Hjalmar Lagast

Single-drug versus combination empirical therapy for gram-negative bacillary infections in febrile cancer patients with and without granulocytopenia.

Empirical therapy with cefoperazone was compared with cefoperazone plus amikacin in granulocytopenic and nongranulocytopenic febrile patients. In nonneutropenic patients the overall response rate to cefoperazone was 88%; 10 of 12 gram-negative bacteremic patients were cured. Cefoperazone plus amikacin resulted in an 88% overall response rate and cured 14 of 15 patients with bacteremia. In neutropenic patients the overall response rate was 77% with cefoperazone alone and 73% with cefoperazone plus amikacin; the cure rates for gram-negative bacteremias were 8 of 11 and 6 of 12 patients, respectively. Our findings support the concept of single-drug empirical therapy with cefoperazone in febrile cancer patients, whether granulocytopenic or not, especially when gram-negative bacteremias are predominantly caused by Escherichia coli or Klebsiella species. The issue of Pseudomonas spp. and other more resistant pathogens needs further assessment with a larger number of patients.

Treatment of gram-negative bacillary septicemia with cefoperazone.

SummaryTherapy with cefoperazone (4 g/day i. v.) was successful in 11 of 14 cases of gram-negative bacillary septicemia (78%). The three failures were related toBacteroides fragilis andAcinetobacter sp. infections, and to one episode of endocarditis caused byEscherichia coli. Minimal bactericidal concentrations of cefoperazone for the causative pathogens were similar to those of gentamicin. A serum bactericidal activity of greater than 1:8 was achieved in 11 of 12 patients one hour after the administration of cefoperazone. Continuous infusion of cefoperazone maintained the serum bactericidal activity at a constant value of greater than 1:8. The clinical results, however, were equally good with intermittent and continuous therapy. Side-effects were minor, rare and most likely not related to cefoperazone.ZusammenfassungDie Therapie mit Cefoperazon (4 g/Tag i. v.) war erfolgreich bei 11 von 14 gramnegativen bakteriellen Septikämien (78%). Bei drei Fällen stand das Therapieversagen in Zusammenhang mit Infektionen durchBacteroides fragilis undAcinetobacter sp., in einem Fall mit einer Endocarditis durchEscherichia coli. Die minimalen bakteriziden Konzentrationen von Cefoperazon für die verantwortlichen Erreger waren ähnlich wie die für Gentamicin. Bei 11 von 12 Patienten wurde eine Stunde nach der Gabe von Cefoperazon eine bakterizide Serumaktivität von über 1:8 erreicht. Die kontinuierliche Infusion von Cefoperazon führte zu einer konstant hohen bakteriziden Serumaktivität von über 1:8, doch waren die klinischen Ergebnisse mit intermittierender und kontinuierlicher Therapie gleich gut. Es traten nur geringgradige Nebenwirkungen auf, sie waren selten und standen wahrscheinlich nicht in Beziehung zu Cefoperazon.

Serum bactericidal activity of ceftazidime and cefoperazone alone or in combination with amikacin against Pseudomonas aeruginosa and Klebsiella pneumoniae.

Sera of volunteers receiving ceftazidime (2 g) or amikacin (500 mg), alone or in combination, or cefoperazone (2, 4, or 6 g) or cefoperazone (2 g) with amikacin (500 mg) were evaluated for bactericidal activity against Klebsiella pneumoniae and Pseudomonas aeruginosa. Serum bactericidal activities were similar for ceftazidime and ceftazidime plus amikacin, but were definitely lower for amikacin alone. Against P. aeruginosa, a 6-g dose of cefoperazone resulted in a higher frequency of peak serum bactericidal activities greater than or equal to 1:8 than a 2-g dose of cefoperazone plus amikacin. Killing studies, performed in 1:8 diluted serum, demonstrated a higher killing rate for cefoperazone plus amikacin than for a 6-g dose of cefoperazone, the more resistant P. aeruginosa excepted. Emergence of resistance was found with a 2-g dose of cefoperazone for K. pneumoniae and with a 6-g dose of cefoperazone for P. aeruginosa, but not with cefoperazone plus amikacin.

