Prospective randomized study of once-daily versus thrice-daily netilmicin regimens in patients with intraabdominal infections

One hundred and ninety-seven patients with intraabdominal infections were enrolled in a prospective randomized multicenter study of netilmicin administered once daily (n=98) versus thrice daily (n=99) in combination with tinidazole administered once daily. Randomization was achieved for the infection site, clinical severity score, daily and total netilmicin dose, and duration of treatment. The mean maximum peak and trough levels of netilmicin in serum were 21.1 and 1.3 mg/l respectively for once daily treated patients, and 10.0 and 2.3 mg/l for thrice daily treated patients (p<0.05 for both parameters). The clinical response did not differ between patients treated once daily and those treated thrice daily. Overall rates for clinical cure, improvement and failure of therapy were 77 %, 17 % and 6 % respectively. No significant differences were found between once daily and thrice daily regimens in the occurrence of auditory, vestibular and renal toxicity, overall rates being 5 %, 1 % and 10 % respectively. Impairment of renal function was significantly related to higher maximum netilmicin serum trough levels during therapy, a higher clinical severity score and advanced age. It is concluded that netilmicin given once daily is as effective and safe as the multiple dose regimen. However, monitoring of aminoglycoside serum through levels is still advisable, especially in the old and severely ill patient.     

Effect of hemoglobin on the development ofPseudomonas aeruginosa infection

The disease caused by injection ofP. aeruginosa suspension in a hemoglobin solution was more severe (greater weight loss and larger abscesses in primary foci) than that induced by the same dose of the microbe in Hanks' solution (control). It was supposed that in the control the viability of the microorganisms was suppressed by iron deficiency in surrounding tissues, which was particularly pronounced upon accumulation in a limited space of great numbers of bacterial cells competing with each other for iron. Iron released from hemoglobin provides better conditions for the development ofP. aeruginosa. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 3, pp. 351–352, March, 1997     

Prophylaxis ofPseudomonas aeruginosa infections in leukopenic mice by a combination of active and passive immunization

Mice rendered leukopenic with cyclophosphamide and then challenged with viablePseudomonas aeruginosa were used to determine the protective efficacy of active immunization against exotoxin A and of passive immunization with human antiserum toEscherichia coli J5, a rough mutant ofEscherichia coli O111∶B4. Neither treatment alone provided a greater degree of protection than its respective control. However, the combination of these treatments produced a moderate, yet consistent, increase in the survival of infected immunosuppressed mice.     

Predictors of multidrug-resistant Pseudomonas aeruginosa in neutropenic patients with bloodstream infection

ObjectivesTo assess risk factors for multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infection in neutropenic patients.MethodsSingle-centre retrospective analysis of consecutive bloodstream infection (BSI) episodes (2004–2017, Barcelona). Two multivariate regression models were used at BSI diagnosis and P. aeruginosa detection. Significant predictors were used to establish rules for stratifying patients according to MDR-PA BSI risk.ResultsOf 661 Gram-negative BSI episodes, 190 (28.7%) were caused by P. aeruginosa (70 MDR-PA). Independent factors associated with MDR-PA among Gram-negative organisms were haematological malignancy (OR 3.30; 95% CI 1.15–9.50), pulmonary source of infection (OR 7.85; 95% CI 3.32–18.56), nosocomial-acquired BSI (OR 3.52; 95% CI 1.74–7.09), previous antipseudomonal cephalosporin (OR 13.66; 95% CI 6.64–28.10) and piperacillin/tazobactam (OR 2.42; 95% CI 1.04–5.63), and BSI occurring during ceftriaxone (OR 4.27; 95% CI 1.15–15.83). Once P. aeruginosa was identified as the BSI aetiological pathogen, nosocomial acquisition (OR 7.13; 95% CI 2.87–17.67), haematological malignancy (OR 3.44; 95% CI 1.07–10.98), previous antipseudomonal cephalosporin (OR 3.82; 95% CI 1.42–10.22) and quinolones (OR 3.97; 95% CI 1.37–11.48), corticosteroids (OR 2.92; 95% CI 1.15–7.40), and BSI occurring during quinolone (OR 4.88; 95% CI 1.58–15.05) and β-lactam other than ertapenem (OR 4.51; 95% CI 1.45–14.04) were independently associated with MDR-PA. Per regression coefficients, 1 point was assigned to each parameter, except for nosocomial-acquired BSI (3 points). In the second analysis, a score >3 points identified 60 (86.3%) out of 70 individuals with MDR-PA BSI and discarded 100 (84.2%) out of 120 with non-MDR-PA BSI.ConclusionsA simple score based on demographic and clinical factors allows stratification of individuals with bacteraemia according to their risk of MDR-PA BSI, and may help facilitate the use of rapid MDR-detection tools and improve early antibiotic appropriateness.     

