Effectiveness of gentamicin and carbenicillin in a rat model against infections with Pseudomonas aeruginosa resistant to gentamicin or gentamicin and carbenicillin.
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Animals↗
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[Letter: Treatment of infections in acute leukemia with therapeutic aplasia. Efficacy of the antibiotic combinations gentamicin-carbenicillin or colistin-carbenicillin after failure of other combinations].
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Carbenicillin↗
In vitro activity of gentamicin, amikacin and netilmicin alone and in combination with carbenicillin against Serratia marcescens.
The inhibitory and bactericidal effects of gentamicin, amikacin, netilmicin (Sch 20569), and carbenicillin were tested against 55 clinical isolates of Serratia marcescens that had been subtyped into 26 strains by biotyping and serotyping. Three major patterns of resistance to gentamicin, netilmicin, and carbenicillin were recognized among these isolates. (i) Most of the 27 isolates that were susceptible to gentamicin (minimal bactericidal concentration [MBC] </=6.25 mug/ml) were susceptible to carbenicillin (MBC </=125 mug/ml) and resistant to netilmicin (MBC >/=12.5 mug/ml). (ii) Most of the 11 isolates with moderate resistance to gentamicin (MBC of 12.5 to 25 mug/ml) were also susceptible to carbenicillin and resistant to netilmicin. (iii) The 17 isolates with high-level resistance to gentamicin (MBC >/= 50 mug/ml) were all highly resistant to carbenicillin (MBC >/=8,000 mug/ml) but susceptible to netilmicin (MBC </=6.25 mug/ml). The susceptibility to amikacin was unpredictable among these groups of isolates but, overall, 80% of the isolates were killed by 25 mug of amikacin/ml, which is within the range of peak serum concentrations used therapeutically. Clinically attainable subinhibitory concentrations of carbenicillin enhanced the activity of the three aminoglycosides against all isolates with MBCs of carbenicillin </=2,000 mug/ml. The 17 isolates with high-level resistance to carbenicillin and gentamicin, as well as the four isolates with high-level resistance to carbenicillin but not to gentamicin, were not susceptible to such enhancement of aminoglycoside activity by carbenicillin.
Amikacin↗
Emergence of gentamicin- and carbenicillin-resistant Pseudomonas aeruginosa in a hospital environment.
Strains of Pseudomonas aeruginosa resistant to either gentamicin or carbenicillin have been noted since their introduction into clinical use. During a 6-month period, twice-weekly cultures were obtained from all patients treated with either gentamicin or carbenicillin and from all patients with a positive culture for P. aeruginosa. Susceptibility testing to gentamicin and carbenicillin and pyocine typing were performed on all isolates. Organisms with a minimal inhibitory concentration greater than 12.5 mug of gentamicin per ml or greater than 100 mug of carbenicillin per ml were defined as resistant. P. aeruginosa was cultured from 238 patients. One patient was initially infected with a gentamicin-resistant isolate. In 11 other patients, serial cultures revealed the emergence of resistance to gentamicin. All but one of these resistant isolates occurred in patients treated with gentamicin. In eight instances the pyocine and/or serological types before and after the change in sensitivity pattern were the same. Gentamicin-resistant P. aeruginosa emerged significantly more often in patients treated with gentamicin than in those who did not receive gentamicin. Carbenicillin-resistant P. aeruginosa emerged in four of 14 patients treated with carbenicillin. Seventeen of the 238 patients were infected de novo with carbenicillin-resistant P. aeruginosa. Carbenicillin-resistant P. aeruginosa emerged significantly more often in patients treated with carbenicillin than in those who did not receive carbenicillin. No evidence was found for in-hospital spread of resistant P. aeruginosa.
Adult↗
Carbenicillin prodrugs: stability kinetics of alpha-phenyl and alpha-indanyl esters in aqueous solution.
Both ester and beta-lactam degradations of alpha-esters of carbenicillin disodium, carbenicillin indanyl sodium, and carbenicillin phenyl sodium in aqueous solution at 35 degrees and at 0.5 ionic strength were investigated. The reactions were followed by spectrophotometric assay, reversed-phase high-pressure liquid chromatography, and colorimetric assay. The degradation pathways were established, and the rate-pH profiles for ester and beta-lactam cleavage reactions are given for pH 1-11. Below pH 3, the beta-lactam degradation of the prodrugs proceeded exclusively. Above pH 7, the degradation was superseded by the ester hydrolysis to carbenicillin, beta-Lactams of both prodrugs are around three times more stable than carbenicillin disodium at pH 1, six times at PH 2, and 17 times at pH 3. The half-lives for carbenicillin production were predicted to be 17 hr for carbenicillin indanyl sodium and 8.5 hr for carbenicillin phenyl sodium at pH 7.0 and 37 degrees.