Comparative study of the serum bactericidal activity of cefoperazone alone and in combination with amikacin or mezlocillin against gram-negative bacilli and staphylococcus aureus

SummarySerum bactericidal activity (SBA) was studiedin vitro after intravenous administration of cefoperazone alone or in combination with mezlocillin or amikacin to human volunteers. One hour after the infusion, cefoperazone (2 g), cefoperazone + mezlocillin (5 g) and cefoperazone + amikacin (500 mg) achieved comparable activity againstEscherichia coli andKlebsiella pneumoniae (100% of the strains being killed by a 1:8 or greater dilution). The activity of the three regimens was also similar againstPseudomonas aeruginosa (87–96% of the sera had an SBA ≥ 1:8) and somewhat less forStaphylococcus aureus (52–60% with SBA ≥ 1:8). Six and ten hours after administration, the SBAs were much lower for all regimens; a small advantage for cefoperazone + mezlocillin againstK. pneumoniae could be shown in comparison to the other regimens.ZusammenfassungDie bakterizide Aktivität im Serum (SBA) wurde nach intravenöser Gabe von Cefoperazon allein oder in Kombination mit Mezlocillin oder Amikacin an freiwillige Probandenin vitro bestimmt. Eine Stunde nach der Infusion erreichten Cefoperazon (2 g), Cefoperazon + Mezlocillin (5 g) und Cefoperazon + Amikacin (500 mg) eine vergleichbare Aktivität gegenEscherichia coli undKlebsiella pneumoniae (bei einer Verdünnung von 1:8 oder darüber wurden 100% der Stämme abgetötet). Die Aktivität der drei Schemata war gegenPseudomonas aeruginosa vergleichbar (87–96% der Seren hatten eine SBA ≥ 1:8), fürStaphylococcus aureus etwas geringer (52–60% hatten eine SBA ≥ 1:8). Sechs und zehn Stunden nach Applikation waren die SBA-Werte für alle Dosierungen erheblich geringer; für die Kombination Cefoperazon + Mezlocillin konnte gegenK. pneumoniae eine gegenüber den anderen Therapieschemata geringfügige Überlegenheit festgestellt werden.

Serum bactericidal activity and killing rate for volunteers receiving imipenem, imipenem plus amikacin, and ceftazidime plus amikacin against Pseudomonas aeruginosa.

Serum bactericidal activity against 20 strains of Pseudomonas aeruginosa was studied in 10 volunteers after administration of imipenem (25 mg/kg), imipenem (25 mg/kg) plus amikacin (7.5 mg/kg), and ceftazidime (25 mg/kg) plus amikacin (7.5 mg/kg). Eight strains were susceptible and 12 were resistant to ticarcillin. Serum levels were measured microbiologically after 30 and 60 min and were, respectively, 97 and 46 micrograms/ml for imipenem given alone and 79 and 45 micrograms/ml for imipenem given with amikacin. Despite the very large dose of imipenem used, imipenem and imipenem plus amikacin appeared slightly less active than ceftazidime plus amikacin (P less than or equal to 0.1; Wilcoxon matched-pairs test), with respective median titers at 30 min of 1:128, 1:128, and 1:256 against ticarcillin-susceptible strains and 1:32, 1:32, and 1:64 against ticarcillin-resistant strains; however, more than 90% of the serum determinations, regardless of the regimen, had a serum bactericidal activity greater than or equal to 1:8. Amikacin significantly increased the rate of killing in serum of P. aeruginosa by imipenem. Imipenem plus amikacin appeared as effective as ceftazidime plus amikacin in reducing the viable counts of P. aeruginosa after 24 h of incubation.

Anaerobic infections in cancer patients--a retrospective analysis of clindamycin, tinidazole, doxycycline, cefoxitin and lamoxactam.

