Penetration of loracarbef into the maxillary sinus: a pharmacokinetic assessment

CLINICAL THERAPEUTICSWOL.

18, NO. 2, 1996

Penetration of Loracarbef into the Maxillary Sinus: A Pharmacokinetic Assessment Monica Stenquist, MD,’ Lam Olen, MD,2 Magnus Jannert, MD, PhD,3 Lurs Niislund, MD,4 and Michael L. Zeckel, M@ ‘Department of Oto-Rhino-Luryngology, Akademiska Hospital, Uppsala, 2Department of Oto-Rhino-Luryngology, Lidkiiping Hospital, Lidkiiping, 3Department of Oto-RhinoLuryngology, Allmiinna Hospital, Malmii, 4Department of Oto-Rhino-Luryngology, Alingsds Hospital, Alingsiis, Sweden, and ‘Lilly Research Laboratories, Indianapolis, Indiana

ABSTRACT Loracarbef, a beta-lactam antibiotic of the carbacephem class, is active in vitro against pathogens associated with acute maxillary sinusitis. To study the extent and duration of maxillary sinus fluid penetration after administration of loracarbef, 20 patients (10 men, 10 women; average age, 41 + 13 years) with acute sinusitis were treated with loracarbef 400 mg every 12 hours for 10 days. A lavage catheter was inserted into the maxillary sinus, and 150pL sinus fluid samples were obtained at 0 (baseline), 0.5, 1, 1.5, 2, and 2.5 hours after the first dose and at 24 and 48 hours (12 hours after the second and fourth doses, respectively). Venous blood samples were obtained at the same times. Maxillary fluid and serum samples were frozen immediately at -20 “C to -70 “C until later bioassay using a direct agar diffusion

0149.2918/96/$3.50

method. Excluding missing data or inappropriately timed samples, the mean (? SD) sinus fluid concentrations were 0.16 + 0.12 pg/mL at baseline, 0.23 + 0.17 pg/rnL at 0.5 hour, 1.11 + 1.44 I.&-nL at 1 hour, 1.63 + 2.07 pg/rnL at 1.5 hours, 1.75 f 2.01 pg/mI_ at 2 hours, and 1.60 + 1.96 pg/mL at 2.5 hours after dose. The mean sinus fluid concentration before the third dose (approximately 12 hours after the second dose) was 1.01 * 0.89 pg/mL and before the fifth dose (approximately 12 hours after the fourth dose) was 0.88 k 0.90 pg/rnL. Taking the highest sinus fluid concentration measured in each patient, the mean peak sinus fluid concentration was 2.12 + 1.98 pg/mL (range, 0 to 6.7 l.~g/mL). The pretherapy peripheral leukocyte count appeared to have a statistically significant association (P < 0.01) with loracarbef sinus fluid penetration as estimated by the sinus fluid area under the concen-

273

CLINICAL THERAPEUTICS”

tration-time curve at 0 to 2.5 hours. Loracarbef 400 mg twice daily achieved sinus fluid concentrations that appeared to exceed the minimum concentration required to inhibit 90% of relevant acute sinusitis pathogens throughout the 12-hour interdose interval in most patients with acute maxillary sinusitis.

INTRODUCTION Acute sinusitis is a common disease, complicating between 0.5% and 5% of upper respiratory tract infections.’ In the United States, the incidence of sinusitis among adults aged 45 to 64 years is 187 per 1000 persons.* In the United Kingdom, sinusitis accounts for an estimated 500,000 lost working days3 Systemic antibiotic therapy is often used to treat sinusitis. The efficacy of an antibiotic in the treatment of acute maxillary sinusitis depends on many factors, including in vitro activity against the causative organism and attainment of adequate inhibitory concentrations at the site of infection. Loracarbef is an orally absorbed synthetic agent of the carbacephem class of beta-lactam antibiotics that has been shown to be efficacious in the treatment of acute maxillary sinusitis.4-7 Although loracarbef achieves high serum concentrations8 and adequate peak concentrations in various interstitial fluids, including maxillary sinus fluid,9 the efficacy of beta-lactam antibiotics may depend more on the time during which the drug concentration exceeds the minimum inhibitory concentration (MIC) of the infecting organism than on the drug’s peak concentration.10 Therefore, this study was designed to determine how long loracarbef concentrations exceed the MIC of potential pathogens between doses.

