Once-daily therapy with ceftriaxone compared with daily multiple-dose therapy with cefotaxime for serious bacterial infections: a randomized, double-blind study

A randomized, double-blind study was done to compare the efficacy and toxicity of daily single-dose therapy with intravenous ceftriaxone (2 g every 24 h) with daily multiple-dose therapy with cefotaxime (2 g every 6 h) for treatment of serious bacterial infections in nonneutropenic patients. Of the 325 patients who were evaluable for toxicity, 241 (74.2%) were evaluable for efficacy. Infection sites included lung (106), urinary tract (42), skin and soft tissue (43), bone and joint (23), bacteremia (21), and hepatobiliary (5). Definite infections were present in 173 cases (71.8%) and possible infections in 68 (28.2%). Analysis of clinical and bacteriologic responses and adverse drug reactions showed no significant differences between the regimens. Values for 95% confidence limits on the differences between regimens for positive clinical and bacteriological outcomes in definite infections were -0.8% to 3.0% and -1.9% to 9.1%, respectively. Thus, daily single-dose therapy with ceftriaxone was comparable to daily multiple-dose therapy with cefotaxime in treating these bacterial infections.     

Clinical evaluation of netilmicin therapy in serious infections.

Netilmicin, a new semisynthetic aminoglycoside, was evaluated in the therapy of 33 episodes of infection in 30 patients. Eighteen patients had documented bacteremia. Infection sites included pulmonary, urinary tract and soft tissue areas. A complete bacteriologic and clinical cure rate of 85 per cent was achieved. No treatment failures occurred in the bacteremic group. Although netilmicin is less effective than gentamicin in vitro against Pseudomonas, it was clinically and bacteriologically effective. Netilmicin bacteriologic cures occurred in patients whose organisms were inhibited by 6.2 microgram/ml or less of netilmicin. Despite a uniform dosing protocol, a wide range of netilmicin serum levels was obtained. Adverse effects were limited to one case of transient nephrotoxicity and one Candida urinary suprainfection. Netilmicin appears to be an effective, safe agent for the therapy of serious infections.     

Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin

The dosing frequency of aminoglycoside antibiotics may alter efficacy and toxicity independent of total daily dose. Once-daily tobramycin dosing was compared with continuous infusion in three models of efficacy. Acute pneumonia due to Pseudomonas aeruginosa in guinea pigs responded better to once-daily dosing, and chronic pneumonia in rats and endocarditis in rabbits responded equally to both regimens. Dogs given gentamicin, tobramycin, or netilmicin once daily, with maximum serum concentrations of greater than 100 mg/liter, had less nephrotoxicity than dogs given continuous infusions. Tobramycin was given once daily or continuously to 52 patients with cystic fibrosis who in 10 days had no change in creatinine clearance or hearing despite maximum serum tobramycin concentrations of 40 mg/liter. Intermittent dosing of aminoglycosides, causing infrequent large maximum serum concentrations, may be less toxic and equally efficacious as frequent dosing.     

Comparison of ceftriaxone with cefotaxime in serious chest infections

Ceftriaxone is a new, third-generation cephalosporin that, because of its long half-life, offers potential advantages of cost and convenience over similar agents such as cefotaxime. We compared the two drugs in a prospective, randomized study of the treatment of chest infections in seriously ill patients. Fifty-one patients (90 percent of whom were mechanically ventilated) received either ceftriaxone, 2g IV once daily, or cefotaxime, 2 g IV thrice daily, for five days. The two groups of patients appeared demographically comparable. Ceftriaxone in a single daily dose of 2 g once daily may not be satisfactory for the treatment of serious chest infections.     

