Penetration of cefprozil into tonsillar and adenoidal tissues.

Penetration of cefprozil into tonsillar and/or adenoidal tissues was investigated for patients undergoing tonsillectomy and/or adenoidectomy. A total of 29 patients ranging in age from 2 to 14 years participated in the study. The tonsils and/or the adenoids were removed at times ranging from 0.33 to 3.17 h after oral administration of a dose of either 7.5 or 20 mg/kg of body weight. A blood sample was also collected as soon as the tissue sample was removed. Plasma, tonsil, and adenoid samples were analyzed for cis and trans isomers of cefprozil by high-performance liquid chromatographic assays. The concentrations of the cis isomer of cefprozil in plasma ranged from 0.60 to 9.87 micrograms/ml at the 7.5-mg/kg dose level and from 1.04 to 20.40 micrograms/ml at the 20-mg/kg dose level. The corresponding concentrations of the cis isomer in tonsil tissue ranged from 0.48 to 2.42 micrograms/g and from 1.00 to 4.29 micrograms/g, respectively. The corresponding concentrations of the cis isomer in adenoid tissue ranged from 0.40 to 4.20 micrograms/g and from 1.74 to 4.94 micrograms/g, respectively. The concentrations of the trans isomer were about 1/10 of those observed for the cis isomer. The median ratios of the cefprozil concentration in tonsillar tissue to that in plasma were 0.37 and 0.47 for patients receiving a 7.5- or a 20-mg/kg oral dose of cefprozil, respectively. The corresponding median ratios for the adenoidal tissue were 0.46 and 0.82, respectively. The cefprozil concentrations in either the tonsillar or the adenoidal tissue at both dose levels over 3.17 h after dosing are much higher than the MICs for common pathogens which cause pharyngitis or tonsillitis.

Oral absolute bioavailability and intravenous dose-proportionality of cefprozil in humans.

The absolute bioavailability (F) and dose proportionality of cefprozil were investigated in a parallel design study with an embedded two-way crossover leg. Twenty-four healthy male subjects divided into 3 dosing groups received a single 250-, 500-, or 1000-mg dose of cefprozil by a 30-minute intravenous infusion. Subjects assigned to the 500-mg dose group also received a 500-mg oral dose of cefprozil in crossover manner with a wash-out period of 7 days between each treatment. Cefprozil consists of cis and trans isomers in an approximate 90:10 ratio. Serial blood and urine samples were collected and analyzed for the concentrations of the cis and trans isomers of the cephalosporin using high-pressure liquid chromatographic assay with UV detection methods. After the 250-, 500-, and 1000-mg intravenous administration of cefprozil, the peak concentrations were 13.2, 26.0, and 48.5 micrograms/mL, and area under the plasma concentration versus time profiles were 17.2, 31.4, and 58.1 micrograms.hour/mL, respectively, for the cis isomer increasing in a dose proportional manner. Total body clearance, renal clearance, and volume of distribution at steady state, adjusted for body weight, were not significantly different among all groups. Mean residence time, elimination half-life, and urinary recovery were invariant with the dose. Based on the plasma and urine data, the estimates of F were 89% and 94% for the cis isomer, respectively. The plasma concentrations of the trans isomer were about 1/10th of the cis isomer, and all parameters were similar to those observed for the cis isomer. In summary, cefprozil exhibits linear pharmacokinetics and is essentially completely absorbed after oral administration.

Safety profile of cefprozil.

The clinical and laboratory safety of cefprozil was analyzed with data from 4,227 patients who received the drug in North American and European clinical efficacy trials. Of these patients, 3,016 adults and children received capsules or tablets, while 1,211 patients (mostly children) were treated with cefprozil suspension. Cefprozil was used in single-daily or twice-daily dosing regimens for treatment of infections of the upper and lower respiratory tracts, sinuses, middle ear, urinary tract, and skin and skin structure. The incidence of adverse clinical events and laboratory abnormalities was similar to that associated with use of other oral cephalosporins. Gastrointestinal adverse effects were the predominant adverse clinical event, although the incidence of diarrhea with cefprozil was much lower than that with cephalosporins that are less well absorbed. The data confirm the safety of cefprozil in both adult and pediatric patients.

Excretion of cefprozil into human breast milk.