274

PATIENTS

AND METHODS

Patients Twenty patients with acute maxillary sinusitis were enrolled in the study. Patients were eligible for study participation if they were between 18 and 65 years of age and had a clinical diagnosis of maxillary sinusitis, defined by purulent rhinorrhea and the presence of purulent material on sinus aspiration. Patients were excluded from the study if they (1) had a history of alcohol or substance abuse; (2) were pregnant; (3) were postpartum women who were breast-feeding; (4) were allergic to cephalosporins or had immediate hypersensitivity to penicillin; (5) had been treated with antibiotics within 72 hours of study entry; (6) had clinical chemistry or blood tests outside the normal range, including a serum creatinine level ~170 pmol/L or hepatic enzymes greater than twice the upper limit of normal; or (7) had been treated with an investigational agent within the preceding 28 days. Women with childbearing potential were asked to use a safe method of contraception during the study. All patients were required to provide witnessed written informed consent before study participation.

Treatment Patients meeting entry criteria were administered two 200-mg loracarbef capsules with 50 mL of water every 12 hours for 10 days. The first, third, and fifth doses were taken at the investigator’s site, and the remaining doses were taken by the patient at home. Concomitant drug therapy for underlying disease was allowed except for antibiotics or probenecid. Antral

M. STENQUIST ET AL.

irrigation was not permitted before sampling of sinus fluid from patients. Procedures Sinus fluid was obtained following local application of the aerosol decongestant xylometazoline hydrochloride* and topical application of lidocaine hydrochloride spray+ below the inferior turbinate. After adequate local anesthesia, a lavage tube (Sinoject@, Bivonia Medical Technology, Gary, Indiana) was inserted according to the manufacturer’s instructions and left in place for subsequent aspiration of sinus fluid. Sinus fluid was obtained through this catheter at 0 (baseline), 0.5, 1, 1.5, 2, and 2.5 hours after administration of the first dose and after 24 and 48 hours (12 hours after the second and fourth doses, respectively). Fluid was obtained by attaching a syringe to the catheter and expelling any residual purulent material in the catheter lumen by the introduction of a small volume of air. Thereafter, 150 p,L of fluid was aspirated from the maxillary sinus and transferred to a sterile plastic tube. The contents were immediately frozen (-20 “C to -70 “C) for later determination of loracarbef concentrations. Venous blood samples (10 mL) were also obtained at 0 (baseline), 0.5, 1, 1.5,2, and 2.5 hours after administration of the first dose and 12 hours after the second and fourth doses. The serum was separated, transferred to sterile plastic tubes, and frozen (-20 “C to -70 “C) for later determination of loracarbef concentrations.

The concentration of loracarbef in sinus fluid samples and serum was determined by using a direct agar diffusion method. Calibration samples of loracarbef were prepared by weighing and dissolving laboratory standard (batch PTA278, activity 95.1%) in distilled water and thereafter diluting it in pooled human serum to concentrations of 0.25, 0.5, 1, 2, 4, and 8 pg/mL. Quality control (QC) samples of loracarbef were prepared by weighing and diluting the substance in serum to provide concentrations of 0.4, 1.5, and 5 p,g/mL. Calibration, QC, and study samples were applied in duplicate to wells in agar plates according to a randomization schedule. The agar plates contained PDM-11 agar (AB Biodisk, Solna, Sweden), at pH 6.5, inoculated with a sensitive indicator strain of Micrococcus luteus (American Type Culture Collection 9341). After application of all the samples, the agar plates were incubated at 37 ‘C for 20 hours. The diameter of the inhibition zones was subsequently measured with a slide caliper. A calibration curve was established from the linear relationship between the logarithm of the concentration and the diameter of the inhibition zone. Using the calibration curve, the loracarbef concentrations in the study samples and control sera were estimated by the mean of the two measured inhibition zones for each sample. The coefficient of variation among the QC samples varied from 6.0% to 11.43% within different runs. The assays were performed by the National Bacteriological Laboratory in Stockholm, Sweden. Safety Measures

*Trademark: Otrivin@ (Geigy Pharmaceuticals, Ardsley, New York). ‘Trademark: Xylocaine@ (Astra Pharmaceutical Products, Inc., Westboro, Massachusetts).