Carbenicillin↗
Ticarcillin vs carbenicillin: clinical pharmacokinetics.
The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were compared to those of carbenicillin in 12 healthy volunteers. Following an intravenous infusion of 2 gm in 5 min, there was a lower average serum level for ticarcillin (218 mug/ml) than for carbenicillin (301 mug/ml), but after 2 hr the differences were not significant. The biologic half-life of ticarcillin was slightly longer than that of carbenicillin (72 and 65 min, P smaller than 0.01) and its volume of distribution was larger (15.7 and 12.3 l, P smaller than 0.01). Eighty-six per cent of the dose of ticarcillin and 99 percent of the dose of carbenicillin was recovered in the urine in 24 hr. Similar but much less marked blood level differences were noted with 2 gm, 30-min infusions. An intravenous infusion of 1 gm/hr gave average steady-state blood levels of about 124 mug/ml for both antibiotics. Probenecid, administered 1 hr before the infusion, caused significant and similar increases in blood levels, half-lives, and volumes of distribution of the 2 antibiotics. Protein binding in 100 percent human serum was 50 percent and 65 percent for carbenicillin and ticarcillin, respectively. These relatively small but definite differences in the pharmacokinetics of ticarcillin and carbenicillin are not likely to be of clinical significance.
Carbenicillin↗
Carbenicillin for treatment of Bacteroides fragilis infections: why not penicillin G?
Carbenicillin has been advocated for treatment of infections caused by Bacteroides fragilis and other anaerobic bacteria. Wide-scale use of the drug in this setting could result in a substantial increase in carbenicillin-resistant Pseudomonas aeruginosa, an effect that would have serious implications. Thirty-four strains of B. fragilis, one-half from bacteremic infections, were tested in vitro, and penicillin G was found to be twice as active as carbenicillin on an equal weight basis; 94% of the strains were inhibited by 32 microgram of penicillin/ml, a level easily achieved therapeutically. Penicillin killed B. fragilis organisms as rapidly as carbenicillin. In two subjects given equivalent doses (100 mg/kg intravenously) of carbenicillin and aqueous penicillin G, the bactericidal activity of serum against B. fragilis after administration of each drug was the same. Controlled clinical trials of treatment of anaerobic bacterial infections with penicillin G in high dosage, carbenicillin (or closely related ticarcillin), clindamycin, and chloramphenicol should be undertaken. Carbenicillin (and ticarcillin) for the present would seem better reserved for P. aeruginosa infections.
Bacteroides Infections↗
Susceptibility testing of anaerobic bacteria with 100-microg carbenicillin disks.
A total of 245 strains of anaerobic bacteria were examined for their susceptibility to carbenicillin by the disk test method and by minimum inhibitory concentration (MIC) determinations. Standard-curve studies with a strain of Bacteroides fragilis subsp. fragilis that was minimally susceptible to carbenicillin and Escherichia coli (ATCC 25922) demonstrated that a disk containing 100 mug of carbenicillin was suitable for testing susceptibility of anaerobes to carbenicillin. Thus, the diameter of zones around the 100-mug carbenicillin disks and MIC values were determined under the following test conditions: Mueller-Hinton agar supplemented with sheep blood, vitamin K(1), and hemin; an incubation temperature of 35 C; and an atmosphere of 80% N(2), 10% H(2), and 10% CO(2). The strains were separated into two populations by correlating zone diameters and geometric mean MICs. The disk test more clearly separated the resistant and susceptible populations and was more reproducible than the MIC test. Thus, a statistical analysis based on the distribution of zone diameters of susceptible and resistant strains was used to derive an interpretive scheme for anaerobic bacteria tested with 100-mug carbenicillin disks. The following interpretive scheme is recommended for testing anaerobes with 100-mug disks of carbenicillin: resistant, 8 mm or less; indeterminate, 9 to 12 mm; and susceptible, 13 mm or greater.
Anaerobiosis↗
Comparative activity in vitro of ticarcillin, BL-P1654, and carbenicillin.