The excretion of cefprozil into breast milk in nine healthy, lactating female subjects was investigated. Each subject received a single 1,000-mg oral dose of cefprozil consisting of cis and trans isomers in an approximately 90:10 ratio. Serial blood, urine, and breast milk samples were collected and analyzed for the concentrations of the cis and trans isomers by a specific high-pressure liquid chromatography-UV assay. The mean pharmacokinetic parameters for both isomers were essentially the same. The mean peak concentrations in plasma for the cis isomer were 14.8 micrograms/ml, and the area under the concentration curve was 54.8 micrograms.h/ml. The mean values of elimination half-life, renal clearance, and urinary excretion for the cis isomer were 1.69 h, 164 ml/min, and 60%, respectively. The mean concentrations in milk of the cis isomer over a 24-h period ranged from 0.25 to 3.36 micrograms/ml, with the maximum concentration appearing at 6 h after dosing. The average maximum concentration in milk of the trans isomer was less than 0.26 micrograms/ml. The concentrations of the trans isomer in plasma and in breast milk were about 1/10 of those for the cis isomer. Less than 0.3% of the dose was excreted in breast milk for both isomers of cefprozil. Even if one assumes that the concentration of cefprozil in milk remains constant at 3.36 micrograms/ml (the highest concentration of cefprozil observed in breast milk), an infant ingesting an average of 800 ml of milk per day will be exposed to a maximum amount of about 3 mg of cefprozil per day. This value represents about 0.3% of the maternal dose. Low excretion of cefprozil in breast milk and the excellent safety profile of cefprozil suggest that this cephalosporin may be administered to nursing mothers when indicated.

Effect of antacid on the bioavailability of cefprozil.

The effect of antacid on the bioavailability of cefprozil was investigated in a two-way crossover study. Eight healthy male subjects received a single 500-mg oral dose of cefprozil with and without coadministration of 30 ml of an antacid suspension containing magnesium hydroxide and aluminum hydroxide (Maalox). Cefprozil consists of cis and trans isomers in an approximate 90:10 ratio. When cefprozil was administered alone (treatment A), the mean maximum concentrations (Cmax) of the cis and trans isomers were 9.2 and 1.2 micrograms/ml, respectively. When cefprozil was coadministered with Maalox (treatment B), the Cmax values of the cis and trans isomers were 8.7 and 1.3 micrograms/ml, respectively. The mean values of the area under the curve from time zero to infinity (AUC0-infinity) were 27.7 and 3.5 micrograms.h/ml for treatment A and 27.5 and 3.5 micrograms.h/ml for treatment B for the cis and trans isomers, respectively. The other pharmacokinetic parameters, time to Cmax, elimination half-life, mean residence time, renal clearance, and percent urinary excretion, were essentially the same for the two isomers. The respective values of the elimination half-life for the cis and trans isomers were 1.36 and 1.32 h for treatment A and 1.36 and 1.42 h for treatment B. Mean urinary excretion was 63 and 60% for treatment A and 58 and 56% for treatment B for the cis and trans isomers, respectively. No significant differences between the two treatments were found for any of the pharmacokinetic parameters for either isomer. For the cis isomer, bioavailability point estimates (90% confidence intervals) of the mean Cmax and AUG0-infinity values for the Maalox treatment relative to those for the reference treatment were 95% (87%, 103%) and 99% (95%, 104%), respectively. For the trans isomer, the value were 109% (92%, 126%) for Cmax and 97% (88%, 106%) for AUC0-infinity. On the basis of the results of this study, it is concluded that the bioavailability of cefprozil is not affected by the coadministration of Maalox.

Cefprozil versus cefaclor in the treatment of mild to moderate skin and skin-structure infections. The Cefprozil Multicenter Study Group.

In a multicenter study, 598 patients with skin or skin-structure infections were randomly assigned to receive 500 mg of cefprozil once daily (or 20 mg/kg once daily) or 250 mg of cefaclor three times daily (or 20 mg/kg daily in three equal doses) for 5 to 10 days. Treatment was evaluated in 212 cefprozil-treated patients and in 210 cefaclor-treated patients. The patients were aged 2 to 99 years (mean, 28 years) and their primary diagnoses were impetigo (in 99 patients), pyoderma (in 98), superficial abscess (in 70), and cellulitis (in 64). A satisfactory clinical response was found in 93% of the cefprozil-treated patients and in 92% of the cefaclor-treated patients, the pathogens were eradicated in 91% and 89%, and overall treatment was rated effective in 87% of both groups. Adverse clinical events were reported by 5% of the patients in both groups; one cefprozil-treated patient and three cefaclor-treated patients withdrew from treatment because of adverse events. It is concluded that cefprozil administered once daily is as effective and safe as cefaclor administered three times daily in the treatment of mild to moderate skin and skin-structure infections.

A noncomparative study of cefprozil at two dose levels in the treatment of acute uncomplicated bacterial sinusitis.