All patients underwent a history and physical examination before study entry. Routine hematology tests (hemoglobin,

275

CLINICAL THERAPEUTICS”

erythrocyte count, white blood cell [WBC] count, platelets) and clinical laboratory tests (sodium, potassium, urea, creatinine, bilirubin, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) were obtained at study entry. Patients were questioned regarding the occurrence and nature of any adverse events at each visit.

Statistical Analysis All values given are mean * SD. Summary statistics, including means and SD, were calculated for continuous variables. Differences in continuous variables between groups were assessed using the Student’s t test (two-tailed). Proportions were compared between groups with a twosided Fisher’s exact test. Multiple linear regression, using Quattro Pro for Windows version 5.0 (Borland International, Scotts Valley, California), was employed to determine the association of both continuous (age, body weight, height, baseline laboratory parameters) and categorical variables and sinus fluid loracarbef penetration as estimated from the area under the concentration-time curve at 0 to 2.5 hours (AUC,,5 J.

RESULTS Patient Characteristics Twenty patients (10 men and 10 women) were enrolled in the study. The average age of the patients was 41 + 13 years (range, 18 to 66 years), and the average body weight was 74 f 14 kg (range, 50 to 98 kg). Twelve patients had concomitant illnesses, including bronchial asthma (5 patients); allergic rhinitis, hay fever, and nasal

276

obstruction (1 patient); hypertension (1 patient); depression (1 patient); Crohn’s disease (1 patient); vasculitis (1 patient); and migraine headache (1 patient). One patient had a history of chronic sinusitis. Concomitant medications included topical corticosteroids (four patients) and terbutaline (six patients). One patient withdrew from the study on day 7 because of abdominal pain; the remaining 19 patients completed the study. There were no significant differences in hematology or other laboratory studies between groups.

Sinus Fluid Concentrations All sinus fluid concentrations obtained at the various time intervals after the first loracarbef dose are listed in Table I. Seven samples from three patients could not be obtained owing to an inability to obtain sufficient purulent material at the time of sampling. Five samples from four patients were obtained at inappropriate times (more than 10 minutes after dosing instead of before the dose, or more than 6 hours before the dose in one patient). One patient underwent sinus fluid aspiration from both left and right maxillary sinuses; the sinus fluid concentration for this patient was calculated from the mean of the two values. Excluding missing data or inappropriately timed samples, the mean sinus fluid concentrations were 0.16 f 0.12 @rnL at baseline, 0.23 f 0.17 pg/mL at 0.5 hour, 1.11 + 1.44 p,g/mL at 1 hour, 1.63 f 2.07 kg/mL at 1.5 hours, 1.75 + 2.01 p,g/mL at 2 hours, and 1.60 + 1.96 pg/mL at 2.5 hours after the dose. The finding of a small concentration of loracarbef at baseline probably represents antibacterial activity (immunoglobulins or other inhibitory substances) present in the sinus fluid aspirate.

M. STENQUIST ET AL.

0

2

4

6

8

10

12

Time Since Last Dose (h) Figure

1. Mean concentration of loracarbef in serum and sinus fluid 0 to 12 hours after dose. The 12-hour value is the mean of the 24-hour and 48-hour samples, each of which was obtained approximately 12 hours after the preceding dose.

Figure 1 displays the mean serum and sinus fluid loracarbef concentrations for each sampling period after the first dose and the mean of the 24- and 48-hour samples, which were obtained approximately 12 hours after the second and fourth doses, respectively. The mean sinus fluid concentration before the third dose (approximately 12 hours after the second dose) was 1.01 f 0.89 p,g/mL. The mean sinus fluid concentration before the fifth dose (approximately 12 hours after the fourth dose) was 0.88 + 0.90 p,g/mL. Six patients had sinus fluid concentrations that never exceeded 0.5 p,g/mL. These six patients did not differ from patients with higher sinus concentrations with respect to demographic variables (sex, age, body weight, height), concomitant diseases

