CARBENICILLIN
DESCRIPTION:
CARBELIN, a semisynthetic penicillin,The chemical name is:
1-(5-Indanyl)-N-(2-carboxy-3,3-dimethyl-7-oxo- 4-thia-1-azabicyclo(3.2.0)hept-
6-yl)-2-phenylmalonamate monosodium salt.
The empirical formula is: C26H25N2NaO6S and mol. wt. is 516.55.
ACTIONS/CLINICAL PHARMACOLOGY:
Free carbenicillin is the predominant pharmacologically active fraction of
CARBELIN. Carbenicillin exerts its antibacterial activity by interference with
final cell wall synthesis of susceptible bacteria.
CARBELIN is acid stable, and rapidly absorbed from the small intestine
following oral administration. It provides relatively low plasma concentrations
of antibiotic and is primarily excreted in the urine. After absorption,
CARBELIN is rapidly converted to carbenicillin by hydrolysis of the ester
linkage. Following ingestion of a single 500 mg tablet of CARBELIN, a peak
carbenicillin plasma concentration of approximately 6.5 mcg/ml is reached in 1
hour. About 30% of this dose is excreted in the urine unchanged within 12 hours,
with another 6% excreted over the next 12 hours.
In a multiple dose study utilizing volunteers with normal renal function, the
following mean urine and serum levels of carbenicillin were achieved:
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Mean Urine Concentration of
Carbenicillin mcg/ml
Hours After Initial Dose
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DRUG DOSE 0-3 3-6 6-24
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CARBELIN 1 tablet q.6 hr 1130 352 292
CARBELIN 2 tablets q.6 hr 1428 789 809
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Mean serum concentrations of carbenicillin in this study
for these dosages are:
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Mean Serum Concentration mcg/ml
Hours After Initial Dose
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DRUG DOSE 1/2 1 2 4 6 24 25 26 28
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CARBELIN 1 tablet q.6 hr 5.1 6.5 3.2 1.9 0.0 0.4 8.8 5.4 0.4
CARBELIN 2 tablets q.6 hr 6.1 9.6 7.9 2.6 0.4 0.8 13.2 12.8 3.8
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MICROBIOLOGY
The antibacterial activity of CARBELIN is due to its rapid conversion to
carbenicillin by hydrolysis after absorption. Though CARBELIN provides
substantial In Vitro activity against a variety of both gram-positive and gram-
negative microorganisms, the most important aspect of its profile is in its
antipseudomonal and antiproteal activity. Because of the high urine levels
obtained following administration, CARBELIN has demonstrated clinical efficacy
in urinary infections due to susceptible strains of:
Escherichia Coli
Proteus Mirabilis
Proteus Vulgaris
Morganella Morganii (formerly Proteus Morganii)
Pseudomonas species
Providencia Rettgeri (formerly Proteus Rettgeri)
Enterobacter species
Enterococci (S. Faecalis)
In addition, In Vitro data, not substantiated by clinical studies, indicate the
following pathogens to be usually susceptible to CARBELIN:
Staphylococcus species (nonpenicillinase producing)
Streptococcus species
RESISTANCE
Most Klebsiella species are usually resistant to the action of CARBELIN. Some
strains of Pseudomonas species have developed resistance to carbenicillin.
SUSCEPTIBILITY TESTING
Geopen (carbenicillin disodium) Susceptibility Powder or 100 mcgm Geopen
Susceptibility Discs may be used to determine microbial susceptibility to
CARBELIN using one of the following standard methods recommended by the
National Committee for Clinical Laboratory Standards:
M2-A3, "Performance Standards for Antimicrobial Disk Susceptibility Tests"
M7-A, "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that
Grow Aerobically"
M11-A, "Reference Agar Dilution Procedure for Antimicrobial Susceptibility
Testing of Anaerobic Bacteria"
M17-P, "Alternative Methods for Antimicrobial Susceptibility Testing of
Anaerobic Bacteria"
Tests should be interpreted by the following criteria:
Disk Diffusion
Zone diameter (mm)
Organisms Suscept. Intermed. Resist.
