Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics.

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

[The effect of different autotransfusion procedures on the antibiotic picture. A study on cephalosporin cefamandole]. / Der Einfluss unterschiedlicher Autotransfusionsverfahren auf Antibiotikaspiegel. Studie zum Cephalosporin Cefamandol.

Infection after open heart surgery is a serious complication since eradication of infection in these cases is difficult even with appropriate antibiotic therapy. In the attempt to avoid this problem, prophylactic administration of antibiotics is common. Their relative safety and their broad spectrum of activity make cephalosporin antibiotics popular choices for prophylaxis prior to and during operations, including cardiovascular procedures. METHODS. Preoperative antibiotic prophylaxis with 2 g cefamandole was performed in a prospective randomized study including 62 male patients divided into three groups. All patients gave informed consent, and the study was approved by the ethics committee of the hospital. Patients in group 1 (n = 21) and group 2 (n = 21) underwent aortocoronary bypass (ACVB) with extracorporeal circulation (ECC), while patients in group 3 (n = 20) had carotid surgery. Anaesthesia, coronary-bypass procedures and infusion regime were standardized. The flow rate during ECC was maintained at 2.41/min/m2 and the rectal temperature between 33 degrees and 34 degrees C. Arterial and urine specimens for the determination of plasma and urine levels of cefamandole were taken at definite times. Autologous blood salvage during operation was performed with haemofiltration techniques (HF) in group 1 (HF 80, Fresenius, Bad Homburg, Germany) and with cell separation techniques (CS) in group 2 (Hemonetics III, Hemonetics). Plasma and urine cefamandole levels were measured by high-pressure liquid chromatography (HPLC). RESULTS. After administration of 2 g cefamandole mean peak levels of 404.6 +/- 141.7 micrograms/ml were seen. Because of haemodilution at the beginning of extracorporeal circulation, group 1 and 2 showed much lower cefamandole plasma levels, 22.1 +/- 11.6 micrograms/ml and 24.3 +/- 14.4 micrograms/ml, than group 3 (after the same time course), with 47.4 +/- 19.1 micrograms/ml. For all patients in group 1 and 2 prebypass time (70.3 +/- 22.4 min) and the duration of the ECC (72.3 +/- 17.7 min) were comparable. There was a significant correlation between prebypass time and cefamandole plasma levels at the beginning of extracorporeal circulation (P < 0.001). No correlation could be seen for the plasma concentration after discontinuation of the extracorporeal circulation and the duration of extracorporeal circulation. The volume of autologous red packed cells and the enclosed amount of cefamandole showed a significant difference (P < 0.001) between group 1 (1120.0 +/- 296.8 ml, 27.5 +/- 17.1 mg) and group 2 (734.3 +/- 186.6 ml, 2.9 +/- 3.2 mg). The plasma cefamandole level after transfusion of autologous blood displayed a significant correlation (p < 0.01) with cefamandole concentration in the autologous red packed cells. Transfusion of the autologous blood produced no significant increase in plasma cefamandole levels. With an operation time of more than 2.5 h during ECC the cefamandole plasma level decreased below the necessary minimal inhibitory concentration (MIC90), particularly for gram-negative bacteria. CONCLUSION. Additional administration of 1 g cefamandole shortly before the beginning of cardiopulmonary bypass is recommended, particularly for surgical procedures with ECC of more than 2.5 h. Adjustment of drug dosage prior to or during surgery may be required to optimize therapy, but before this can be achieved precisely, more information on drug disposition during the operative procedures is needed.

A comparative study of cefamandole and ceftriaxone as prophylaxis in cardiac surgery.

We compared the prophylactic use of cefamandole and ceftriaxone in 40 patients undergoing elective cardiac surgery. Postoperative wound infection occurred in one and two patients, respectively, in each group (n.s.), and bronchial superinfection in one patient in each group. In 12 additional patients drug concentrations in plasma and pericardial fluid were measured at different times following the administration of ceftriaxone. Plasma and pericardial fluid concentrations of ceftriaxone were above the minimal inhibitory concentration of susceptible microorganisms for up to 24 h after intravenous administration. We conclude, firstly, that the incidence of infection after cardiac surgery is low with both cefamandole and ceftriaxone prophylaxis. Secondly, efficient plasma and pericardial fluid levels of ceftriaxone last for up to 24 h after intravenous administration.

Antibiotic prophylaxis for cardiovascular surgery. Efficacy with coronary artery bypass.