The efficacy and safety of cefprozil at two dose levels were evaluated in 110 patients with acute uncomplicated bacterial sinusitis in an uncontrolled, noncomparative, Phase II trial. Ninety patients received 250 mg of cefprozil (low-dose group) and 20 patients received 500 mg of cefprozil (high-dose group) every 12 hours for ten days. Evaluable patients had symptoms consistent with acute sinusitis, pathogens isolated at pretreatment susceptible to cefprozil, and a radiograph positive for sinusitis within 48 hours before treatment. A satisfactory clinical response was achieved in 34 of 39 evaluable patients (87%) in the low-dose group and in all 16 evaluable patients (100%) in the high-dose group. Pathogens were eradicated in 35 of 39 patients (90%) in the low-dose group and in 15 of 16 patients (94%) in the high-dose group. A total of 140 of 155 pathogens (90%) isolated pretreatment were susceptible to cefprozil. Six patients (7%) in the low-dose group and one patient (5%) in the high-dose group reported at least one adverse clinical event.

Cefprozil versus cefaclor in the treatment of acute and uncomplicated urinary tract infections. Cefprozil Multicenter Study Group.

Cefprozil is a new oral cephalosporin with an in vitro spectrum of activity that includes the pathogens most commonly associated with acute and uncomplicated urinary tract infections (UTIs). A multicenter, randomized study was conducted to compare the clinical efficacy and safety of cefprozil, administered once daily, with cefaclor, administered three times a day, for ten days in patients 2 years of age or older who had acute and uncomplicated UTIs. The rate of satisfactory clinical response in evaluable patients was 87% in the cefprozil group and 84% in the cefaclor group. The patient bacteriologic response rates were also similar: 83% for cefprozil and 85% for cefaclor. The overall effective response rate for both cefprozil and cefaclor was 77%. Both drugs were well tolerated, with no difference in the incidence of drug-related adverse events. Because of its efficacy and once-daily dosing regimen, cefprozil may be an alternative to currently available oral antibiotics in the treatment of UTIs.

Pharmacokinetics of cefprozil in healthy subjects and patients with renal impairment.

Cefprozil, a new broad-spectrum oral cephalosporin, is composed of cis and trans isomers in an approximate 90:10 ratio. The pharmacokinetics of a single oral 1000-mg dose of cefprozil were evaluated in 6 healthy subjects and 24 patients with various degrees of renal impairment. Six of these subjects were studied both while receiving hemodialysis and during an interdialytic period. Plasma, urine, and hemodialysate that were collected at predetermined times were analyzed for concentrations of the cis and trans isomers of cefprozil using reverse-phase HPLC assay with UV detection. The maximum plasma concentration of the cis isomer ranged from 12.3 micrograms/mL in subjects with normal renal function to 36.7 micrograms/mL in hemodialysis patients. Similarly the area under the plasma concentration-time curve and the elimination half-life increased from 46 micrograms.h/mL to 373 micrograms.h/mL and from 1.72 hours to 5.94 hours, respectively. Renal clearance of the cis isomer decreased from 198 mL/min in normal subjects to 19 mL/min in volunteers with creatinine clearances of less than or equal to 30 mL/min; there was a strong correlation (r2 greater than or equal to .93) between the renal clearance of the cis isomer and creatinine clearance. Urinary recovery of the cis isomer decreased from 57% in those with normal renal function to 24% in the group with a creatinine clearance of less than or equal to 30 mL/min. Hemodialysis decreased the half-life of the cis isomer to 2 hours and removed approximately 55% of it from the body during a 3-hour dialysis period (hemodialysis clearance equaled approximately 87 mL/min). The pharmacokinetics of the trans isomer were similar to those observed for the cis isomer and were affected similarly by declining renal function. A reduction in dosage is recommended in patients with a creatinine clearance of 30 mL/min or less. It may be necessary to administer a dose after hemodialysis to maintain therapeutic plasma concentrations.

Pharmacokinetics of cefprozil in healthy subjects and patients with hepatic impairment.

The pharmacokinetics of cefprozil were studied in 12 (9 men, 3 women) subjects with hepatic impairment and in 12 healthy subjects who were matched for age, sex, and weight. Each subject received a single 1000 mg oral dose of cefprozil, which consists of cis and trans isomers in approximately a 90:10 ratio. Serial blood and urine samples were collected and analyzed using validated HPLC/UV methods for the concentration of each isomer. The results of the plasma and urine analyses were subjected to noncompartmental pharmacokinetic analysis. The values for the peak plasma concentrations (Cmax), area under the plasma concentration versus time curve (AUC0-infinity), apparent total body clearance (Clt/F), renal clearance (Clr), and percent of drug excreted in urine (%UR) of each isomer were not significantly different in healthy subjects and patients with hepatic impairment. The only parameters that were significantly (P less than or equal to .05) longer in patients with hepatic impairment were mean residence time in the body (MRT) and half-life; the MRT for the cis isomer in healthy subjects and subjects with hepatic impairment were 3.33 hr and 3.88 hr, respectively, and for the trans isomer 3.17 hr and 3.68 hr; the half-life for the cis isomer was 1.62 hr and 2.22 hr, respectively, and for the trans isomer 1.21 hr and 1.54 hr. The pharmacokinetics of the cis and trans isomers of cefprozil were virtually identical in healthy subjects as well as those with hepatic impairment.