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Enterobacter >/= 23 18-22 = 17
Pseudomonas sp. >/= 17 14-16 = 13
Dilution
MIC (mcgm/ml)
Moderately
Organisms Suscept. Suscept. Resist.
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Enterobacter = 16 32 >/= 64
Pseudomonas sp. = 128 -- >/= 156
Interpretations of susceptible, intermediate, and resistant correlate zone size
diameters with MIC values. A laboratory report of "susceptible" indicates that
the suspected causative microorganism most likely will respond to therapy with
carbenicillin. A laboratory report of "resistant" indicates that the infecting
microorganism most likely will not respond to therapy. A laboratory report of
"moderately susceptible" indicates that the microorganism is most likely
susceptible if a high dosage of carbenicillin is used, or if the infection is
such that high levels of carbenicillin may be attained as in urine. A report of
"intermediate" using the disk diffusion method may be considered an equivocal
result, and dilution tests may be indicated.
INDICATIONS AND USAGE:
CARBELIN (carbenicillin indanyl sodium) is indicated in the treatment of acute
and chronic infections of the upper and lower urinary tract and in asymptomatic
bacteriuria due to susceptible strains of the following organisms:
Escherichia Coli
Proteus Mirabilis
Morganella Morganii
(formerly Proteus Morganii)
Providencia Rettgeri
(formerly Proteus Rettgeri)
Proteus Vulgaris
Pseudomonas
Enterobacter
Enterococci
CARBELIN is also indicated in the treatment of prostatitis due to susceptible
strains of the following organisms:
Escherichia Coli
Enterococcus (S. Faecalis)
Proteus Mirabilis
Enterobacter sp.
WHEN HIGH AND RAPID BLOOD AND URINE LEVELS OF ANTIBIOTIC ARE INDICATED, THERAPY
WITH GEOPEN (CARBENICILLIN DISODIUM) SHOULD BE INITIATED BY PARENTERAL
ADMINISTRATION FOLLOWED, AT THE PHYSICIAN'S DISCRETION, BY ORAL THERAPY.
NOTE: Susceptibility testing should be performed prior to and during the course
of therapy to detect the possible emergence of resistant organisms which may
develop.
CONTRAINDICATIONS:
CARBELIN is ordinarily contraindicated in patients who have a known penicillin
allergy.
WARNINGS:
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have
been reported in patients on oral penicillin therapy. Although anaphylaxis is
more frequent following parenteral therapy, it has occurred in patients on oral
penicillins. These reactions are more apt to occur in individuals with a history
of penicillin hypersensitivity and/or a history of sensitivity to multiple
allergens.
There have been reports of individuals with a history of penicillin
hypersensitivity who have experienced severe hypersensitivity reactions when
treated with a cephalosporin, and vice versa. Before initiating therapy with a
penicillin, careful inquiry should be made concerning previous hypersensitivity
reactions to penicillins, cephalosporins, or other allergens. If an allergic
reaction occurs, the drug should be discontinued and the appropriate therapy
instituted.
SERIOUS ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH
EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING
INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
PRECAUTIONS:
GENERAL: As with any penicillin preparation, an allergic response, including
anaphylaxis, may occur particularly in a hypersensitive individual.
Long term use of CARBELIN may result in the overgrowth of nonsusceptible
organisms. If superinfection occurs during therapy, appropriate measures should
be taken.
Since carbenicillin is primarily excreted by the kidney, patients with severe
renal impairment (creatinine clearance of less than 10 ml/min) will not achieve
therapeutic urine levels of carbenicillin.
In patients with creatinine clearance of 10-20 ml/min it may be necessary to
adjust dosage to prevent accumulation of drug.
LABORATORY TESTS: As with other penicillins, periodic assessment of organ system
function including renal, hepatic, and hematopoietic systems is recommended
during prolonged therapy.