Two hundred twenty patients were randomly assigned to receive either ceforanide or cephalothin as perioperative antibiotic prophylaxis during cardiovascular surgery. More infections were seen among cephalothin recipients (8 deep, 32 total) than among ceforanide recipients (1 deep, 17 total). Among patients who had only coronary artery bypass grafting, more cephalothin recipients had infection than did ceforanide recipients (19 of 82 as opposed to 7 of 83; p = 0.001; relative risk, 2.7; 95% confidence interval, 1.22 to 6.18). The difference between the two regimens was attributable to fewer blood, wound, and urinary tract infections. Among patients who had other procedures, there was no difference in the efficacy of the two regimens. Cephalothin recipients who developed wound or blood stream infections had lower antibiotic levels in their atrial appendages than recipients not developing such infections (p = 0.02). If one assumes that cephalothin does not increase the risk of infection, then these data show that antibiotic prophylaxis prevents infection after coronary artery bypass surgery, and, in the dosages used, that ceforanide is superior to cephalothin.

Effectiveness of cefamandole against methicillin-resistant strains of Staphylococcus aureus in vitro and in experimental infections.

An investigation was carried out into the effectiveness of cefamandole as compared to that of cephalothin against methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus both in vitro and in mice with the experimental peritonitis-induced septicaemia as a model for a generalized infection. In the agar-diffusion test 95% of 118 and in the broth-dilution test 80% of 30 methicillin-resistant strains were sensitive to cefamandole. In experimental infections the ED50 with methicillin-resistant strains was 20 times greater than that required for the methicillin-sensitive strain although the MIC was only twice that for the latter. Doses of cephalothin required for treatment of infections due to methicillin-resistant strains were also twenty times greater than for those due to the methicillin-sensitive strain. But these differences were consistent with those in MIC (by factors of 16-32). Thus, the results of in-vitro testing of cefamandole are not predictive for its therapeutic efficacy in staphylococcal infections with methicillin-resistant strains. Therefore, rather than relying on inhibition zone diameter and MIC, the information that a staphylococcal strain is methicillin-resistant should be used as an indication not to choose cefamandole for chemotherapy.

Clinical and laboratory evaluation of cefamandole in the therapy of Haemophilus spp. Bronchopulmonary infections.

A prospective, randomized, single-blind comparison of parenteral cefamandole and ampicillin was conducted in 27 hospitalized adult patients with pneumonia or purulent tracheobronchitis due to Haemophilus spp. Patients received either parenteral cefamandole or ampicillin in a dose of 1 g every 6 h. Cefamandole was as effective and safe as ampicillin. Of the 14 patients treated with cefamandole, 13 were considered cured, as were 12 of the 13 treated with ampicillin. One patient in each treatment group improved clinically but did not clear his sputum of Haemophilus spp. One patient treated with cefamandole had a recurrence of Haemophilus spp. bronchitis 9 days after cure. Adverse effects were more common in the cefamandole-treated group (50% versus 15%), but were mild and did not require discontinuation of therapy in any patient. The in vitro susceptibilities of 64 clinical isolates of Haemophilus spp. to 10 antibiotics were determined. Cefamandole was the most active of the cephalosporin-cephamycin antibiotics tested, inhibiting 98% of 61 non-beta-lactamase-producing isolates at 2 mug/ml and 100% at 4 mug/ml. Cefamandole inhibited the three ampicillin-resistant isolates at 2 mug/ml or less. Cephapirin, cefoxitin, and cephalothin were the next most active, whereas cefazolin and cephradine were the least active.

Clinical and laboratory investigation of cefamandole in infections of infants and children.

Forty-seven infants and children with a variety of infections including bacteremia, ethmoiditis, and periorbital cellulitis, soft tissue infection, pneumonia, and lymphadenitis were treated with intravenous cefamandole. The infections were due to Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae. The clinical response was prompt, and, with the exception of two cases who developed skin rash, significant side effects were not noted. In vitro cefamandole was very effective in inhibiting the growth of H. influenzae, including ampicillin-resistant isolates.

Clinical and laboratory investigation of cefamandole therapy of infections in infants and children.

Cefamandole nafate was effective in the treatment of a variety of infections caused by Staphylococcus aureus, Streptococcus pyogenes group A, Streptococcus pneumoniae, and Haemophilus influenzae in infants and children. The infections included periorbital cellulitis and ethmoiditis, bacteremia, cellulitis, pneumonia, and lymphadenitis. In vitro, cefamandole was effective in inhibiting the growth of H. influenzae isolated from blood or cerebrospinal fluid of patients with meningitis or sepsis. In two patients rash developed and cefamandole was discontinued. Other significant adverse effects were not noted.