The activity of ticarcillin, BL-P1654, and carbenicillin was compared in vitro using a microtiter tube dilution test in Mueller-Hinton broth against 50 recent clinical isolates each of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella species, Enterobacter species, Proteus species, and Pseudomonas aeruginosa. Bactericidal end points were determined using a modified Steers replicator. Ticarcillin was generally two to four times more active against all organisms tested except S. epidermidis against which BL-P1654 was most active. Median minimum inhibitory concentrations in micrograms per milliliter were for S. aureus: ticarcillin (6.2), carbenicillin (12.5), BL-P1654 (25); for S. epidermidis: BL-P1654 (1.6), ticarcillin (3.2), carbenicillin (3.2); for E. coli: ticarcillin (3.2), BL-P1654 (6.2), carbenicillin (6.2); for Klebsiella sp.: >100 for all three drugs; for Enterobacter sp.: ticarcillin (3.2), carbenicillin (6.2), BL-P1654 (12.5); for Proteus sp.: ticarcillin (1.6), carbenicillin (1.6), BL-P1654 (3.2); for P. aeruginosa: ticarcillin (31), BL-P1654 (62), carbenicillin (125). Bactericidal end points were dependent on both the drug and the species but were in general no more than twofold more than the minimum inhibitory concentration with the exception of BL-P1654 against P. aeruginosa. BL-P1654 was bactericidal for only 60% of the strains tested at a concentration of 500 mug/ml.
Bacteria↗
In vitro synergism between carbenicillin and aminoglycosidic aminocyclitols against Acinetobacter calcoaceticus var. anitratus.
Acinetobacter caleoaceticus var. anitratus is a nonfermentative, gram-negative bacillus that has been demonstrated to cause severe infections, usually in hospitalized patients. Since mild to moderate resistance of A. calcoaceticus to one or more aminoglycosidic aminocyclitols has been noted to occur, a study was undertaken to evaluate the activity of combinations of carbenicillin with either kanamycin, tobramycin, or gentamicin against 28 isolates of A. calcoaceticus obtained from clinical sources. Synergism (defined as at least 100-fold-increased killing at 24 h by the combination as compared with the most efficacious of the individual antibiotics) was demonstrated against 26 of 28 strains of A. calcoaceticus with carbenicillin plus kanamycin and carbenicillin plus tobramycin and against 25 of 28 strains with carbenicillin plus gentamicin. The median increased killing for the 28 strains was 4.2 log(10) with carbenicillin plus kanamycin and with carbenicillin plus tobramycin and 3.1 log(10) with carbenicillin plus gentamicin. The most important determinant of synergistic potential of each combination was the level of resistance of each strain of A. calcoaceticus to the aminoglycoside component of the combination.
Acinetobacter↗
Effect of time and concentration upon interaction between gentamicin, tobramycin, Netilmicin, or amikacin and carbenicillin or ticarcillin.
An aminoglycoside antibiotic and carbenicillin or ticarcillin are widely used in the treatment of patients with gram-negative bacillus infections. This study evaluated the effect of time upon in vitro interaction between mixtures of four aminoglycosides at two concentrations with carbenicillin or ticarcillin at four concentrations. By linear regression analysis, the inactivation of each aminoglycoside was shown to be directly proportional to the concentration of carbenicillin (P < 0.001). Inactivation was significantly (P < 0.01) greater for gentamicin and tobramycin than for amikacin or netilmicin at all carbenicillin concentrations. At carbenicillin concentrations of 300 and 600 mug/ml, significantly (P < 0.005) less inactivation of amikacin occurred when compared to netilmicin. Ticarcillin produced a significant (P < 0.025) inactivation of gentamicin and tobramycin, with inactivation being directly proportional to ticarcillin concentration. No inactivation of amikacin or netilmicin activity occurred unless the ticarcillin concentration was 600 mug/ml. No significant change in aminoglycoside activity occurred when stored with ticarcillin or carbenicillin at concentrations ranging from 100 to 600 mug/ml at -70 degrees C for 56 days. When an aminoglycoside and carbenicillin or ticarcillin are indicated in patients with renal failure, this study supports the use of ticarcillin with either amikacin or netilmicin.
Amikacin↗
Carbenicillin-gentamicin interaction in acute renal failure.