Molecular epidemiological analysis ofPseudomonas aeruginosa strains causing failure of antibiotic therapy in cystic fibrosis patients

A combination of esterase electrophoretic typing and analysis of the restriction fragment length polymorphism of ribosomal DNA regions (ribotyping) was used to compare 27Pseudomonas aeruginosa strains isolated before and after two-week courses of anti-pseudomonal treatment in seven cystic fibrosis patients. A total of 12 courses of therapy were studied in which ciprofloxacin, ceftazidime, azlocillin or imipenem were used alone or in combination with tobramycin. Isolates at a count of 10⁶ cfu/ml of sputum were collected when there was evidence of therapeutic failure on the basis of persistence of isolates whether or not they were resistant to the antibiotic used for therapy. Emergence of resistance was observed in ten cases and failure to eradicate sensitive strains in five cases. Among the 27 isolates, eight zymotypes and five ribotypes were identified. With this typing approach, resistant post-therapy isolates were found to be identical to pre-therapy isolates in all cases but one. However, in one case an additional resistant strain was isolated after therapy besides that initially present. In all five cases in which susceptibility was still observed after treatment, pretherapy and post-therapy isolates were indistinguishable. Using this molecular typing approach, all the strains were typable. Thus combination of esterase typing and ribotyping should improve the analysis of therapeutic failure in cystic fibrosis patients.     

Evaluation of ciprofloxacin in the treatment ofPseudomonas aeruginosa infections

The efficacy and safety of ciprofloxacin in the treatment ofPseudomonas aeruginosa infections was evaluated in 72 patients suffering from upper urinary tract infection (19 patients), deep soft tissue infection (16), chronic osteomyelitis (12), abscess (7), chronic otitis media (6), otitis externa (3) and bronchopneumonia (9). Forty-eight patients received an oral dose of 500 mg or 750 mg b.i.d. and five patients an i.v. dose of 200 mg b.i.d., while 19 patients were given both oral and parenteral doses. The duration of therapy ranged from seven days to more than four months. The MICs of ciprofloxacin for thePseudomonas aeruginosa strains isolated were in the range < 0.06–2 mg/l; 36% of the strains were resistant to all other available antibiotics. At follow-up after a minimum of six months the clinical success rate was 75% and the infecting organism was permanently eradicated in 49% of the patients. In nine patients the organism developed resistance, particularly when the initial MIC was higher than 0.5 mg/l. No significant adverse reactions were observed. Ciprofloxacin is the first antipseudomonal antimicrobial agent which can be administered orally and therefore fulfills a need in chemotherapy.     

Use of ciprofloxacin in the treatment ofPseudomonas aeruginosa infections

The therapeutic efficacy and safety of ciprofloxacin was studied in 30 patients withPseudomonas aeruginosa infections. In 20 patients ciprofloxacin was given alone and in 10 patients (including 8 compromized hosts) in combination with an aminoglycoside (9) or azlocillin (1). Ciprofloxacin was given in doses of 500 mg orally or 200–300 mg i. v. every 12 h. In patients receiving only ciprofloxacin clinical cure with eradication of bacteria was obtained in 15 patients (75%) with infections of bone and joint (6), skin and soft tissue (4), lung (2), middle ear (2) and CSF (1). Two patients with lymphoma andPseudomonas aeruginosa pneumonia died. In patients receiving combination therapy a definite therapeutic success was achieved in four (40%). Three patients withPseudomonas aeruginosa septicemia died. In seven patients nine bacterial strains with decreasing susceptibility of ciprofloxacin (increase in MIC from 0.5g/ml to 2–16 g/ml) were selected (6Pseudomonas aeruginosa, 1Enterobacter cloacae, 1Serratia marcescens, 1Staphylococcus aureus). Ciprofloxacin was well tolerated. This new quinolone seems to be suitable for single drug treatment ofPseudomonas aeruginosa infections in patients with normal host defense mechanisms, while its therapeutic potential in compromized hosts requires further evaluation.     

Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection

Combinations of ciprofloxacin with azlocillin, piperacillin and ticarcillin were tested in vitro against clinical isolates. Azlocillin plus ciprofloxacin showed synergy against 30% of Pseudomonas aeruginosa isolates; it was either synergistic or additive against 78% of all isolates tested even those resistant to the beta-lactam. Synergism was rarely noted for Klebsiella pneumoniae, Escherichia coli, Enterobacter spp. or Branhamella spp. isolates. Minimum inhibitory concentrations of ciprofloxacin plus azlocillin, plus piperacillin and plus ticarcillin against Pseudomonas spp. were reduced 4 or 2 fold, respectively. However, the combination azlocillin plus ciprofloxacin showed primarily indifference against gram-positive strains. Neutropenic mice infected with a lethal challenge of Pseudomonas spp. were protected by a combination of azlocillin and ciprofloxacin. Its additive and/or synergistic effects and expanded spectrum of activity against streptococci, methicillin-resistant staphylococci and JK corynebacteria may provide an alternative to traditional therapy.     

