Combination of amikacin and carbenicillin with or without cefazolin as empirical treatment of febrile neutropenic patients. The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer.

A total of 841 febrile neutropenic patients from 20 centers were randomized to receive carbenicillin (or ticarcillin) plus amikacin or these antibiotics plus cefazolin to compare outcome and incidence of nephrotoxicity. Infection with Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, or Staphylococcus aureus accounted for most of the microbiologically documented febrile episodes. The response to therapy was similar in the two treatment groups for all infections and for bacteremia. Improvement occurred in 35 (64%) of 55 bacteremic patients treated with two antibiotics and 39 (65%) of 60 treated with three antibiotics. An increase in serum creatinine to 2 mg/dL over baseline occurred in eight (2.1%) of 381 patients in the former and in 50 (2.4%) of 364 patients in the latter group. Thus, the two antibiotic regimens were equal in efficacy and in nephrotoxicity. Although not the primary focus of this study, a significant decrease in incidence of infection, including bacteremias, was found in neutropenic patients treated with any oral intestine decontamination regimen.

Acute interstitial nephritis associated with carbenicillin therapy.

Although acute interstitial nephritis has been documented during therapy with many antibiotics of the penicillin class, it has not previously been reported in association with carbenicillin therapy. We report here the case of a patient who developed the characteristic clinical features of this form of injury while receiving prolonged large doses of carbenicillin. Histologic examination confirmed the presence of a striking interstitial nephritis. Carbenicillin should be considered a potential cause of renal damage in patients who develop rash, eosinophilia, and microscopic hematuria in association with deterioration of renal function.

Piperacillin v Carbenicillin in the therapy for serious infections.

One hundred seven patients were treated with either piperacillin (56) or carbenicillin (51) in an open randomized trial of hospitalized patients with pleuropulmonary (40), urinary tract (26), gynecologic (21), skin and soft-tissue (eight), joint (five), bone (three), and miscellaneous other infections (four). Patients with urinary tract infections were given 150 mg/kg/day of piperacillin sodium or 200 mg/kg/day or carbenicillin sodium in divided doses every six hours intravenously. Patients with other infections were given 250 mg/kg/day of piperacillin sodium and 450 mg/kg/day of carbenicillin sodium; 53/56 (95%) patients treated with piperacillin and 45/51 (88%) patients treated with carbenicillin were cured clinically. In general, the drugs were well tolerated. There were, however, more adverse experiences in the groups taking carbenicillin. Of special interest was the finding of liver function test abnormalities in 17/78 (21%) carbenicillin recipients (evaluative and nonevaluative cases). We concluded that piperacillin was effective and safe. It has potential for use in a great variety of infections.

Piperacillin and gentamicin v carbenicillin and gentamicin for treatment of serious gram-negative infections.

Piperacillin sodium, a new penicillin with remarkable in vitro activity against Pseudomonas aeruginosa and other Gram-negative bacilli, and gentamicin sulfate were compared with carbenicillin disodium and gentamicin in a prospective, randomized, double-blind comparison for treating serious Gram-negative infections. Of the 32 patients whose courses were "evaluable" for efficacy, 12 of 14 who received piperacillin and gentamicin and 13 of 18 who received carbenicillin and gentamicin had favorable outcomes. Of the 99 patients whose courses were evaluable for toxicity, nine of 51 recipients of piperacillin and gentamicin and 15 of 48 recipients of carbenicillin and gentamicin suffered clinical reactions possibly, probably, or definitely related to the penicillin. No statistically significant differences were found in the two groups in the frequencies of biochemical abnormalities, including hypokalemia, that occurred in 19 or 44 recipients of piperacillin and gentamicin and 16 of 45 recipients of carbenicillin and gentamicin. Thus, this study did not prove differences in efficacy of toxicity for piperacillin and gentamicin plus carbenicillin and gentamicin for serious Gram-negative infections.

Clinical use of the anion gap.

The concepts underlying the clinical use of the anion gap (AG) and those disorders associated with its alteration are reviewed. A substantial increase in the AG usually indicates the presence of a metabolic acidosis, unless large doses of certain antibiotics or sodium salts of organic acids are being used. The etiology, pathogenesis and diagnosis of high AG metabolic acidoses are discussed. Stress is placed upon the utility of the AG in defining the cause of the acidosis, and as a guide to therapy in certain organic acidoses. A decrease in the normal AG occurs in dilutional states, hypoalbuminemia, hypercalcemia, hypermagnesemia, hypernatremia, diseases associated with hyperviscosity, bromide intoxication, and in certain paraproteinemias. The important clue provided by a low or negative AG in the diagnosis of certain of these life-threatening disorders is emphasized.

