Ceftazidime-avibactam and intrapleural amikacin therapy for extensively drug-resistant Pseudomonas aeruginosa thoracic empyema
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Thoracic empyema and concomitant bronchopleural fistula are serious complications of pneumonia. The treatment of empyema caused by extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) has become increasingly challenging.A 57-year-old woman with controlled schizophrenia developed hospital-associated bacterial pneumonia secondary to P. aeruginosa on day 13 of hospitalization for brain meningioma surgery.Chest radiography and computed tomography revealed right-sided necrotizing pneumonia with pneumothorax, a focal soft tissue defect over the right lower chest wall, and a mild right-sided encapsulated pleural effusion with consolidation. XDR-PA was isolated on empyema cultures.The patient was treated with intrapleural amikacin as a bridge to video-assisted thoracoscopic surgery, followed by novel ceftazidime-avibactam therapy.On the 104th day of admission, the patient underwent chest wall debridement and closure. The patient was discharged on day 111. Twenty-eight days after discharge, there were no observable sequelae of empyema.Although the minimum inhibitory concentration of ceftazidime-avibactam for XDR-PA is relatively high (8 mg/L), this report emphasizes the efficacy of ceftazidime-avibactam treatment for XDR-PA empyema, as well as the importance of source control.Keywords:
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Treatment of severe Pseudomonas infections often calls for multidrug therapy. Combinations of aminoglycosides, beta-lactams and/or quinolones are generally administered, the effect of which may be additive, synergistic or indifferent. The present in vitro study was designed to find out the exact outcome of the postantibiotic effect (PAE). The minimal inhibitory concentrations and the PAE of three antibiotics (amikacin, ceftazidime and ciprofloxacin) were determined both singly and in combination. Ceftazidime alone exhibited a negative PAE but a synergistic effect was observed for the combination of ceftazidime with amikacin. The combination of ceftazidime with ciprofloxacin and ciprofloxacin with amikacin however gave an indifferent PAE. This synergistic PAE of amikacin with ceftazidime has a significant effect on designing optimal dosage regimens.
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The in vivo efficacies of ceftazidime, aztreonam, and the combinations of ceftazidime with amikacin and aztreonam with amikacin were studied in the rabbit left-sided endocarditis model by using two strains of Pseudomonas aeruginosa, one multisusceptible and one multiresistant, in a total of 156 animals. Antibiotics were given intramuscularly for 10 days, as follows: amikacin, 7 mg/kg of body weight every 8 h, and ceftazidime and aztreonam, 50 mg/kg every 8 h. All regimens except amikacin alone significantly reduced the number of CFU per gram of vegetation (P < or = 0.008), but only for the multisusceptible strain for which sterile vegetations were obtained in 20, 25, 21, 75, and 53% of the groups treated with amikacin, ceftazidime, aztreonam, and the combination groups ceftazidime-amikacin and aztreonam-amikacin, respectively (ceftazidime plus amikacin versus controls, P = 0.001). Regarding the decrease in the numbers of colonies in vegetations, (i) all regimens significantly reduced the number of CFU per gram of vegetation (P < 0.001), (ii) results with ceftazidime-amikacin compared with those with monotherapy were significantly different (P < or = 0.007), and (iii) results with aztreonam-amikacin, although better than those with monotherapy, were marginally not statistically significant. At 1 h postdose, mean amikacin, aztreonam, and ceftazidime levels in serum were 35 +/- 19.4, 89.6 +/- 8.16, and 92.61 +/- 11.52 micrograms/ml, respectively. It was concluded that the combination of ceftazidime, and possibly aztreonam, with amikacin given at high doses and short intervals could have a place in the therapy of patients with left-sided endocarditis caused by P. aeruginosa.
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We investigated the efficacy of a potent new antipseudomonal beta-lactam agent, ceftazidime, in a model of right-sided Pseudomonas endocarditis in 72 rabbits. Animals received either: no therapy (controls), amikacin (15 mg/kg/day), ceftazidime (100 mg/kg/day) or amikacin + ceftazidime. Amikacin + ceftazidime was significantly more effective than single-drug regimens in terms of reduction of mortality (p less than 0.01), prevention of pulmonary infarction (p less than 0.05), reduction of mean vegetation titers of Pseudomonas aeruginosa (p less than 0.05-p less than 0.0005), sterilization of vegetations (p less than 0.0005) and reduction in prevalence of bacteriologic relapses after therapy (p less than 0.005). There was no development of resistance in vivo to either amikacin or ceftazidime.
