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Background
Infections caused by MDR Gram-negative (GN) organisms in critically ill patients are a therapeutic challenge. The administration of high-dose aminoglycoside (HDA) therapy coupled with high-flow continuous veno-venous haemodiafiltration (CVVHDF) could allow required high drug peaks to be achieved with acceptable drug elimination.
Methods...
Context in source publication
Context 1
... all patients, the regimen was applied after failure of previous combinations of different drugs, which were nevertheless continued in 10 of the patients. In total, 11 patients were treated with amikacin, 3 with gentamicin and 1 with tobramycin, at doses listed in Table 3. The median duration of therapy was 13 (range 10 -16) days. ...Similar publications
Different microorganisms that resist multiple antibiotics is considered to be most threatening problems to public health now a days. The aim of this study was to evaluate antibiotic resistance of Pseudomonas aeruginosa in burn wound infection and the antibiotic susceptibility pattern of P. aeruginosa isolates.Wound pus was collected using a sterile...
Neonatal sepsis causes up to an estimated 680,000 deaths annually worldwide, predominantly in low- and middle-income countries (LMICs). A significant and growing proportion of bacteria causing neonatal sepsis are resistant to multiple antibiotics, including the World Health Organization-recommended empiric neonatal sepsis regimen of ampicillin/gent...
Objectives
his study was aimed to identify diverse β-lactamase genes produced by multiple drug-resistant Pseudomonas aeruginosa isolates procured from burn/wound infectedpatients hospitalized in GeneralAl- thawrah hospitalofHodeidahcity, Yemenduring (July to December 2018).
Methods
From 200 burn wound swabs, total 200 single strain per patient was...
Acinetobacter baumannii is a multidrug-resistant bacteria responsible for nosocomial infections with significant fatality rates globally. Therapeutic failure and relapse of infection has been associated with persister cells formation which can also lead to resistance in A. baumannii. In the present study, we observed that A. baumannii ATCC 17978 in...
In this study, the correlation between the antibiotic resistance genes and antibiotic susceptibility among the carbapenem-resistant Gram-negative pathogens (CRGNPs) recovered from patients diagnosed with acute pneumonia in Egypt was found. A total of 194 isolates including Klebsiella pneumoniae (89; 46%), Escherichia coli (47; 24%) and Pseudomonas...
Citations
... 6 Some authors claim that doses between 30 mg/kg and 40 mg/kg may be required in critically ill septic patients with increased volume of distribution. 13 25 26 A recent paper by Marsot et al reported using doses of up to 40.8 mg/kg TBW in critically unwell patients (n=56). 27 One ongoing debate with regard to initiating aminoglycosides is which weight to use when calculating doses, 28 29 and the literature included in our review does not provide enough evidence to resolve this debate. ...
Background:
Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30 mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. The objectives of this review were to identify clinical evidence for high-dose amikacin regimens and to determine drug exposures that are related to adverse events and toxicity.
Methods:
The literature search was conducted in October 2021 and updated in May 2022 using electronic databases for any study reporting adult participants treated with amikacin at doses ≥20 mg/kg/day. Reference lists of included papers were also screened for potential papers. Data were extracted for pharmacokinetic parameters and clinical outcomes, presented in a summary table and consolidated narratively. Meta-analysis was not possible. Each study was assessed for bias before, during and after the intervention using the ROBINS-I tool.
Results:
Nine studies (total 501 participants in 10 reports) were identified and included, eight of which were observational studies. Assessment of bias showed substantial flaws. Dosing regimens ranged from 25 to 30 mg/kg/day. Six studies adjusted the dose in obesity when participants had a body mass index of ≥30 kg/m2. Target peak serum concentrations ranged from 60 mg/L to 80 mg/L and 59.6-81.8% of patients achieved these targets, but there was no information on clinical outcomes. Two studies reported the impact of high-dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified.
Conclusion:
All included papers were limited by a significant risk of bias, while methodological and reporting heterogeneity made drawing conclusions challenging. Lack of information on the impact on renal function or ototoxicity means high-dose regimens should be used cautiously in older people. There is a need for a consensus guideline for high-dose amikacin to be written.
Trial registration number:
PROSPERO (CRD42021250022).
... Our review found twelve studies, two studies [13,14] were non-evaluable as outcome data from the three aminoglycosides gentamicin, amikacin and tobramycin, were combined (figure 1). Of ten evaluable studies, four were conducted in France, three in Iran, three in Belgium and included 665 participants receiving high-dose amikacin. ...