Meropenem monotherapy versus cefotaxime plus metronidazole combination treatment for serious intra-abdominal infections

Summary In an open, randomised, multicentre trial, the efficacy and tolerability of empirical meropenem monotherapy (1 g intravenously every 8 hours) and cefotaxime (2 g every 8 hours) plus metronidazole (0.5 g intravenously every 8 hours) for 5 to 10 days was compared in 94 patients with serious intra-abdominal infection who required surgery. Eighty-three patients had an evaluable clinical response. Significantly more patients in the meropenem group had a satisfactory clinical response at the end of treatment (41/43 [95.3%] vs 30/40 [75.0%]; p=0.008). The bacteriological response was also higher in the meropenem group (31/33 vs 26/32). In the bacteriologically evaluable population, a satisfactory clinical response was observed in 31/33 of those who received meropenem compared to 24/32 of the cefotaxime/metronidazole recipients (p=0.03). Empirical meropenem monotherapy should prove a useful alternative to the currently standard combination treatment for serious intraabdominal infections.

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Meropenem Monotherapie im Vergleich zu Cefotaxim plus Metronidazol in der Therapie schwerer intraabdomineller Infektionen

Zusammenfassung In einer offenen, randomisierten Multicenter-Studie wurden die Wirksamkeit und Verträglichkeit einer initialen Monotherapie mit Meropenem (MEM, 1 g 3 × tägl. i.v.) mit der etablierten Kombinationstherapie Cefotaxim (CTX) plus Metronidazol (MTR) (2 g CTX+0.5 g MTR 3×tägl. i.v.) verglichen. 94 Patienten mit operationspflichtigen schweren intraabdominellen Infektionen wurden einbezogen. Davon waren 83 Patienten bezüglich klinischem Ansprechen auswertbar. Die klinische Wirksamkeit war in der MEM-Gruppe signifikant höher (41/43 Pat.=95.3% vs 30/40 Pat.=75%; p=0.008). Das bakteriologische Ansprechen war in der MEM-Gruppe ebenfalls höher im Vergleich zur Kombinationsgruppe (31/33 vs 26/32), der Unterschied war jedoch statistisch nicht signifikant. In der bakteriologisch auswertbaren Population war das klinische Ansprechen in der MEM-Gruppe signifikant höher als im Vergleichskollektiv (31/33 vs 24/32; p=0.03). MEM erscheint somit für die initiale empirische Monotherapie bei schweren intraabdominellen Infektionen geeignet.

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On behalf of the German Peritonitis Study Group: Dr.Griesenbeck, Prof. Dr.Wendling, Prof. Dr.Männl, Prof. Dr.Rückert, Germany.     

Ceftriaxone compared with cefotaxime for serious bacterial infections

Ceftriaxone was compared with cefotaxime for the treatment of serious bacterial infections in a prospective, randomized, double-blind clinical trial. The dose of ceftriaxone was 2 g once a day, and the dose of cefotaxime was 2 g every 4 h. Metronidazole was added if anaerobic infection was suspected. Explicit criteria were used to define infections, clinical response, and adverse effects. Ceftriaxone was given to 88 patients and cefotaxime to 83. The two treatment groups did not differ in types of infection, infecting organisms, and severity of underlying disease. The response rate was 81% (71/88) for ceftriaxone and 80% (66/83) for cefotaxime. The power of the study to detect a 15% difference in response rate at P less than .1 was 90%. The frequency of diarrhea, thrombophlebitis, prothrombin time, prolongation, colonization, and superinfection did not differ between treatment groups. Ceftriaxone 2 g once a day was as safe and effective as cefotaxime 2 g every 4 h for suspected serious bacterial infections.     

Aztreonam-flucloxacillin double beta-lactam treatment as empirical therapy of serious infections in very elderly patients

Aztreonam, the first monocyclic beta-lactam antibiotic with pure anti-Gram-negative activity, combined with flucloxacillin, a penicillinase resistant penicillin, was given as empirical treatment of 53 serious infections in very elderly people. Eighteen of the cases had positive blood cultures and 11 had a clinical picture of sepsis without positive blood cultures: Of 49 evaluable infections, 45 (92%) were cured. In 40% of the infections, antibiotic treatment could be narrowed after 72 hours to one antibiotic. Diarrhoea, mostly transitory, was the only side-effect. Aztreonam-flucloxacillin combination is a safe and effective empirical treatment regimen for serious infections in very elderly patients.     