(asthma), or concomitant medications (corticosteroids or terbutaline). There appeared to be a significant difference (P = 0.038; t = 2.24) between the mean pretherapy peripheral leukocyte count in the 6 patients demonstrating peak sinus fluid concentrations 10.5 l.r.g/mL (mean WBC count, 6.35 f 1.69 Gl/L) and that in the remaining 14 patients with peak sinus fluid concentrations >0.5 p,g/mL (mean WEK count, 8.49 + 2.04 GI/L). One patient had sinus fluid concentrations 10.3 p&nL at 1.5, 2, and 2.5 hours after dose but had a concentration of 1.6 pg/mI_ at 24 hours (approximately 12 hours after the second 400mg loracarbef dose), suggesting delayed entry of drug into the maxillary sinus. Taking the highest sinus fluid concentration measured in each patient, the mean peak si-

277

CLINICAL THERAPEUTICS’

nus fluid concentration was 2.12 + 1.98 l.@nL (range, 0 to 6.7 u&nL). Table I also lists the estimated AUC,,5 ,, of loracarbef in sinus fluid calculated using the trapezoidal rule. Multiple linear regression analysis was conducted to determine whether any relationship existed among demographic variables (sex, age, body weight, height), concomitant diseases (asthma), concomitant medications (topical corticosteroids), or baseline laboratory parameters (creatinine, hemoglobin, peripheral leukocyte count) and sinus fluid penetration as reflected in the sinus fluid AU&, ,, Only pretherapy peripheral leukocyte count appeared to have a statistically significant association (P c 0.01; r = 3.26; 18 G!! with loracarbef sinus flmd penetration as estimated by AUC,,s h For every lOOO-cell/mm3 increase in peripheral leukocyte count, the AUC,,, ,, increased a mean of 0.87 pg * hhL (95% confidence interval, 0.31 to 1.43 pg/mL). Figure 2 displays a plot of pretherapy peripheral leukocyte count and sinus fluid loracarbef AUC,,s h for all 20 patients.

pg/mL at 2.5 hours after dose. The mean serum concentration before the third dose (approximately 12 hours after the second dose) was 0.02 -c 0.07 pg/mL. The mean serum concentration before the fifth dose (approximately 12 hours after the fourth dose) was 0.01 f 0.05 pg/mL. Taking the highest serum concentration measured in each patient, the mean peak serum concentration was 14.47 f 4.68 p,g/mL (range, 5.9 to 24.0 kg/mL).

Serum Concentrations

DISCUSSION

Table II lists all serum concentrations obtained at the various time intervals after the first loracarbef dose. Five samples from two patients were not obtained. Eight samples from six patients were obtained at inappropriate times (more than 10 minutes after dosing instead of before the dose, or more than 6 hours before the dose in one patient). Excluding missing data or inappropriately timed samples, the mean serum concentrations were 0.0 It 0.0 p,g/mL at baseline, 3.50 f 4.55 pg/mL at 0.5 hour, 11.41 + 5.80 l&nL at 1 hour, 10.63 f 5.13 l.~g/mL at 1.5 hours, 7.90 f 2.94 @mL at 2 hours, and 5.36 f 2.35

Three conclusions are suggested by the data: (1) mean peak loracarbef concentrations in sinus fluid usually exceed the MIC to inhibit 90% (MIC,) of common sinus pathogens; (2) loracarbef concentrations are likely to exceed the MIC,, of common sinus pathogens throughout much of the 1Zhour interval between doses; and (3) the degree of inflammation, as reflected by the peripheral leukocyte count, may play a role in the penetration of loracarbef into sinus fluid. Several studies have explored the in vitro activity of loracarbef. Based on an analysis of these studies in one review,”

278

During the study, four patients experienced adverse events of mild severity including diarrhea, nausea, and abdominal pain (for which one patient withdrew from the study). All adverse events resolved during the study and follow-up period. No adverse events related to the lavage catheter were recorded. Although occasional laboratory abnormalities were noted before therapy, follow-up laboratory studies were not deemed necessary during the study.

