacy in vivo of beta-lactam combinations against Proteus vulgaris.

The pharmacokinetics and antibacterial efficacy of mezlocillin, cefotaxime, cefoperazone and the mezlocillin/cefalosporin combinations, respectively, were studied by adopting the granuloma pouch model in rats. Exudate concentrations of mezlocillin were higher after combined i.v. injection with a cefalosporin as determined microbiologically and by high performance liquid chromatography (HPLC). Cefoperazone levels, however, were not affected. Not metabolized cefotaxime concentrations as determined by HPLC were also not increased following simultaneous injection with mezlocillin. Cefotaxime metabolite concentrations, however, were generally higher than unchanged cefotaxime and increased upon repeated administration of cefotaxime alone and to a greater extent when combined with mezlocillin. Antibacterial efficacy of mono- or combined chemotherapy was correlated to beta-lactamase inducibility of the test strains insofar as drugs acting as good or moderate enzyme inducers were ineffective in vivo. The combined therapy of mezlocillin with cefotaxime was effective in this case. This result was also correlated to the bioavailability of the beta-lactams in infected pouches. Due to the degree of beta-lactamase inducibility and production, drug levels were either decreased or not detectable.

Pharmacokinetics of mezlocillin in bronchial secretions

This study was designed to measure the penetration of mezlocillin into respiratory secretions taken from tracheostomized patients admitted to an intensive care unit. In these patients, samples can be taken at set intervals. Eighteen patients were divided into two groups, one group received a single i. v. dose of 5 g mezlocillin and the other a one day treatment with eight-hourly infusions of 5 g mezlocillin, samples being taken after the fourth infusion. Antibiotic concentrations were measured in simultaneous samples of serum and bronchial secretions by an agar diffusion method. The results showed considerable penetration of mezlocillin into bronchial secretions. Two hours after the end of the infusion, the peak of bronchial mezlocillin concentrations varied from 10 to more than 20 µg/ml. The kinetics of bronchial levels exhibited slow elimination, with still measurable levels at the sixth hour (1.5 to 3 µg/ml). Important individual variations were seen in patients with different clinical conditions (respiratory insufficiency, acute intoxication in forced diuresis). There was no difference between the two groups of patients, which showed that no cumulation took place. It is concluded that the passage of mezlocillin in the human respiratory tract results in high bronchial concentrations which are bactericidal to most species ofEnterobacteriaceae.

Clinical pharmacology of mezlocillin.

Mezlocillin is a new broad-spectrum semisynthetic penicillin that has shown encouraging in vitro activity against the infecting organisms most likely to cause mortality and morbidity in cancer patients receiving chemotherapy. The serum clearances and urine recoveries of mezlocillin, ampicillin, and carbenicillin were compared after the intravenous administration of single 3-g doses. The peak mean serum concentrations of mezlocillin and carbenicillin were 269 and 278 mug/ml, respectively, whereas the peak ampicillin level was lower at 167 mug/ml. The terminal half-life of mezlocillin, 66 min, was not significantly different from those of ampicillin and carbencillin (63 and 77 min, respectively). Recoveries of mezlocillin, ampicillin, and carbenicillin from urine over 6-h periods after drug dosage were 45, 61, and 80%, respectively. A further study in 11 cancer patients examined serum maintenance levels of mezlocillin when 3-g doses were given intravenously every 4 h for at least 7 consecutive days. After 3 days of therapy, the mean serum concentrations were maintained above 50 mug/ml. Although therapeutic efficacy was not an objective of this study, all of three documented bacterial infections were cured, and no serious toxicity was encountered.