Phase I study of multiple-dose cefprozil and comparison with cefaclor.

The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after administration of multiple doses of the drug, and to compare these pharmacokinetic parameters with those obtained with cefaclor. The volunteers received 28 doses of 250, 500, or 1,000 mg of cefprozil or 500 mg of cefaclor every 8 h for 10 days. Serial blood samples and the total volume of urine voided by each individual were collected for pharmacokinetic evaluation on days 1, 5, and 10. Both cephalosporins were well tolerated after multiple oral dosing. The peak levels in plasma (Cmax) of cefprozil ranged from 5.7 to 18.3 micrograms/ml after oral administration of 250- to 1,000-mg doses. The regression analysis of Cmax on cefprozil dose showed a dose-linear response. The mean Cmax of cefaclor ranged from 15.2 to 16.7 micrograms/ml and did not change significantly on multiple dosing. The overall mean terminal half-life of cefprozil was 1.2 h and was invariant with respect to dose or duration of dosing. The area under the plasma-concentration-versus-time curve from 0 h to infinity (AUC0-infinity) of cefprozil increased in a dose-proportional manner with an increase in dose. The overall urinary recovery (61% of dose) and renal clearance values of cefprozil were generally invariant with respect to dose and duration of dosing. While cefprozil was apparently absorbed less rapidly and achieved lower Cmax values than cefaclor, the AUC0-infinity of cefprozil was nearly twofold greater than that of cefaclor. The half-life of cefprozil was also twofold longer than that observed for cefaclor. Although the urinary recovery of cefaclor (75% of dose) was significantly higher than that of cefprozil (61% of dose), the concentrations of cefprozil in urine remained significantly higher than those of cefaclor from 2 to 8 h postdosing. If the therapeutic concept is maintained that levels of beta-lactam antibiotics in plasma should exceed the MIC for the offending organisms over a period that approximates the dosing interval, then cefprozil would appear to be suitable for twice-daily administration, whereas cefaclor should probably be administered three or even four times a day.

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration.

The pharmacokinetics and tissue penetration, as judged by skin blister fluid, of cefprozil and cefaclor were examined in 12 healthy male volunteers. Doses of 250 and 500 mg of each drug were given to fasting subjects in a crossover fashion. Serially obtained plasma, skin blister fluid, and urine samples were analyzed for cefprozil or cefaclor by validated high-pressure liquid chromatographic methods. After oral administration of 250 and 500 mg of cefprozil, mean concentrations in plasma rose to peak levels (Cmax) of 6.1 and 11.2 micrograms/ml, respectively, and those of cefaclor were 10.6 and 17.3 micrograms/ml, respectively. The elimination half-life of cefprozil (1.3 h) was significantly longer than that of cefaclor (0.6 h), and as a result, the area under the curve for cefprozil was about two times greater than that for cefaclor. Both cephalosporins were primarily excreted unchanged in urine. The mean skin blister Cmax values were 3.0 and 5.8 micrograms/ml for cefprozil and 3.6 and 6.5 micrograms/ml for cefaclor after the 250- and 500-mg oral doses, respectively. The mean Cmax values in skin blister fluid for both cephalosporins were comparable and were significantly lower than the corresponding Cmax values in plasma. However, the levels of cefprozil and cefaclor in skin blister fluid declined more slowly than they did in plasma. The skin blister fluid half-life estimates for cefprozil were significantly longer than they were for cefaclor. Parallel to the observation in plasma, the mean skin blister fluid areas under the curve for cefprozil were significantly higher than they were for cefaclor. The plasma and skin blister fluid pharmacokinetic analyses suggest that the exposure of humans to cefprozil is significantly greater than that to cefaclor at the same dose.

Phase I study of single-dose BMY-28100, a new oral cephalosporin.