0.23 0.19 0.30 0.00 0.30 0.50 0.20 0.20 0.00 0.00 0.40 0.20 0.20 0.20 0.10 0.30 0.50 0.00 NA 0.50 0.23 it 0.17 19 0 0.5

0.5

0.22 0.20 1.84 0.00 0.28 0.90 0.20 0.30 2.10 0.00 2.50 0.20 0.20 0.20 0.00 3.90 5.10 2.10 0.10 1.80 1.11 f 1.44 20 0 5.1

1 0.22 0.67 3.98 0.00 0.31 0.70 0.20 3.00 0.30 0.80 2.10 0.20 0.30 0.30 0.20 4.90 6.70 4.50 NA NA 1.63 i 2.07 18 0 6.7

1.5

2 0.19 1.18 5.86 0.00 0.25 0.50 0.20 2.10 NA 0.40 1.80 0.20 0.30 0.30 0.10 4.80 5.60 3.00 2.05 NA 1.60 f 1.96 18 0 5.86

2.5

0.80 0.20 1.60 0.50 0.00 1.90 2.80 0.50 1.75 1.90 1.01 * 0.89 19 0 2.8

0.18 0.35 2.41 0.00 0.27 0.60 0.20 1.50 1.80 -

24 Maximum 0.23 1.18 5.86 0.00 0.31 2.40 0.30 3.00 2.10 1.70 2.50 0.20 1.60 0.70 0.20 4.90 6.70 4.50 2.05 1.90 2.12 f 1.98 20 0 6.7

48 0.19 0.90 1.91 0.26 0.20 0.20 1.60 1.50 0.30 0.70 0.10 2.10 3.10 0.40 0.60 0.00 0.88 f 0.90 16 0 3.1

every 12 hours.

h

1.21 7.44 0.00 0.74 2.50 0.55 3.58 1.20 1.35 4.25 0.50 0.63 0.58 0.28 8.25 10.40 5.90 0.65 1.20 2.59 f 3.07 20 0 10.4

0.53

AUC,.,

= sample obtained at inappropriate time; NA = not available; N = number of obser-

0.21 0.69 5.71 0.00 0.31 2.40 0.30 2.50 NA 1.70 2.50 0.20 0.30 0.20 0.20 4.90 5.60 3.70 0.13 NA 1.75 f 2.01 18 0 5.71

to 2.5 hours; vations, at the time period, used to calculate the mean f SD. *Average of right and left maxillary sinus fluid concentrations.

0.18 0.15 0.25 0.00 0.31 0.50 0.20 0.20 0.00 0.00 0.20 0.20 0.20 0.20 0.00 0.20 0.20 0.00 0.10 0.20 0.16 f 0.12 20 0 0.5

0

in sinus aspirates after 400-mg oral doses administered

Sampling Time (hours after first dose)

(p,g/mL) of loracarbef

AUC&,.,h = area under the concentration-time curve at 0

101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 201 202 203 301’ 501 Mean i SD N Minimum Maximum

Patient

Table I. Concentrations

n

8

2

g

CLINICAL THERAPEUTICS”

4

6

8

10

12

Leukocyte Count (xl 000) Figure 2. Relationship between pretherapy peripheral leukocyte count and calculated nus fluid area under the ~oncen~ation-time curve at 0 to 2.5 hours (AUC,,,,

the modal MIC,, of loracarbef is 1 PglmL for Streptococcus pneumoniae, 1 pg/rnL for beta-lactamase-positive strains of Moraxella catarrhalis, 0.25 pg/mL for beta-lactamase-negative strains of M caturrhalis, 1 pg/mL for beta-lactamasenegative strains of Haemophilus injluenzae, and 0.12 pg/mL for Streptococcus ~yoge~e~. Furthermore, in combination with phagocytic cells, loracarbef may have antimicrobial activity at concentrations lower than the MIC.‘* Taking the highest sinus fluid concentration from each patient, the mean peak loracarbef concentration after the first loracarbef dose was 2.12 f 1.98 p,g/mL. Therefore, it is probable that the mean peak sinus fluid concentration of loracarbef after a

280

si,,).