... EUCAST guidelines advise that doses above 25 mg/kg are required to obtain sufficient peak concentrations for Gram-negative organisms [6]. Some authors claim that doses between 30-40 mg/kg may be required in critically ill septic patients with increased volume of distribution [13,26,27]. A recent paper by Marsot et al reported using doses of up to 40.8 mg/kg TBW in critically unwell patients (n=56) [28]. ...
Background
Amikacin is an aminoglycoside with activity against Gram negative pathogens. Updated EUCAST amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. We undertook a literature review to report preferred dosing regimens, monitoring and toxicities associated with the use of amikacin at doses ≥20mg/kg/day.
Methods
This literature search was conducted in electronic databases for any study reporting adult participants treated with amikacin at doses ≥20mg/kg/day. Data were extracted for pharmacokinetic parameters and clinical outcomes, while papers were assessed for bias using the ROBINS-I tool.
Results
Nine papers were identified and included, eight of which were observational studies; assessment of bias showed substantial flaws. Dosing regimens ranged from 25-30mg/kg/day. Six studies adjusted the dose in obesity when participants BMI ≥30 kg/m2. Target peak serum concentrations ranged from 60mg/L-80mg/L and 59.6-81.8% of patients achieved these targets. Two studies reported the impact of high dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified.
Conclusions
Dosing amikacin at 25-30mg/kg achieved peak concentration targets in the majority of patients, but there was no information on clinical outcomes. There is little information about the impact on renal function or ototoxicity; caution with use of high dose regimens in older patients for prolonged periods is recommended. Given the paucity of information, there is a need for a consensus guideline for high dose amikacin or a prospective study.
What is already known on this topic
Amikacin is receiving increased interest as an antibiotic option for multidrug resistant organisms
Amikacin and other aminoglycosides require therapeutic drug monitoring to minimise the risk of nephrotoxicity
Increasing prevalence of antimicrobial resistance in key pathogens has led to changes to susceptibility breakpoints and theoretical dosing recommendations in European-wide guidelines, including a recommendation for high-dose amikacin for certain pathogens
What this study adds
The current literature reporting data and outcomes with high-dose amikacin regimens has a high degree of bias and is confounded by poor study design and as a result there in insufficient evidence base to provide guidance on how to manage high-dose amikacin.
Appropriate dosing weight for obese patients, adjustment for renal impairment, monitoring interval, potential toxicity and key PK/PD targets to guide treatment with high-dose amikacin regimens remain poorly defined in the current literature.
How this study might affect research, practice or policy
Further evidence and/or consensus guidelines based on expert judgement are required to ensure patients can receive optimal therapy when amikacin is the treatment of choice.
... In patients with severely reduced kidney functions, T 1/2 is significantly prolonged, and with concern to ESRD patients treated via iHD, the T 1/2 is as long as 2-3 days during the inter-dialytic period with HD providing the only significant CL mechanism. Due to these profound PK changes, target peak plasmatic levels of 8 times higher than the MIC would lead to an unacceptably long elimination phase, as well as extreme drug exposure without the occurrence of a washout period [30][31][32], unless the patient was being treated with CRRT [33][34][35]. Therefore, AG target plasmatic levels used for pulse dosing strategy are unsuitable for this group of patients, thus necessitating the application of the conventional dosing approach with a lower target C max and a higher C troughs [14]. ...
Background:
The dosing of aminoglycosides (AGs) in patients with kidney disease is challenging due to their markedly prolonged half-life, which renders pulse dosing schedules unsuitable. We performed a review of the literature that describes the pharmacokinetics of, and dosing recommendations for, AG for patients with abnormal renal functions and various renal replacement therapy modalities, focusing on patients treated with intermittent hemodialysis (iHD).
Summary:
During one iHD session, dialysis removes a remarkable amount of the drug regardless of the dialyzer type. In patients with severely reduced kidney functions, the distribution phase is prolonged, which needs to be taken into account when drawing samples shortly after drug administration or following an iHD session.
Key messages:
The doses recommended for the pulse dosing of patients without kidney disease leads to unacceptably high overall systemic exposure for patients with severely reduced kidney functions even with dosing intervals extended up to 48 h. Therefore, lower doses accompanied by extended dosing intervals must be applied for this patient group. The clinical evidence and current recommendations support the dosing of AG following, rather than before, HD sessions. In patients with end-stage kidney disease, the samples for TDM of AGs should not be drawn earlier than 2 h after end of the infusion and 4 h after the end of iHD session to allow full (re)distribution of the drug.