The objective of this Phase I study was to evaluate the safety, tolerance, and pharmacokinetics of BMY-28100 in 36 male subjects after the administration of single oral doses of 250, 500, and 1,000 mg. The subjects were divided into groups of 12 per dose group. All subjects completed the study, and BMY-28100 was well tolerated at all doses. The maximum concentration of the drug in plasma ranged from 6.2 to 17.7 micrograms/ml for the 250- and 1,000-mg doses, respectively, and the area under the curve increased in a dose-proportional manner. The elimination half-life and renal clearance averages were 1.2 h and 200 ml/min, respectively. The values for renal clearance suggest that BMY-28100 is excreted by glomerular filtration and tubular secretion. Mean concentrations of the drug in urine were highest during the first 4 h after the doses and ranged from 175 to 658 micrograms/ml following the 250- and 1,000-mg doses, respectively. The mean urinary recovery ranged from 57 to 70% of the dose. The results from this Phase I study indicate that BMY-28100 is well tolerated and exhibits linear pharmacokinetics.

Beta-lactam therapy of osteomyelitis and septic arthritis.

The goal of therapy in osteomyelitis is to eradicate established bone infection and to prevent progression into the chronic form. Beta-lactams generally lack organ toxicity or serious side effects when used in high doses for the prolonged intervals necessary to eradicate osteomyelitis. Also, the spectrum of many beta-lactams covers the usual etiologic agents of bone and joint infections. Penetration of beta-lactams into joint fluid is variable but adequate. The significance of measurable "bone levels" is unclear. Staphylococcus aureus in some series accounts for up to 80% of acute haematogenous osteomyelitis, and anti-staphylococcal penicillins and cephalosporins are the drugs of choice in these cases. Other clinical types of osteomyelitis and septic arthritis are associated with a wider range of etiologies. Factors such as the age of the patient (neonates with Gram-negative infections, infants with Haemophilus influenzae arthritis), host defense status (sickle cell patients with Salmonella osteomyelitis) as well as the site of infection (vertebral osteomyelitis associated with UTI), have an increased frequency of causes other than staphylococci, necessitating broader coverage. If environmental contamination has been introduced into the systemic circulation (drug addicts), or into the joint, bone, or contiguous soft tissue (by trauma), the spectrum of causative agents is diverse, and may necessitate concomitant therapy with aminoglycosides and/or anti-anaerobe drugs. As experience is gained with expanded spectrum cephalosporins and carbapenems, their role in the therapy of bone and joint infections will be better defined. Non-beta-lactam antibiotics have been evaluated, but at least for staphylococcal infections should probably be reserved for use in patients with known hypersensitivity or those infected with methicillin resistant or tolerant strains. The development of a non-toxic agent active against these pathogens is a challenge for the future.

Rapid diagnosis of systemic candidiasis in children with cancer by pyrolysis gas liquid chromatography.

A pyrolysis gas liquid chromatographic method for detection of Candida antigen in patients with disseminated candidiasis is described. The test was positive in 73% of cases and no false positives or false negatives were noted in controls.

Chemoprophylaxis for Pneumocystis carinii pneumonitis: outcome of unstructured delivery.

Sulfamethoxazole-trimethoprim was administered prophylactically to 786 patients judged to be at sufficient risk for development of Pneumocystis carinii pneumonitis. The selection of patients, administration of the agents, and surveillance for compliance were the responsibility of the attending oncologists rather than specialists in infectious diseases, as in an earlier trial at this center. The recommended dosage was trimethoprim, 150 mg/sq m/day, and sulfamethoxazole, 750 mg/sq m/day. Over a three-year study period, nine cases of P carinii pneumonitis occurred at this institution, with none attributable to drug failure. Adverse reactions, skin rashes mainly, were noted in 43 patients, and one patient died with Stevens-Johnson syndrome. These results confirm the efficacy of sulfamethoxazole-trimethoprim in preventing P carinii pneumonitis in childhood cancer patients and illustrate the feasibility of large-scale unstructured delivery of the combination to patients with malignant diseases frequently associated with this pneumonia.

Histoplasmosis mimicking childhood non-Hodgkin lymphoma.

Cell surface markers are becoming increasingly important in the diagnosis of malignant lymphoid diseases. We present a case of pulmonary histoplasmosis with a pleural effusion. The differential diagnosis included non-Hodgkin lymphoma because the pleural fluid cells were cytologically identical to convoluted lymphoblasts; the cells also formed rosettes with sheep erythrocytes at 37 degrees C, suggesting that they were malignant thymus-derived lymphoblasts. Since cultures of pleural fluid were negative for bacteria and fungi, the correct diagnosis of histoplasmosis was made only after conventional histology identified Histoplasma capsulatum organisms in pleural nodules. Thus, until we have a better understanding of the significance of cell surface markers, we should continue to rely on conventional histology for the diagnosis of lymphomas.