CLINICAL PHARMACOLOGY
Loracarbef, after oral administration, was approximately 90% absorbed from the gastrointestinal tract. When capsules were taken with food, peak plasma concentrations were 50% to 60% of those achieved when the drug was administered to fasting subjects and occurred from 30 to 60 minutes later. Total absorption, as measured by urinary recovery and area under the plasma concentration versus time curve (AUC), was unchanged. The effect of food on the rate and extent of absorption of the suspension formulation has not been studied to date.
The pharmacokinetics of loracarbef were linear over the recommended dosage range of 200 to 400 mg, with no accumulation of the drug noted when it was given twice daily.
Average peak plasma concentrations after administration of 200-mg or 400-mg single doses of loracarbef as capsules to fasting subjects were approximately 8 and 14 μg/mL, respectively, and were obtained within 1.2 hours after dosing. The average peak plasma concentration in adults following a 400-mg single dose of suspension was 17 μg/mL and was obtained within 0.8 hour after dosing (see Table).
| Mean Plasma Loracarbef |
| Concentrations (μg/mL) |
| Dosage | Peak | Time to Peak |
| (mg) | Cmax | Tmax |
| Capsule (single dose) | | |
| 200 mg | 8 | 1.2 h |
| 400 mg | 14 | 1.2 h |
| Suspension (single dose) | | |
| 400 mg (adult) | 17 | 0.8 h |
| 7.5 mg/kg (pediatric) | 13 | 0.8 h |
| 15 mg/kg (pediatric) | 19 | 0.8 h |
Following administration of 7.5 and 15 mg/kg single doses of oral suspension to children, average peak plasma concentrations were 13 and 19 μg/mL, respectively, and were obtained within 40 to 60 minutes.
This increased rate of absorption (suspension > capsule) should be taken into consideration if the oral suspension is to be substituted for the capsule, and capsules should not be substituted for the oral suspension in the treatment of otitis media (see DOSAGE AND ADMINISTRATION).
The elimination half-life was an average of 1.0 h in patients with normal renal function. Concomitant administration of probenecid decreased the rate of urinary excretion and increased the half-life to 1.5 hours.
In subjects with moderate impairment of renal function (creatinine clearance 10 to 50 mL/min/1.73 m2), following a single 400-mg dose, the plasma half-life was prolonged to approximately 5.6 hours. In subjects with severe renal impairment (creatinine clearance<10 mL/min/1.73 m2), the half-life was increased to approximately 32 hours. During hemodialysis the half-life was approximately 4 hours. In patients with severe renal impairment, the Cmax increased from 15.4 μg/mL to 23 μg/mL (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
In single-dose studies, plasma half-life and AUC were not significantly altered in healthy elderly subjects with normal renal function.
There is no evidence of metabolism of loracarbef in humans.
Approximately 25% of circulating loracarbef is bound to plasma proteins.
Middle-ear fluid concentrations of loracarbef were approximately 48% of the plasma concentration 2 hours after drug administration in pediatric patients. The peak concentration of loracarbef in blister fluid was approximately half that obtained in plasma. Adequate data on CSF levels of loracarbef are not available.
Microbiology —Loracarbef exerts its bactericidal action by binding to essential target proteins of the bacterial cell wall, leading to inhibition of cell-wall synthesis. It is stable in the presence of some bacterial β-lactamases. Loracarbef has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE):
Gram-positive aerobes:
Staphylococcus aureus (including penicillinase-producing strains)
NOTE: Loracarbef (like most β-lactam antimicrobials) is inactive against methicillin-resistant staphylococci.
Staphylococcus saprophyticus
Streptococcus pneumoniae
Streptococcus pyogenes
Gram-negative aerobes:
Escherichia coli
Haemophilus influenzae ( including β-lactamase-producing strains)
Moraxella (Branhamella) catarrhalis (including β-lactamase producing strains)
The following in vitro data are available; however, their clinical significance is unknown.
Loracarbef exhibits in vitro minimum inhibitory concentrations (MIC) of 8 μg/mL or less against most strains of the following organisms; however, the safety and efficacy of loracarbef in treating clinical infections due to these organisms have not been established in adequate and well-controlled trials.
Gram-positive aerobes:
Staphylococcus epidermidis
Streptococcus agalactiae (group B streptococci)
Streptococcus bovis
Streptococci, groups C, F, and G viridans group streptococci
Gram-negative aerobes:
Citrobacter diversus
Haemophilus parainfluenzae
Klebsiella pneumoniae
Neisseria gonorrhoeae (including penicillinase-producing strains)
Pasteurella multocida
Proteus mirabilis
Salmonella species
Shigella species
Yersinia enterocolitica
NOTE: Loracarbef is inactive against most strains of Acinetobacter , Enterobacter, Morganella morganii , Proteus vulgaris , Providencia, Pseudomonas , and Serratia.
Anaerobic organisms:
Clostridium perfringens
Fusobacterium necrophorum
Peptococcus niger
Peptostreptococcus intermedius
Propionibacterium acnes
Susceptibility Testing
Diffusion Techniques —Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standardized method1 has been recommended for use with the 30-μg loracarbef disk. Interpretation involves the correlation of the diameter obtained in the disk test with MIC for loracarbef. Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30-μg loracarbef disk should be interpreted according to the following criteria:
| Zone Diameter (mm) | Interpretation |
| ≥18 | (S) Susceptible |
| 15–17 | (MS) Moderately Susceptible |
| ≤14 | (R) Resistant |
A report of “susceptible” implies that the pathogen is likely to be inhibited by generally achievable blood concentrations. A report of “moderately susceptible” indicates that inhibitory concentrations of the antibiotic may be achieved if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic concentrations are attained. A report of “resistant” indicates that achievable concentrations of the antibiotic are unlikely to be inhibitory and other therapy should be selected.
Standardized procedures require the use of laboratory control organisms. The 30-μg loracarbef disk should give the following zone diameters with the NCCLS approved procedure:
| Organism | Zone Diameter (mm) |
| E. coli ATCC25922 | 23–29 |
| S. aureus ATCC 25923 | 23–31 |
Dilution Techniques—Use a standardized dilution method2 (broth, agar, or microdilution) or equivalent with loracarbef powder. The MIC values obtained should be interpreted according to the following criteria:
| MIC (μg/mL) | Interpretation |
| ≤8 | (S) Susceptible |
| 16 | (MS) Moderately Susceptible |
| ≥32 | (R) Resistant |
As with standard diffusion methods, dilution procedures require the use of laboratory control organisms. Standard loracarbef powder should give the following MIC values with the NCCLS approved procedure:
| Organism | MIC Range (μg/mL) |
| E. coli ATCC 25922 | 0.5–2 |
| S. aureus ATCC 29213 | 0.5–2 |
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