... They concluded that a 7-mg/kg dose of tobramycin every 24 h, given in 0.5-h infusions, combined with imipenem was needed to achieve adequate bacterial killing and prevent regrowth at 48 h of carbapenem and aminoglycoside resistant P. aeruginosa. [15,16] Intravenous fosfomycin in combination with other antimicrobials has reemerged for the treatment of infections caused by MDR P. aeruginosa. ...
An abscess is a collection of bacterial detritus inside of a tissue in the body that can create micro or macro communications with deeper regions if they are not treated on time. Some bacteria can produce necrotizing soft tissue infections that spreads rapidly through the subcutaneous tissue and fascia, producing rapid tissue necrosis. Situation may be more complicated in patients with multiple comorbidities. It reports the case of a young adult patient with insulin-dependent Diabetes Mellitus with poor metabolic control and a history of analgesics and corticosteroids injections in the gluteal region who was diagnosed with COVID-19 and then bilateral gluteal abscess with compromise of the fascia and the muscle in the first weeks of hospitalization.
... When fosfomycin is used it should be combined with a second antibiotic. 6 High-dose aminoglycoside therapy (such as amikacin 50 mg/kg/day) may be a useful option for CACT-resistant P. aeruginosa with borderline MIC (e.g., amikacin MIC = 16 mg/dl) and can be combined with hemodialysis to reduce nephrotoxicity [184,186,187]. 7 Until cefiderocol becomes widely available, synergistic combinations (e.g., based on colistin [120,121], fosfomycin [122,123] .: Plazomicin is no better than other aminoglycosides against P. aeruginosa [10].: Similar to other tetracyclines, P. aeruginosa is resistant to eravacycline [91].: Aztreonam/avibactam cannot overcome resistance against most MBL-producing P. aeruginosa [112], but may be useful against selected strains with borderline/intermediate MICs to aztreonam or ceftazidime/avibactam [81,113] predominantly against carbapenem-resistant polymyxin-susceptible A. baumannii, and clinical benefit has not yet been found in most studies [2,[139][140][141][142][143][144]. ...
... In both patients, the peak amikacin concentration was eight to ten times the MIC and renal function was preserved [184]. Combining high-dose aminoglycosides (to achieve PD targets) with hemodialysis (to increase clearance and decrease nephrotoxicity) is an interesting option [186,187], especially when no alternatives are available, but requires further study. ...
The management of carbapenem-resistant infections is often based on polymyxins, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review, we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, polymyxins and tigecycline (CAPT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CAPT-resistant GNB are scarce and based exclusively on few case reports and small case series, but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review, we consolidate the available literature to inform clinicians dealing with CAPT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CAPT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Several treatment options are currently available for CAPT-resistant K. pneumonia. Newer β-lactam-β-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-β-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-β-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g., polymyxin- or fosfomycin-based synergistic combinations) may represent a last resort option, but their use against CAPT-resistant GNB requires further study.
... As such, high-dose amikacin therapy (Ͼ30 mg/kg) may be considered. Limited clinical data exist for such dosing regimens, but doses of Ն60 mg/kg have been used as part of salvage therapy in conjunction with renal replacement therapy to minimize the probability of toxicity in a small case series (19). Furthermore, the use of a single dose of amikacin in patients with severe sepsis or septic shock may mitigate the risk of nephrotoxicity, which is unlikely to occur for an aminoglycoside duration of Ͻ3 days (20). ...
Given that aminoglycosides, such as amikacin, may be used for multi-drug resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia and sepsis treatment choices.
A hollow-fibre infection model with two P. aeruginosa isolates (MIC 2 and 8 mg/L) with an initial inoculum ∼10 ⁸ colony-forming unit/mL was used to test different amikacin dosing regimens. Three regimens (15, 25 and 50 mg/kg) simulating a blood exposure and a 30 mg/kg regimen simulating the epithelial lining fluid (ELF) for potential respiratory tract infection were tested. Data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole genome sequencing was used to identify mutations associated with resistance emergence.
While bacterial density was reduced by >6-logs within the first 12 h in simulated blood exposures, following this initial bacterial kill, there was amplification of a resistant sub-population with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (<5-log) bacterial killing in the simulated ELF exposure for either isolate tested. Simulation studies suggest that a dose of 30 and 50 mg/kg may provide maximal bacterial killing for bloodstream and VAP infections respectively.
Our results suggest that amikacin efficacy may be improved with the use of high dose therapy to rapidly eliminate susceptible bacteria. Subsequent doses may have reduced efficacy given the rapid amplification of less-susceptible bacterial subpopulations with amikacin monotherapy.
