Continuous high-dose infusion of doripenem in a pneumonia patient infected by carbapenem-resistant Pseudomonas aeruginosa: a case report
Kazutaka OdaHidenobu KamoharaTomomi KatanodaYumi HashiguchiKoji IwamuraKisato NosakaHirofumi JonoHideyuki Saito
3
Citation
16
Reference
10
Related Paper
Citation Trend
Abstract:
Despite the high mortality of patients with sepsis and carbapenem-resistant bacteria infection, appropriate antimicrobial therapies are yet to be established. Here, we have reported the case of a patient with pneumonia that subsequently developed by carbapenem-resistant Pseudomonas aeruginosa infection and was treated with a continuous high-dose infusion of doripenem.We started a continuous intravenous infusion of doripenem 3 g/day although the 59-year-old woman (body weight, 45 kg) had developed septic acute kidney injury, followed by continuous renal replacement therapy (the effluent flow rate was 650 mL/h). The minimum inhibitory concentration (MIC) of doripenem was 8 mg/L. The concentration of unbound doripenem in the serum was measured by using high-performance liquid chromatography. Twenty hours after the initial dose, the patient's serum level of doripenem was 47.8 μg/mL; the level decreased to 33.6 μg/mL at 111 h after initial dosing. The unbound doripenem concentration in the serum was maintained four times above the MIC throughout the treatment. After the completion of 11 days of dosing, the patient was discharged from the intensive care unit. During the treatment period, the MIC remained at 8 mg/L.A continuous high-dose infusion of doripenem is a potentially efficient strategy for the treatment of antimicrobial-resistant bacteria. Moreover, therapeutic drug monitoring may be useful for patients displaying variable pharmacokinetics, because the MIC is generally high in resistant bacteria.Keywords:
Doripenem
Carbapenem
AbstractDoripenem is a new 1-β-methyl carbapenem with broad-spectrum activity against clinically important pathogens. Its activity matches imipenem or ertapenem againstGram-positive bacteria and meropenem against Gram-negative bacteria. It may offerslightly more activity than meropenem against selected pathogens. It does not requirethe addition of cilastatin. Doripenem is stable to hydrolysis by most of the β-lacta-mases, excluding carbapenem-hydrolyzing β-lactamases. We performed dockings ofimipenem, meropenem, ertapenem and doripenem with imipenem-hydrolyzing β-lacta-mase, Sme1, separately. Energy calculations revealed that the complex involving doripenem was much less stable. Hence doripenem resists attack by carbapenem-hy-drolyzing β-lactamases at least to some extent. Empiric therapy with doripenem may be useful in hospital settings where multidrug resistance has emerged. However, the proper place for this drug in current antibiotic prescribing practices needs to be determined.Keywords: Doripenemmultidrug resistanceantipseudomonalsantibiotic armory
Doripenem
Cite
Citations (9)
Doripenem
Ertapenem
Carbapenem
Cite
Citations (12)
Doripenem is a carbapenem antibiotic that covers a wide range of gram-positive and gram-negative pathogens. In vitro studies have provided insight into certain features of doripenem's activity profile that may have particular relevance in the clinical setting. For instance, in vitro data indicate that doripenem combines the intrinsic activity of meropenem against gram-negative pathogens with the intrinsic activity of imipenem against gram-positive pathogens. Also notable is the fact that the in vitro activity of doripenem against problematic gram-negative pathogens, in particular Pseudomonas aeruginosa, is potent-recent data show that the minimum concentration necessary for inhibition of 90% of all isolates (MIC(90)) of doripenem with respect to P. aeruginosa (4 microg/mL) is 2-4 times lower than the corresponding MIC(90) values of meropenem and imipenem. Furthermore, doripenem shows a limited ability to select for carbapenem-resistant mutants in vitro. Such experimental findings suggest that doripenem may represent a valuable option when carbapenem therapy is warranted for the treatment of serious infection.
Doripenem
Carbapenem
Ertapenem
Gram
Cite
Citations (21)
ABSTRACT Only limited data exist on Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) treated with imipenem, meropenem, or doripenem. Therefore, we conducted a prospective observational study in 169 patients who developed Pseudomonas aeruginosa VAP. Imipenem, meropenem, and doripenem MICs for Pseudomonas aeruginosa isolates were determined using Etests and compared according to the carbapenem received. Among the 169 isolates responsible for the first VAP episode, doripenem MICs were lower ( P < 0.0001) than those of imipenem and meropenem (MIC 50 s, 0.25, 2, and 0.38, respectively); 61%, 64%, and 70% were susceptible to imipenem, meropenem, and doripenem, respectively ( P was not statistically significant). Factors independently associated with carbapenem resistance were previous carbapenem use (within 15 days) and mechanical ventilation duration before VAP onset. Fifty-six (33%) patients had at least one VAP recurrence, and 56 (33%) died. Factors independently associated with an unfavorable outcome (recurrence or death) were a high day 7 sequential organ failure assessment score and mechanical ventilation dependency on day 7. Physicians freely prescribed a carbapenem to 88 patients: imipenem for 32, meropenem for 24, and doripenem for 32. The remaining 81 patients were treated with various antibiotics. Imipenem-, meropenem-, and doripenem-treated patients had similar VAP recurrence rates (41%, 25%, and 22%, respectively; P = 0.15) and mortality rates (47%, 25%, and 22%, respectively; P = 0.07). Carbapenem resistance emerged similarly among patients treated with any carbapenem. No carbapenem was superior to another for preventing carbapenem resistance emergence.