Outcome of 8-hour dosing intervals with beta-lactam antibiotics in adult acute bacterial meningitis

The outcome of dosing with beta-lactam antibiotics at 8-h intervals for adult patients with community-acquired acute bacterial meningitis was retrospectively analysed at Sahlgrenska University Hospital, Gothenburg, Sweden. 80 medical records were identified for a 6-y period from 1999 to 2004. The most common pathogens noted were Streptococcus pneumoniae (47.5%), Neiseria meningitidis (12.5%), and Listeria monocytogenes (5.0%). Other bacteria were diagnosed in 16.3% of all episodes, but the bacteriological aetiology remained unknown in 18.8%. 79 episodes of bacterial meningitis were treated with beta-lactam antibiotics at 8-h dosing intervals. The mortality rate in these patients was 6.3%, with an incidence of permanent neurological deficiencies of 24.1%. Our study shows that a low mortality rate can be achieved using beta-lactam antibiotics at longer dosing intervals than usually recommended by international guidelines.     

A prospective randomised comparison of cefotaxime vs. netilmicin vs. cefotaxime plus netilmicin in the treatment of hospitalised patients with serious sepsis

93 patients were enrolled into a prospective randomised study to determine the efficacy and safety of netilmicin, cefotaxime or their combination in the treatment of sepsis caused by susceptible strains of Enterobacteriaceae or staphylococci. 83 patients were evaluable for safety, 74 for clinical efficacy and 63 for microbiological response including 36 patients (57%) with positive blood cultures. There were significantly more clinical failures with cefotaxime than with netilmicin even when urinary tract sepsis was excluded. Microbiological failures occurred more frequently in the cefotaxime arm and were associated with Klebsiella and Enterobacter spp. Four cefotaxime failures were subsequently successfully treated with netilmicin. More mixed infections were however enrolled by chance into the cefotaxime arm. The statistical difference between netilmicin and cefotaxime is not significant if mixed infections are excluded. There was no difference in efficacy between the netilmicin and combination groups although superinfection was seen in the latter group. The incidence of nephrotoxicity was greater in the netilmicin group but not significantly so. Only one minor case of ototoxicity was detected in the 41 patients receiving netilmicin who had serial audiograms. The results suggest that netilmicin is a more effective agent than cefotaxime for treating life-threatening infections with susceptible Enterobacteriaceae or staphylococci particularly with infections in non-urinary tract sites. If dosage of netilmicin is closely monitored by measuring serum concentrations, toxicity is minimal.     

A comparative study of ticarcillin plus tobramycin versus carbenicillin plus gentamicin for the treatment of serious infections due to gram-negative bacilli.

The combination of ticarcillin plus tobramycin (TT) or carbenicillin plus gentamicin (CG) was used to treat 82 patients with severe systemic gram-negative infection in a prospective, randomized study. Pseudomonas aeruginosa was the primary pathogen in 7 (93 per cent) of these patients. Patients treated with TT responded more frequently (92 per cent or 37 of 40) than patients treated with CG (71 per cent or 30 of 42) (p is less than 0.05). This difference was primarily due to a greater response to TT in patients with pulmonary infections (93 per cent versus 68 per cent) and infections due to Pseudomonas (92 per cent versus 70 per cent). Severity of underlying disease was also an important determinant of response. Except for a greater incidence of hepatotoxicity with CG (23 per cent versus 3 per cent; p is less than 0.02), there was no difference in toxicity, colonization with drug-resistant microorganisms or superinfection between the two treatment groups. The combination of TT appears to be superior to CG for the treatment of pulmonary infections due to Pseudomonas aeruginosa.     