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".

Relative efficacy of carbenicillin indanyl sodium and of trimethoprim/sulfamethoxazole in urinary-tract infections.

In a 10-day study, carbenicillin indanyl sodium cured urinary-tract infections in 22 of 30 patients (ages, 24-91). In 3 of the remaining patients the treatment was a failure; in 3 others the drug had to be discontinued because of diarrhea and vomiting; and in 2 instances it induced overgrowth of Candida albicans in the urine. Carbenicillin was lethal to Pseudomonas aeruginosa in all 9 cases, to Proteus mirabilis in all 6 cases, and to enterococcus in all 3 cases. A trimethoprim/sulfamethoxazole combination cured urinary-tract infections in 18 of 30 other patients (ages, 28-91), but failed in 3. In 3 patients it gave rise to a skin rash; in 2 to elevation of blood urea nitrogen and creatinine levels; in 1 to neutropenia; and in 1 to overgrowth of Candida albicans in the urine. Reinfection occurred in 2 patients. Carbenicillin indanyl sodium was more effective than the sulfonamide/trimethoprim combination.

Comparison of mezlocillin and carbenicillin as therapy for various infectious diseases.

The efficacy and safety of mezlocillin, a new broad-spectrum semisynthetic penicillin, were compared with those of carbenicillin in a nonblind, controlled clinical study in 89 adult patients. The infections treated were primarily those of the urinary tract, skin, and gastrointestinal or hepatobiliary tract. Escherichia coli, Proteus mirabilis, Proteus morganii, and Pseudomonas aeruginosa were the causative organisms isolated most frequently. A complete resolution of signs and symptoms was achieved in 78% of the mezlocillin patients and in 71% of the carbenicillin patients. In the mezlocillin group, causative organisms were eliminated in 80% of the courses, and in the carbenicillin group the elimination rate was 86%. Two adverse reactions, rash and diarrhea, were reported in mezlocillin-treated patients; none were reported for the carbenicillin group.

Clinical experience with indanyl carbenicillin in urinary tract infections.

A trial was carried out in 30 patients to assess the effectiveness of indanyl carbenicillin in acute or chronic urinary tract infections, many of which were complicated by a pathological urological or medical condition. In all patients, infection was due to a single species of pathogen: E. coli (19), Proteus (6), and Pseudomonas (5). Oral doses of 1 g indanyl carbenicillin were given 6-hourly for an average of 10 days. Results showed a clinical and bacteriological cure in 13 (43.8%) patients. In 6 patients, although there was initial clinical improvement, the pathogen developed resistance during therapy. In 7 patients, there was super-infection with another organism. Four patients were withdrawn early in treatment because of side-effects, mainly gastrointestinal in origin. Indanyl carbenicillin proved very effective in eradicating all strains of Proteus and Pseudomonas and 12 (70.6%) of the 17 strains of E. coli in patients completing the full course of treatment.

The treatment of chronic pyelonephritis with carindacillin.

Forty-two patients with a radiologically confirmed diagnosis of chronic pyelonephritis were treated with 1 g carindacillin every 6 hours over a period of 6 weeks. An underlying urological disease was present in 84% of the 38 patients for whom sufficient data were available for evaluation. The results of carindacillin treatment, as judged by bacteriological evaluation 1 month post-treatment, were good in 12 (32%) and moderate in 9 of the patients. This success rate was remarkable in that all of the patients had been treated previously with one or more other antibiotics and chemotherapeutic agents with little or no response. The authors recommend that, because carindacillin has proved so valuable in treating chronic as well as acute urinary tract infections, its use should be limited to patients with serious disease who have not responded to other treatment.

Carbenicillin and ticarcillin.