single 400-mg dose will exceed the MIC, for pathogens most commonly implicated as causes of acute maxillary sinusitis. The mean peak sinus fluid concentration noted in this study is somewhat higher than the mean loracarbef concentration of 1,l pg/mL noted by Stenquist et aL9 who sampled sinus fluid between 2 and 3 hours after a single 400-mg loracarbef dose. The difference between the results in that study and the current one may be related to the timing of sinus fluid sampling. Sinus fluid concentrations noted in this study are similar to middle-ear fluid concentrations after administration of loracarbef to children. Kusmiesz et ali3 noted that middleear fluid obtained 60 to 165 minutes after oral administration of loracarbef 15 mglkg

g e

-=

0

13.50 12.60 17.40 6.59 21.50 6.00 9.50 6.90 17.00 3.90 21.00 1.20 8.00 2.10 15.00 13.00 14.00 11.00 13.00 15.00 11.41 2 5.80 20 1.2 21.50

1

4.83 13.20 12.60 9.40 7.07 6.80 5.40 8.60 NA 14.00 7.20 5.90 7.50 11.00 6.10 5.00 6.00 5.30 6.30 NA 7.90 zt 2.94 18 4.83 14.00

2

N = number of observations,

8.40 24.00 13.60 9.60 14.10 21.00 7.20 11.00 12.00 5.60 12.00 4.20 10.00 3.50 12.00 7.00 7.40 9.30 10.00 NA 10.63 + 5.13 19 3.5 24.00

1.5 2.5

0.00 0.00 0.00 0.00 -

0.00

0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.02 * 0.07 18 0 0.21

13.50 24.00 17.40 9.60 21.50 21.00 9.50 11.00 17.00 14.00 21.00 5.90 10.00 12.00 15.00 14.00 14.00 11.00 13.00 15.00 14.47f 4.68 20 5.9 24.00

Maximum

the mean + SD.

0.20 0.00 0.00 0.00 0.00 0.00 0.01 f 0.05 15 0 0.20

0.00

-

-

0.00 -

0.00

0.00

0.00

0.00

0.21 0.00 0.00 0.00 0.20 0.00 -

48

24

every 12 hours.

at the time period, used to calculate

3.55 7.50 8.00 7.02 5.45 4.50 4.10 5.40 NA 5.90 5.60 4.60 5.70 12.00 4.10 3.20 4.40 0.70 4.80 NA 5.36 + 2.35 18 0.7 12.00

Sampling Time (hours after first dose)

of loracarbef in serum after 400-mg oral doses administered

time; NA = not available;

6.67 0.30 7.58 0.42 2.9 1 0.00 3.90 1.70 0.80 0.00 4.40 0.00 1.40 0.30 0.20 14.00 11.00 0.20 13.00 1.30 3.50 + 4.55 20 0 14.00

0.5

(kg/mL)

sample obtained at inappropriate

101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 201 202 203 301 501 Mean f SD N Minimum Maximum

Patient

Table II. Concentrations

P

2

2

?

2 g

F

CLINICAL THERAPEUTICS”

contained an average loracarbef concentration of 3.9 + 2.6 pg/mL (42% of the concentration in serum). This concentration exceeded the MIC,, for strains of the usual pathogens in 16 of 17 specimens. Lepage et all4 noted mean maximum skin blister fluid concentrations of 4.3 p,g/mL a mean of 1.1 hours after the seventh dose of loracarbef 200 mg administered every 12 hours. Lees et all5 noted mean skin blister exudate maximum concentrations of 8.9 f 4.0 p,g/mL 2 hours after administration of a single 400-mg loracarbef dose. The highest interstitial fluid concentration achieved with loracarbef may be related to the high serum concentrations, low serum protein binding of 25%, or marked chemical stability.16 The mean peak loracarbef sinus fluid concentration noted in the present study is higher than that noted for other betalactam agents. Cherrier et all7 found the mean sinus fluid cefotiam concentration to be 1.04 f 0.60 FglrnL 2 hours after the second of two 200-mg cefotiam hexetil doses administered 12 hours apart. After administration of single doses of 400-mg bacampicillin to 25 patients with acute maxillary sinusitis, Sorri et alI8 noted the highest peak sinus fluid bacampicillin concentration to be 0.60 p,g/mL. Among the 22 samples obtained at various times after the dose, 13 sinus fluids contained undetectable concentrations of bacampicillin. In this same study, another cohort of 23 patients received single 1200-mg doses of bacampicillin, with the highest peak sinus fluid concentrations reaching 2 pg/mL; however, the majority of fluid samples contained
282