Cost-effective choice of antimicrobial therapy for serious infections

The authors evaluated the financial and health implications of treatment choices for three serious classes of infection: hospital-acquired pneumonia, intra-abdominal infection, and sepsis of unknown origin. Data were obtained from a systematic review of clinical literature and published data bases, by written questionnaire from a panel of infectious disease authorities, and from actual costs at a tertiary-care hospital. For pneumonia and sepsis, the third-generation cephalosporin evaluated (ceftizoxime) was found to be less expensive than other regimens, when costs of dose preparation and administration, monitoring, and toxicity were added to drug acquisition costs. The lowestcost regimen for intra-abdominal infection was metronidazole plus gentamicin. Modest differences in efficacy would easily outweigh differences in toxicity, however, and could justify the use of more expensive regimens (e.g., mezlocillin plus gentamicin for hospital-acquired pneumonia, and cefoxitin plus gentamicin for intra-abdominal infection). If all regimens are assumed to be equally efficacious, then the third-generation cephalosporin was both lowest in cost and, owing to its low toxicity, greatest in net health benefit. Supported by a grant from Smith Kline and French Laboratories and by the Harvard Community Health Plan Foundation through the Institute for Health Research, a joint program of the Harvard Community Health Plan and Harvard University.     

Success of ampicillin plus ceftriaxone rescue therapy for a relapse of Enterococcus faecalis native-valve endocarditis and in vitro data on double beta-lactam activity

We report a patient with Enterococcus faecalis native-valve endocarditis who relapsed after 4 weeks of treatment with ampicillin plus gentamicin. The relapse was cured with ampicillin plus ceftriaxone, which was introduced after gentamicin-induced acute renal failure. This double beta-lactam combination showed a bactericidal effect in time-killing curve studies.     

Oritavancin: a new opportunity for outpatient therapy of serious infections

Oritavancin is a new antibiotic for the treatment of serious infections with Gram-positive bacteria. It has been shown to be effective against methicillin-susceptible and -resistant Staphylococcus aureus as well as enterococci. With a terminal half-life of 393 hours, oritavancin lends itself to a convenient and potentially cost-effective single-dose regimen. The single-dose regimen is currently being evaluated in pivotal phase 3 studies. This unique property provides an opportunity to assure consistent, effective, and safe treatment for serious infections while reducing the costs of care through the elimination of multiple infusions, reduced medical care staff, shorter hospital stays, and avoidance of hospital-acquired infections. These features seem ideal for the use of oritavancin in the outpatient management of serious infections. The impact that oritavancin will have on outpatient therapy is unclear. Current models will need to change with only a single infusion. Physician monitoring of the infection and underlying diseases may not be as frequent despite the need for close follow-up and frequent evaluations. There will be less need for a team of outpatient infusion specialists. Outpatient therapy will be compensated less without multiple infusions. With the possibility of fewer physician and other medical visits, there will be more responsibility for the patient and family and a reliance on patients to care for themselves. Although oritavancin offers tremendous theoretical advantages in the outpatient treatment of serious infections, care should be taken to assure the quality of care through changes in reimbursement, patient education, and development of systems to monitor care and outcomes.     

Cefotaxime therapy of serious infections with multiresistant gram-negative bacilli

33 patients with serious gram-negative bacillary infections were treated with cefotaxime. In patients with normal renal function the dose varied between 1.5 to 4 g/day. 17 patients had urinary tract infections, 5 respiratory tract infections, 1 combined urinary tract infection and respiratory tract infection, and 10 miscellaneous infections. 16 patients had septicemia. 25 infections were due to pathogens resistant in vitro to ampicillin, cephalothin, gentamicin and/or tobramycin. 15 infections had failed to respond to ampicillin, cefazolin, gentamicin or tobramycin therapy. 32/33 patients responded favourably to cefotaxime (cure or improvement) but 4 patients developed superinfection with cefotaxime-resistant bacteria. No evidence of nephrotoxicity was observed except for a transient moderate rise in creatinine in one patient.