Carbenicillin and ticarcillin are penicillins which were initially developed as agents to treat serious Pseudomonas infections in the seriously ill hospitalized patient. These drugs have made a major contribution to improved survival in the neutropenic patients with Pseudomonas infection, the burn patient and to the care of the patient with cystic fibrosis. Areas of use for the compounds have enlarged to include aspiration pneumonitis in hospitalized patients, intra-abdominal and pelvic sepsis, and infections due to Proteus and Enterobacter species. Careful attention to the pharmacology of the agents is necessary to achieve clinical and bacteriologic success and to avoid the toxic side-effects such as bleeding and hypokalemia associated with the use of these agents. A decade of use has shown that the agents have remained effective agents in institutions in which their use has not been abused. It is too early to clearly position azlocillin, mezlocillin, and piperacillin. In the next few years the role of these potent compounds will be established. As noted in this review, these three agents have been used with success to treat all of the aforementioned infections. With these drugs it is also essential that the physician closely correlate in vitro data and the human pharmacology of the drugs if he or she wishes to achieve the most effective response from the agents.

Postoperative hemorrhage associated with carbenicillin administration. Report of two cases and review of the literature.

Two patients receiving preoperative carbenicillin manifested platelet dysfunction and severe wound hemorrhage. Platelet transfusions appeared beneficial. Investigations indicate that hemostatic abnormalities, especially platelet aggregation defects, may be produced by carbenicillin. Extreme caution and awareness of possible hemorrhage are advised when carbenicillin is used preoperatively.

Continuous infusion tobramycin combined with carbenicillin for infections in cancer patients.

The cure rate of infections in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum creatinine greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients.

Comparison of cefamandole and carbenicillin in preventing sepsis following penetrating abdominal trauma.

One hundred and five patients with penetrating abdominal injuries were treated with single-antibiotic regimens. Forty-seven patients were treated with intravenous (IV) cefamandole and for comparison 58 patients were treated with IV carbenicillin previously shown to be effective against postoperative infections associated with abdominal trauma. The overall incidence of deep infection on a single antibiotic therapy was 8.6 per cent, including two patients on cefamandole alone (4.3%) and seven (12.1%) on carbenicillin alone. One in each antibiotic group died of sepsis with a total mortality of 1.9 per cent. The authors concluded that cefamandole when used alone was found to be safe and more effective than carbenicillin alone in preventing sepsis in patients with abdominal trauma.

[Hemorrhagic complications during therapy with carbenicillin in 2 cases of acute renal insufficiency]. / Complicanze emorragiche in corso di terapia con carbenicillina in due casi di insufficienza renale acuta

During the treatment of two patients with acute renal insufficiency with carbenicillin for Pseudomonas aeruginosa sepsis haematemesis, melaena and omnipresent petechiae were observed. Suspension was followed by rapid regression and the normalisation of clotting. Attention is drawn to haemorrhage as clotting. Attention is drawn to haemorrhage as a possible complication of carbenicillin management in patients with acute renal insufficiency.

[Comparative study of ticarcillin and of carbenicillin as prophylactic treatment in the oncologic surgery of head and neck (author's transl)]. / Etude comparative de la ticarcilline et de la carbénicilline comme traitement prophylactique associé à la chirurgie carcinologique cervico-faciale

The frequency of postoperative infections in oncologic head and neck surgery can be reduced by the prophylactic use of antibiotics. In order to assess such preventive treatments as to their advantages and disadvantages, a controlled clinical trial was undertaken. The prophylactic use of antibiotics was used in 107 patients, operated for tumors of the upper airway-digestive tract. According to a previous randomisation, the patients received either carbenicillin either ticarcillin. The efficiency of carbenicillin and ticarcillin proved similar. The results obtained with these antibiotics turned out to be superior to those previously obtained with combined ampicillin and cloxacillin; the number of wound infections, primary and secondary, was lessened. The most frequent complications were thrombophlebitis at the site of intravenous perfusion of the antibiotics and hypokaliemia.

[The use of clindamycin and netilmicin for preventing postoperative wound infection in patients with cancer of the upper respiratory and digestive tracts]. / Primenenie klindamitsina i netilmitsina dlia profilaktiki posleoperatsionnoi ranevoi infektsii u bol'nykh rakom verkhnikh dykhatel'nykh i pishchevaritel'nykh putei.

Clindamycin (2.7 g/day) and netilmicin (5.6 mg/kg) were used for 6-10 days in 27 patients with laryngeal and oral cancer versus beta-lactam antibiotics and aminoglycosides received by 56 matched patients to prevent infection of the operative wound. Suppuration was observed in 11.1 and 41.4% of the patients, respectively (p < 0.05), the temperature rose over 38 degrees C in 22.2% and 42.9% of the patients, respectively (p < 0.05). The regimens showed similar toxicity. The findings proved high efficacy of clindamycin combination with netilmicin in infection prophylaxis in patients operated on for upper respiratory and digestive tract cancer.