times daily. Sudderick et al*O noted median sinus tissue concentrations of 1.2 kg/g in biopsy samples obtained up to 4.5 hours after a single dose of cefuroxime axetil in 19 patients with chronic sinusitis. Because several studies*‘,** suggest that sinus mucosal concentrations are generally higher than simultaneously obtained sinus fluid concentrations, it is possible that cefuroxime axetil concentrations in sinus fluid may be lower than concentrations noted in sinus tissue. Several studies10*23 have suggested that the efficacy of beta-lactam antibiotics is associated more closely with the time during which concentrations exceed the MIC than with the absolute peak concentration. Loracarbef sinus fluid concentrations, obtained at 24 and 48 hours, averaged 1.01 + 0.89 pg/mL and 0.88 + 0.90 p,g/mL, respectively. These sampling times were also approximately 12 hours after the second and fourth doses, respectively. The small decrease in mean sinus fluid concentrations between 2 hours and 12 hours suggests that the loracarbef half-life within the sinus fluid may be approximately 8 to 10 hours. This persistence of loracarbef in sinus fluid may be due to slow clearance of purulent fluid from an infected paranasal sinus, as well as the notable stability of loracarbef to chemical degradation. These data suggest that a 12hour dosing schedule may provide sinus fluid concentrations that exceed the MIC of common organisms for most of the interdose interval. In six patients (30%), sinus fluid loracarbef levels remained below 0.5 p,g/mL at all times measured. Because no sinus fluid samples were taken between 2.5 and 24 hours, a delayed peak concentration occurring between 2.5 and 12 hours postdose may have been missed. This possi-

M. STENQUIST

ET AL.

bility is suggested as an explanation for the sinus fluid concentrations noted in one patient, which reached 2.05 pg/mL only at the 25hour point. Of the demographic, disease, therapeutic, or laboratory parameters studied, only pretherapy blood leukocyte count appeared to be positively correlated with loracarbef sinus fluid penetration, as estimated by the sinus fluid AUC,,,, s. Although all patients had leukocyte counts within the normal range, it is possible that patients with higher leukocyte counts had greater local sinus inflammation. If this is true, the apparent association between higher leukocyte counts and higher sinus fluid loracarbef concentrations may be due to increased penetration of loracarbef into inflamed sinuses.

CONCLUSIONS Among most patients with acute maxillary sinusitis, oral administration of loracarbef 400 mg every 12 hours appears to provide sinus fluid concentrations greater than the MIC of common sinusitis pathogens for most of the interdose interval. Mean peak sinus fluid concentrations exceed those reported for many other beta-lactam agents, including penicillin V, bacampicillin, cefuroxime axetil (tissue concentrations), and cefotiam. The degree of loracarbef penetration into the sinus may be related to the degree of sinus inflammation.

Address correspondence to: Michael L. Zeckel, MD, Infectious Disease Research, Drop Code 2133, Lilly Corporate Center, Indianapolis, IN 46285.

REFERENCES 1. Wald ER. Epidemiology, pathophysiology and etiology of sinusitis. Pediatr lnfecf Dis J. 1985;4:S51-S54. 2. National Center for Health Statistics. Current estimates from the National Health Interview Survey, United States, 1986. Vital and Health Statistics Series 10, No. 164. Washington, DC: US Government Printing Office; 1987. 3. Department of Health and Social Security. Digest of Health Statistics. London: HMSO; 1971. 4. Nielsen RW. Acute bacterial maxillary sinusitis: Results of U.S. and European comparative therapy trials. Am J Med. 1992;92(Suppl 6A):70S-73s. 5. Sydnor TA Jr, Scheld WM, Gwaltney J Jr, et al. Loracarbef (LY 163892) vs amoxicillinklavulanate in bacterial maxillary sinusitis. Ear Nose Throat J. 1992;71: 225-232. 6. Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: A fifteenyear experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol. 1992;90(3 Pt 2):457461.

ACKNOWLEDGMENT This study was supported by grants from Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.

I. Scandinavian Study Group. Loracarbef versus doxycycline in the treatment of acute bacterial maxillary sinusitis. J Antimicrob Chemothe,: 1993;31:949-961.

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8. DeSante

KA, Zeckel ML. Pharmacokinetic profile of loracarbef. Am J Med. 1992;92(Suppl 6A): 16S-19s.

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