A case is reported in which carbenicillin inactivation of gentamicin resulted in subtherapeutic serum gentamicin levels in a 77-year-old man with acute renal failure. The drugs were administered separately to prevent in vitro inactivation. Carbenicillin inactivation of gentamicin resulted in subtherapeutic serum gentamicin levels (less than 2 microgram/ml) even with unusually large doses of gentamicin (1.8 mg/kg/day). The large dose of carbenicillin (15 g/day) resulted in serum carbenicillin levels more than 500 microgram/ml and an increased rate of gentamicin inactivation. After carbenicillin was discontinued, therapeutic serum gentamicin levels were achieved and maintained with doses of 0.9 - 1.8 mg/kg/day. It is suggested that if the combination of carbenicillin and gentamicin is used in patients with severe renal failure, the dose of carbenicillin should be reduced to prevent rapid inactivation of gentamicin. Further, to assure therapeutic gentamicin levels, serum levels of both drugs should be monitored frequently.
Acute Kidney Injury↗
Bleeding in uremic patients after carbenicillin.
Hemorrhagic diathesis was observed in patients with renal insufficiency after carbenicillin at serum levels greater than 300 mug/ml. Normal coagulation factors (F. I, II, V, VII, VIII, X), normal PTT, normal platelet counts, negative ethanol gelation test (fibrin monomers) were found as well as a prolongation of thromboplastin time (Quick), thrombin time, reptilase time and thrombin coagulase time. Platelet function was disturbed. In addition, the plasmatic system was involved: inhibition of fibrinogen-fibrin conversion (Belitser assay) and enhanced antithrombin III activity; in vivo the latter was ascribed to a heparin-like activity. In vitro, abnormal III was seen: however an enhanced antithrombin III activity in vitro was not found with carbenicillin and various penicillin derivatives. This study demonstrates that carbenicillin, in addition to its known effect on platelet function, also disturbs the plasmatic coagulation system. This additional effect of carbenicillin is clinically important since protamin chloride effectively blocks bleeding without interfering with antibacterial activity. Both penicillin and penicillin derivatives have been shown to interfere with hemostasis and to cause clinically manifest hemorrhagic diathesis (Fleming and Fish 1947, Lurie et al. 1970a, b, McClure et al. 1970, Yudis et al. 1972, Demos 1971, Waisbren et al. 1971). Carbenicillin interferes with ADP-, collagen- or thrombin-induced platelet aggregation and with the release reaction both in vivo (McClure et al. 1970, Cazenae et al. 1973) and in vitro (McClure et al. 1970, Cazenave et al. 1973). In addition Lurie and colleagues (1970b) concluded that an inhibition of the conversion of fibrinogen to fibrin is involved although no experimental details were given. Later Brown and colleagues (1974) concluded that carbenicillin at usual dose levels "only affects the platelet component of hemostasis and has little effect on fibrin formation or other phases of coagulation in patients with normal renal function".
Adult↗
The behavior of carbenicillin as a nonreabsorbable anion.
In order to study the mechanism of hypokalemic alkalosis which occurs in some patients being treated with disodium carbenicillin, renal clearance experiments were carried out in rats and observations were made on electrical changes in isolated toad bladders. In rats maintained on a sodium-free diet, intravenous infusion of carbenicillin at 40 mg. per hour resuited in an immediate diuresis characterized by a striking increase in K and NH4 excretion, and progressive acidification of the urine. In a control group of rats, also prepared with a sodium free diet, intravenous infusion of mannitol resulted in a comparable diuresis, but no significant changes in K and NH4 excretion, and no acidification of the urine. The urinary changes in the carbenicillin-treated rats could not be accounted for by any alterations in blood electrolytes, acid-base values, or glomerular filtration rate (GFR). Isonatric, isohydric substitution of carbenicillin for chloride in the mucosal bathing media of toad bladders mounted in Ussing chambers resulted in a reversible increase in electrical potential (PD) and resistance (R) without a comparable change in short-circuit current (SCC). Substitution in the serosal medium resulted in a reversal of polarity of PD and SCC in 4 of 9 experiments, a finding best explained by more rapid movement of chloride from M leads to S than carbenicillin movement from S leads to M (a chloride diffusion potential). The observations in both the rat and toad bladder experiments are consistent with the view that carbenicillin behaves as a nonreabsorbable anion. Hypokalemic alkalosis in patients receiving this drug can thus be attributed to increased electrical negativity of the distal nephron with subsequent enhancement of K and H secretion.