DRUG INTERACTIONS: CARBELIN (carbenicillin indanyl sodium) blood levels may be
increased and prolonged by concurrent administration of probenecid.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: There are no long-term
animal or human studies to evaluate carcinogenic potential. Rats fed 250-1000
mg/kg/day for 18 months developed mild liver pathology (e.g., bile duct
hyperplasia) at all dose levels, but there was no evidence of drug-related
neoplasia. CARBELIN administered at daily doses ranging to 1000 mg/kg had no
apparent effect on the fertility or reproductive performance of rats.
PREGNANCY CATEGORY B: Reproduction studies have been performed at dose levels of
1000 or 500 mg/kg in rats, 200 mg/kg in mice, and at 500 mg/kg in monkeys with
no harm to fetus due to CARBELIN. There are, however, no adequate and well
controlled studies in pregnant women. Because animal reproduction studies are
not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
LABOR AND DELIVERY: It is not known whether the use of CARBELIN in humans
during labor or delivery has immediate or delayed adverse effects on the fetus,
prolongs the duration of labor, or increases the likelihood that forceps
delivery or other obstetrical intervention or resuscitation of the newborn will
be necessary.
NURSING MOTHERS: Carbenicillin class antibiotics are excreted in milk although
the amounts excreted are unknown; therefore, caution should be exercised if
administered to a nursing woman.
PEDIATRIC USE: Since only limited clinical data is available to date in
children, the safety of CARBELIN administration in this age group has not yet
been established.
DRUG INTERACTIONS:
CARBELIN (carbenicillin indanyl sodium) blood levels may be increased and
prolonged by concurrent administration of probenecid.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse reactions have been reported as possibly related to
CARBELIN administration in controlled studies which include 344 patients
receiving CARBELIN.
GASTROINTESTINAL: The most frequent adverse reactions associated with CARBELIN
therapy are related to the gastrointestinal tract. Nausea, bad taste, diarrhea,
vomiting, flatulence, and glossitis were reported. Abdominal cramps, dry mouth,
furry tongue, rectal bleeding, anorexia, and unspecified epigastric distress
were rarely reported.
DERMATOLOGIC: Hypersensitivity reactions such as skin rash, urticaria, and less
frequently pruritus.
HEMATOLOGIC: As with other penicillins, anemia, thrombocytopenia, leukopenia,
neutropenia, and eosinophilia have infrequently been observed. The clinical
significance of these abnormalities is not known.
MISCELLANEOUS: Other reactions rarely reported were hyperthermia, headache,
itchy eyes, vaginitis, and loose stools.
ABNORMALITIES OF HEPATIC FUNCTION TESTS: Mild SGOT elevations have been observed
following CARBELIN administration.
OVERDOSAGE:
CARBELIN is generally nontoxic. CARBELIN when taken in excessive amounts may
produce mild gastrointestinal irritation. The drug is rapidly excreted in the
urine and symptoms are transitory. The usual symptoms of anaphylaxis may occur
in hypersensitive individuals.
Carbenicillin blood levels achievable with CARBELIN are very low, and toxic
reactions as a function of overdosage should not occur systematically. The oral
LD50 in mice is 3,600 mg/kg, in rats 2,000 mg/kg, and in dogs is in excess of
500 mg/kg. The lethal human dose is not known.
Although never reported, the possibility of accumulation of indanyl should be
considered when large amounts of CARBELIN are ingested. Free indole, which is a
phenol derivative, may be potentially toxic. In general 8-15 grams of phenol,
and presumably a similar amount of indole, are required orally before toxicity
(peripheral vascular collapse) may occur. The metabolic by-products of indole
are nontoxic. In patients with hepatic failure it may be possible for
unmetabolized indole to accumulate.
The metabolic by-products of CARBELIN, indanyl sulfate and glucuronide, as well
as free carbenicillin, are dialyzable.
DOSAGE AND ADMINISTRATION:
CARBELIN is available as a coated tablet to be administered orally.
USUAL ADULT DOSE
URINARY TRACT INFECTIONS
Escherichia Coli, Proteus 1-2 tablets
species, and Enterobacter 4 times
daily
Pseudomonas and Enterococcus 2 tablets
4 times
daily
PROSTATITIS
Escherichia Coli, Proteus 2 tablets
Mirabilis, Enterobacter and 4 times
Enterococcus daily
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