Doripenem
Carbapenem
Ventilator-associated Pneumonia
Cite
Citations (68)
A consensus exists among clinicians that imipenem/cilastatin is the most epileptogenic carbapenem, despite inconsistencies in the literature. We conducted a meta-analysis of all randomized controlled trials comparing carbapenems with each other or with non-carbapenem antibiotics to assess the risk of seizures for imipenem, meropenem, ertapenem and doripenem. In the risk difference (RD) analysis, there were increased patients with seizure (2 per 1000 persons, 95% CI 0.001, 0.004) among recipients of carbapenems versus non-carbapenem antibiotics. This difference was largely attributed to imipenem as its use was associated with an additional 4 patients per 1000 with seizure (95% CI 0.002, 0.007) compared with non-carbapenem antibiotics, whereas none of the other carbapenems was associated with increased seizure. Similarly, in the pooled OR analysis, carbapenems were associated with a significant increase in the risk of seizures relative to non-carbapenem comparator antibiotics (OR 1.87, 95% CI 1.35, 2.59). The ORs for risk of seizures from imipenem, meropenem, ertapenem and doripenem compared with other antibiotics were 3.50 (95% CI 2.23, 5.49), 1.04 (95% CI 0.61, 1.77), 1.32 (95% CI 0.22, 7.74) and 0.44 (95% CI 0.13, 1.53), respectively. In studies directly comparing imipenem and meropenem, there was no difference in epileptogenicity in either RD or pooled OR analyses. The absolute risk of seizures with carbapenems was low, albeit higher than with non-carbapenem antibiotics. Although imipenem was more epileptogenic than non-carbapenem antibiotics, there was no statistically significant difference in the imipenem versus meropenem head-to-head comparison.
Doripenem
Ertapenem
Carbapenem
Cilastatin
Cite
Citations (103)
This study aimed to analyse the in vitro activity of dual combinations of carbapenems against Klebsiella pneumoniae producing the main carbapenemase types. MIC values of the carbapenems, imipenem, meropenem, ertapenem and doripenem were determined alone and in dual combinations for 20 clinical K. pneumoniae isolates producing representative carbapenemases, i.e. OXA-48 (n = 6), NDM-1 (n = 4), NDM-1 + OXA-48 (n = 2) and KPC-2 (n = 8). MICs were also determined for Escherichia coli recombinant strains with or without permeability defects producing NDM-1, OXA-48 or KPC-2. In vitro synergy combination testing was performed using the microdilution and chequerboard techniques. Fractional inhibitory concentration indexes were calculated to determine whether the combinations were synergistic, indifferent or antagonistic. All carbapenemase producers were resistant to the tested carbapenems, with most isolates showing MICs of carbapenems >32 mg/L. None of the combinations was antagonistic. For KPC producers, synergistic combinations were observed with imipenem/ertapenem (5/8 isolates), imipenem/doripenem (4/8), imipenem/doripenem (4/8), meropenem/doripenem (3/8) and ertapenem/doripenem (3/8), while no synergy was observed with meropenem/ertapenem. For OXA-48 producers, synergies were observed with imipenem/ertapenem and with imipenem/meropenem for both isolates tested. Notably, combining imipenem with a non-carbapenem β-lactam (cefalotin) did not give any synergistic result. No synergy was observed for all NDM-1 and NDM-1+OXA-48 producers. Time–kill assays confirmed most of the data obtained by chequerboard testing. The data strongly support the hypothesis that dual carbapenem combinations might be effective against serine-β-lactamase producers (KPC, OXA-48). The imipenem-containing combinations appeared to be the most efficient.
Ertapenem
Doripenem
Carbapenem
Cilastatin
Cite
Citations (66)
Ertapenem
Doripenem
Carbapenem
Acinetobacter baumannii
Cite
Citations (14)
Ertapenem
Doripenem
Carbapenem
Acinetobacter baumannii
Cite
Citations (25)
Doripenem is a new parental 1-beta-methyl carbapenem which, unlike imipenem, does not require the addition of cilastatin on administration because of the protection afforded to doripenem by the 1-beta-methyl component. It combines the in vitro activities of imipenem and ertapenem against gram-positive bacteria with the in vitro activity of meropenem against gram-negative bacteria. It has excellent bactericidal activity against Streptococcus neumoniae. Carbapenem resistant mutants were selected with less frequency and lower minimum inhibitory concentrations (MICs) after exposure to doripenem than to imipenem or meropenem. High concentration levels of doripenem may be achieved in plasma. The half life of doripenem is higher than imipenem or meropenem. This new antibiotic has excellent in vitro activity and pharmacological properties. but how it may best be utilized still needs to be determined.
Doripenem
Ertapenem
Carbapenem
Cilastatin
Cite
Citations (28)