Characteristics ofPseudomonas aeruginosa strains causing septicemia in a Spanish hospital 1981–1990

The epidemiological and biochemical characteristics ofPseudomonas aeruginosa strains causing septicemia in a Spanish hospital over a ten-year period (1981–1990) were analyzed. A total of 207 episodes, corresponding to 0.7 episodes per 1,000 inpatients and 3.2 % of the total number of episodes of septicemia, were registered. Males were more often affected than females (rate 3.2:1). The respiratory (24.6 %) and urinary (21.2 %) tracts were the main portals of entry, while haematologic and solid tumours (15.4 %) were the most frequent underlying diseases. More than 86 % of the strains were susceptible to ceftazidime, mezlocillin, piperacillin and amikacin. Seventy strains were subjected to typing and analysis of virulence factors. Serotypes O:6, O:11 and O:2 could be considered endemic (each present in more than 11.4 % of strains). Pyocin typing, antibiotyping and resistotyping were preferred as secondary typing methods to phage typing and plasmid profile analysis. The combination of methods revealed a large diversity of strains although some cluster predominated. More than 80 % of the strains produced several exoenzymes, possessed pyoverdin and showed haemolytic activity, and all except one showed serum resistance. All strains were susceptible to silver and more than 80 % to mercury and boron, but all were resistant to iodine.     

Treatment with a piperacillin and netilmicin combination of patients with agranulocytosis

Sixty infections episodes in granulocytopenic patients have been treated in first line with a piperacillin and netilmicin combination. Treatment has been successful in 78% bacterial infections. So, this antibiotic combination appears as a very effective therapy of infection in neutropenic patients.     

Direct evaluation of Pseudomonas aeruginosa biofilm mediators in a chronic infection model

Biofilms contribute to Pseudomonas aeruginosa persistence in a variety of diseases, including cystic fibrosis, burn wounds, and chronic suppurative otitis media. However, few studies have directly addressed P. aeruginosa biofilms in vivo. We used a chinchilla model of otitis media, which has previously been used to study persistent Streptococcus pneumoniae and Haemophilus influenzae infections, to show that structures formed in vivo are biofilms of bacterial and host origin within a matrix that includes Psl, a P. aeruginosa biofilm polysaccharide. We evaluated three biofilm and/or virulence mediators of P. aeruginosa known to affect biofilm formation in vitro and pathogenesis in vivo--bis-(3',5')-cyclic dimeric GMP (c-di-GMP), flagella, and quorum sensing--in a chinchilla model. We show that c-di-GMP overproduction has a positive impact on bacterial persistence, while quorum sensing increases virulence. We found no difference in persistence attributed to flagella. We conclude from these studies that a chinchilla otitis media model provides a means to evaluate pathogenic mediators of P. aeruginosa and that in vitro phenotypes should be examined in multiple infection systems to fully understand their role in disease.     

Cefotaxime versus ampicillin, methicillin and netilmicin in combination for treatment of febrile episodes in patients with haematologic malignancy

A prospective, randomized trial comparing treatment of 61 febrile episodes with cefotaxime (CTX) versus a combination of ampicillin, methicillin, and netilmicin (AMN) was carried out in 58 patients with leukaemia or malignant lymphoma, of whom 28 had a granulocyte count of less than or equal to 500 X 10(6)/l. The overall response frequency was 63% for CTX against 49% for the AMN combination, the latter figure being lower than generally reported in the literature. The difference was not statistically significant. In 21 episodes pathogens were isolated, 16 of them from the blood. All isolated bacteria but one, a strain of Bacteroides fragilis, were fully sensitive to at least one of the three antibiotics in the combination, and all but one, a strain of Listeria monocytogenes, were fully sensitive to CTX. These results indicate that CTX seems to be a promising alternative as monotherapy for empiric treatment of febrile episodes in patients with haematologic malignancies. Further investigations will, however, be required before completely rational choices between mono and combination therapy of febrile episodes in immunosuppressed patients can be made.     

Evaluation of the E test in testing susceptibility ofPseudomonas aeruginosa to tobramycin

The E test, a new technique for measuring MICs of antimicrobial agents with the ease of disc diffusion tests, was evaluated in testing the susceptibility of 94 clinical isolates ofPseudomonas aeruginosa to tobramycin. The use of the E test was found acceptable; 93 % of the MIC results were within one log₂ dilution step and 100 % were within two log₂ dilution steps when the MICs obtained by the E test were compared to those obtained by the conventional agar dilution method. When the E test was compared to the broth microdilution method the corresponding figures were 84 % and 100 %, respectively.     

Avirulence of a Pseudomonas aeruginosa algC mutant in a burned-mouse model of infection.

The virulence of wild-type Pseudomonas aeruginosa PAO1 and that of a genetically defined algC mutant, PAO1 algC::tet, were compared in a burned-mouse model of infection. Unlike PAO1, PAO1 algC::tet was avirulent, grew less well in the eschar, and did not disseminate to the liver of challenged animals. We have previously shown that the P. aeruginosa algC gene is required for biosynthesis of alginate and lipopolysaccharide (M.J. Coyne, Jr., K.S. Russell, C.L. Coyle, and J.B. Goldberg, J. Bacteriol. 176:3500-3507, 1994). In order to determine whether the alginate or lipopolysaccharide (LPS) defect was responsible for the avirulence of this strain, we constructed a strain with a mutation in an alginate-specific gene, algD. PAO1-algD was virulent in the burned-mouse model, thus implicating the LPS defect in PAO1 algC::tet as the relevant alteration responsible for the avirulence of this strain.