SummaryThe results of three consecutive clinical trials on the therapy of anaerobic infections in cancer patients have been compared. The success rate with lamoxactam (94%) (6000 mg/d i. v.) was statistically different from that of doxycycline (63%) (300 mg/d per os) and tinidazole (61%) (1200 mg/d per os). Clindamycin (1200 mg/d per os), clindamycin (2700 mg/d i. v.) and cefoxitin (6000 mg/d i. v.) resulted in a favourable outcome in approximately 80% of the patients. Mixed aerobic and anaerobic infections had a similar response rate (80%). Even when the anaerobic pathogen was resistant to therapy, six of ten patients were cured. Surgical drainage played an important role, but was difficult to assess precisely.ZusammenfassungDie Ergebnisse von drei nacheinander durchgeführten klinischen Studien zur Therapie anaerober Infektionen bei Krebspatienten wurden verglichen. Die Erfolgsrate von 94% mit Lamoxactam, 6000 mg/die i. v., unterschied sich signifikant von derjenigen mit 300 mg/die Doxycyclin per os (63%) und von 1200 mg/die Tinidazol per os (61%). Clindamycin (1200 mg/die, per os), Clindamycin (2700 mg/die, i. v.) und Cefoxitin (6000 mg/die, i. v.) führten bei etwa 80% der Patienten zu einem günstigen Ergebnis. Eine ähnliche Erfolgsrate wurde bei aeroben und anaeroben Mischinfektionen beobachtet (80%). Sechs von zehn Patienten wurden geheilt, obwohl der anaerobe Erreger therapieresistent war. Eine wesentliche Rolle kam der chirurgischen Drainage zu, doch war eine präzise Auswertung ihrer Wertigkeit schwierig.

Serum bactericidal activity of moxalactam and cefotaxime with and without tobramycin against Pseudomonas aeruginosa and Staphylococcus aureus

Serum bactericidal activity was determined against 10 strains each of Pseudomonas aeruginosa and Staphylococcus aureus in serum from volunteers 1 and 6 h after intravenous infusion of cefotaxime, tobramycin, and the combination; or of moxalactam, tobramycin, and the combination. High serum bactericidal activity against P. aeruginosa was found significantly more frequently with moxalactam plus tobramycin than with cefotaxime, moxalactam, and tobramycin alone or with cefotaxime plus tobramycin.

Comparative in vitro activities of temocillin and cefazolin against Klebsiella pneumoniae.

Temocillin (BRL 17421) a new penicillin, was compared with cefazolin against 20 strains of Klebsiella. The in vitro minimal bactericidal concentration of cefazolin was twice as active as that of temocillin. Serum bactericidal levels obtained in volunteers treated with temocillin were consistently higher than those levels reached after the administration of cefazolin at the 6-h sampling.

Moxalactam treatment of anaerobic infections in cancer patients.

Of 30 patients with predominantly anaerobic localized infections superimposed on chronic tissue damage related to trauma, ischemia, or tumor, 22 (73%) responded satisfactorily to moxalactam therapy. Moxalactam-resistant anaerobic pathogens emerged in two patients and were responsible for treatment failure. In six patients, two of whom also acquired resistant anaerobic pathogens, isolation of moxalactam-resistant aerobic pathogens increased during therapy.

Synergism of trimethoprim combined with aminoglycosides in vitro and in serum of volunteers

In vitro synergism of trimethoprim plus amikacin and trimethoprim plus sisomicin against 66 gramnegative bacilli was studied by microtiter checkerboard dilution. Synergism was defined as an FIC or FBC index equal to or less than 0.5. Fifty-two percent of strains were inhibited and 65 % killed synergistically by the former combination, and 27% and 36% respectively by the latter combination (p<0.01). Serum bactericidal activity against 16 strains resistant to ampicillin and/or cephalothin was studied using serum from five volunteers one and six hours after intravenous administration of trimethoprim (160 mg), amikacin (250 mg) or the combination, and from six volunteers after administration of trimethoprim, tobramycin (1 mg/kg) or the combination. With trimethoprim and amikacin serum bactericidal titers ⩾ 1∶8 were found more frequently with the combination (77 of 80 samples) than with either drug alone (trimethoprim 19 of 80 samples, amikacin 60 of 80 samples, p<0.01). Trimethoprim plus amikacin may be useful in the treatment of infections with gram-negative rods resistant to cephalothin and ampicillin.