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The in vivo efficacies of amikacin, ceftazidime, and their combination were evaluated in experimental aortic valve endocarditis due to Pseudomonas aeruginosa. Eighty catheterized rabbits were infected with a P. aeruginosa strain susceptible to both amikacin and ceftazidime and then received no therapy (controls), amikacin (15 mg/kg per day), ceftazidime (100 mg/kg per day), or amikacin-ceftazidime. Amikacin-ceftazidime significantly lowered vegetation titers of P. aeruginosa at day 7 of therapy versus other regimens (P less than 0.0005). However, by day 14 of therapy, vegetation titers in animals receiving amikacin or ceftazidime regimens or both were not different from those of untreated controls; this was associated with in vivo development of amikacin resistance in most infected vegetations (79%), a phenomenon not seen at day 7 of therapy. Amikacin resistance was unstable in vivo, being undetectable in vegetations examined 5 days after treatment with amikacin had been completed. In contrast, ceftazidime resistance (first noted at day 7 of therapy in 12% of vegetations) persisted after termination of treatment with this agent. These in vivo observations on loss of amikacin resistance and persistence of ceftazidime resistance were mirrored during in vitro passage studies of amikacin- or ceftazidime-resistant P. aeruginosa strains isolated from cardiac vegetations. Amikacin resistance was no longer detectable by passage 5 in antibiotic-free media; however, ceftazidime resistance was stable despite 15 such passages. In vivo development of aminoglycoside-beta-lactam resistances was associated with poor bacteriologic efficacy in this model.
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Ceftazidime-avibactam and comparator antibiotics were tested by the broth microdilution method against 200 Enterobacteriaceae and 25 Pseudomonas aeruginosa strains resistant to fluoroquinolones (including strains with the extended-spectrum β-lactamase [ESBL] phenotype and ceftazidime-resistant strains) collected from our institution. The MICs and mechanisms of resistance to fluoroquinolone were also studied. Ninety-nine percent of fluoroquinolone-resistant Enterobacteriaceae strains were inhibited at a ceftazidime-avibactam MIC of ≤4 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference). Ceftazidime-avibactam was very active against ESBL Escherichia coli (MIC90 of 0.25 mg/liter), ESBL Klebsiella pneumoniae (MIC90 of 0.5 mg/liter), ceftazidime-resistant AmpC-producing species (MIC90 of 1 mg/liter), non-ESBL E. coli (MIC90 of ≤0.125 mg/liter), non-ESBL K. pneumoniae (MIC90 of 0.25 mg/liter), and ceftazidime-nonresistant AmpC-producing species (MIC90 of ≤0.5 mg/liter). Ninety-six percent of fluoroquinolone-resistant P. aeruginosa strains were inhibited at a ceftazidime-avibactam MIC of ≤8 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference), with a MIC90 of 8 mg/liter. Additionally, fluoroquinolone-resistant mutants from each species tested were obtained in vitro from two strains, one susceptible to ceftazidime and the other a β-lactamase producer with a high MIC against ceftazidime but susceptible to ceftazidime-avibactam. Thereby, the impact of fluoroquinolone resistance on the activity of ceftazidime-avibactam could be assessed. The MIC90 values of ceftazidime-avibactam for the fluoroquinolone-resistant mutant strains of Enterobacteriaceae and P. aeruginosa were ≤4 mg/liter and ≤8 mg/liter, respectively. We conclude that the presence of fluoroquinolone resistance does not affect Enterobacteriaceae and P. aeruginosa susceptibility to ceftazidime-avibactam; that is, there is no cross-resistance.
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Recently, concern has been expressed regarding the choice of amikacin sulfate as the companion drug to vancomycin hydrochloride for intravitreal injection in the initial treatment of patients with postoperative endophthalmitis.1The concern arises because of reports suggesting that amikacin may cause macular infarction. It has been recommended that ceftazidime be used in its place. Because of these reports, investigators and consultants of the Endophthalmitis Vitrectomy Study (EVS), sponsored by the National Eye Institute, reviewed their choice of antibiotics for intravitreous injection in the treatment of postoperative endophthalmitis. In vitro, both amikacin and ceftazidime are highly active against gram-negative bacilli, and few strains are resistant. Data from a retrospective series of cases of endophthalmitis caused by gram-negative bacilli showed one of 35 strains resistant to amikacin and none to ceftazidime.2So far, in the EVS, three of 21 isolates were resistant to ceftazidime and two to amikacin. Based on
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The in vitro activity of ceftazidime-avibactam was evaluated against 341 Gram-negative isolates from 333 patients in a randomized, phase 3 clinical trial of patients with complicated urinary tract or intra-abdominal infections caused by ceftazidime-nonsusceptible pathogens (NCT01644643). Ceftazidime-avibactam MIC90 values against Enterobacteriaceae and Pseudomonas aeruginosa (including several class B or D enzyme producers that avibactam does not inhibit) were 1 and 64 μg/ml, respectively. Overall, the ceftazidime-avibactam activity against ceftazidime-nonsusceptible isolates was comparable to the activity of ceftazidime-avibactam previously reported against ceftazidime-susceptible isolates. (This study has been registered at ClinicalTrials.gov under identifier NCT01644643.).
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