Acid-Base Equilibrium↗
Low-dose carbenicillin prophylaxis for vaginal and abdominal hysterectomy.
A double-blind prospective study of 99 patients undergoing vaginal and abdominal hysterectomy was performed at North Carolina Baptist Hospital of the Bowman Gray School of Medicine at Wake Forest University. The study indicated that low-dose intravenous carbenicillin begun preoperatively and continued for 24 hours resulted in decreased febrile morbidity, postoperative infection rate, and shortened hospital stay in patients undergoing both vaginal and abdominal hysterectomy. The indications for operation, clinical characteristics of patients, and operative and postoperative management were similar for the control and study groups. For the vaginal hysterectomy group, febrile morbidity was reduced from 34.6% in the control group to 7.7% in the group receiving carbenicillin. For patients undergoing abdominal hysterectomy, febrile morbidity was reduced from 54.1% in the control group to 4.0% in the group receiving prophylactic carbenicillin. Similar reductions for the carbenicillin study group in fever index and average total hospital stay were also noted. Urinary tract infections were determined to be present more commonly in the group of patients with febrile morbidity receiving no prophylactic antibiotics. The incidence of pelvic infections were reduced in both carbenicillin-treated groups. This investigation suggests that low-dose carbenicillin prophylaxis is beneficial in reduction of morbidity following both vaginal and abdominal hysterectomy.
Adult↗
Resistance types in Escherichia coli. I. Occurrence and resistance to ampicillin, carbenicillin and cephalothin.
An investigation of the resistance types in lactose fermenting E. coli is presented. The frequency and sensitivity to beta-lactam antibiotics of different resistance types was investigated. The strains were divided into three groups according to sensitivity to penicillin derivatives. Group 1 contained the ampicillin-carbenicillin sensitive (A-s/Ca-s), group 2 the ampicillin resistant-carbenicillin sensitive (A-r/Ca-s) and group 3 the ampicillin-carbenicillin resistant (A-r/Ca-r). A-s/Ca-r were not observed. One third of the A-r strains were sensitive to carbenicillin. The distribution of resistance types was different in the three groups. Group 1 was dominated by the usual sensitive E. coli. Group 3 contained a very high proportion of multiresistant types. The IC50 against ampicillin, carbenicillin and cephalothin of 55 strains was determined. Group 3 (A-r/Ca-r, 25 strains) was much more ampicillin resistant than group 2 (A-r/Ca-s, 16 strains). Group 2 was less sensitive to carbenicillin than group 1 (A-s/Ca-s, 14 strains). Group 3 did not differ significantly from group 1 with respect to cephalothin sensitivity, while group 2 was much more resistant than the others.
Ampicillin↗
Kinetics of mezlocillin and carbenicillin.
The kinetics of mezlocillin, a semisynthetic acylureido penicillin, more active than carbenicillin against many gram-negative bacteria, were compared with those of carbenicillin. Following an intravenous infusion of 4 gm in 5 min to 8 normal men there was an average serum level of 294 microgram/ml for mezlocillin and 365 microgram/ml for carbenicillin. The t1/2 for mezlocillin was 47 min and that for carbencillin was 70 min. The apparent volume of distribution was 13.4 L for mezlocillin and 14.4 L for carbenicillin. The mean urinary recovery of mezlocillin was 72% and that for carbenicillin was 92%. Constant infusion of 5 mg of mezlocillin over 2 hr gave steady-state levels of 234 microgram/ml. Half-life, apparent volume of distribution, and serum and renal clearance of mezlocillin after constant infusion were in the same range as those after rapid infusion.
Adult↗
Preparation, hydrolysis, and oral absorption of alpha-carboxy esters of carbenicillin.
Twelve alpha-carboxy esters of carbenicillin, a parenteral broad spectrum semisynthetic penicillin, were synthesized and examined as potential oral carbenicillin derivatives. The rates at which the esters were hydrolyzed in vitro to carbenicillin by animal and human tissues were compared and the carbenicillin serum levels arising after oral administration of the esters were measured in squirrel monkeys and human volunteer subjects. The alpha-carboxyphenyl ester of carbenicillin [carfecillin (British Pharmacopoeia approved name), BRL 3475] WAS SELECTED FOR FURTHER STUDY AND IS PRESENTLY UNDERGOING CLInical trial.
Absorption↗