... When fosfomycin is used it should be combined with a second antibiotic. 6 High-dose aminoglycoside therapy (such as amikacin 50 mg/kg/day) may be a useful option for CACT-resistant P. aeruginosa with borderline MIC (e.g., amikacin MIC = 16 mg/dl) and can be combined with hemodialysis to reduce nephrotoxicity [184,186,187]. 7 Until cefiderocol becomes widely available, synergistic combinations (e.g., based on colistin [120,121], fosfomycin [122,123] .: Plazomicin is no better than other aminoglycosides against P. aeruginosa [10].: Similar to other tetracyclines, P. aeruginosa is resistant to eravacycline [91].: Aztreonam/avibactam cannot overcome resistance against most MBL-producing P. aeruginosa [112], but may be useful against selected strains with borderline/intermediate MICs to aztreonam or ceftazidime/avibactam [81,113] 1 3 ...
... In both patients, the peak amikacin concentration was eight to ten times the MIC and renal function was preserved [184]. Combining high-dose aminoglycosides (to achieve PD targets) with hemodialysis (to increase clearance and decrease nephrotoxicity) is an interesting option [186,187], especially when no alternatives are available, but requires further study. ...
The management of carbapenem-resistant infections is often based on colistin, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, colistin and tigecycline (CACT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CACT-resistant GNB are scarce and based exclusively on few case reports and small case series but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review we consolidate the available literature to inform clinicians dealing with CACT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CACT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Several treatment options are currently available for CACT-resistant K. pneumonia. Newer β-lactam-β-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-β-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-β-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g. colistin- or fosfomycin-based synergistic combinations) may represent a last resort option but their use against CACT-resistant GNB requires further study.
... Patients are particularly at risk for underdosing, which may cause treatment failure and enhance resistance. Table 5 depicts dose recommendations for some major antibiotic and antifungal drugs during CVVH (at a dose of 25 mL/kg/h) that are based upon relevant literature data [69][70][71][72][73][74][75][76][77] and our own findings. ...
Background:
Hemofiltration rate, changes in blood and ultrafiltration flow, and discrepancies between the prescribed and administered doses strongly influence pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents during continuous veno-venous hemofiltration (CVVH) in critically ill patients.
Methods:
Ancillary data were from the prospective multicenter IVOIRE (hIgh VOlume in Intensive caRE) study. High volume (HV, 70 mL/kg/h) was at random compared with standard volume (SV, 35 mL/kg/h) CVVH in septic shock patients with acute kidney injury (AKI). PK/PD parameters for all antimicrobial agents used in each patient were studied during five days.
Results:
Antimicrobial treatment met efficacy targets for both percentage of time above the minimal inhibitory concentration and inhibitory quotient. A significant correlation was observed between the ultrafiltration flow and total systemic clearance (Spearman test: P < 0.005) and between CVVH clearance and drug elimination half-life (Spearman test: P < 0.005). All agents were easily filtered. Mean sieving coefficient ranged from 38.7% to 96.7%. Mean elimination half-life of all agents was significantly shorter during HV-CVVH (from 1.29 to 28.54 h) than during SV-CVVH (from 1.51 to 33.85 h) (P < 0.05).
Conclusions:
This study confirms that CVVH influences the PK/PD behavior of most antimicrobial agents. Antimicrobial elimination was directly correlated with convection rate. Current antimicrobial dose recommendations will expose patients to underdosing and increase the risk for treatment failure and development of resistance. Dose recommendations are proposed for some major antibiotic and antifungal treatments in patients receiving at least 25 mL/kg/h CVVH.
... V těchto případech je pro dosažení optimálního terapeutického efektu zapotřebí vysoké maximální koncentrace po podání antibiotika. Nežádoucí účinky aminoglykosidů (nefrotoxicita a ototoxicita) také korelují s celkovou kumulativní dávkou a s dlouhodobou expozicí vysokým koncentracím [22]. Amikacin je hydrofil-ní antibiotikum s relativně malým distribučním objemem (0,25 l/kg), je tedy koncentrován v centrálním kompartmentu (je možno zanedbat významnou kumulaci v tkáni), taktéž vazebnost na plazmatické proteiny je nízká (0−10 %). ...
... V individuálních případech lze pak zvážit vhodné načasování podání dávky před použitím eliminační metody (především intermitentní). Výhodné je dosažení optimálního terapeutického efektu vysoké koncentrace a zároveň snížení rizika nežádoucích účinků vyplývajících z kumulace látky a z dlouhodobé expozice toxické koncentraci při eliminaci látky vlivem RRT [22]. Nelze ovšem jednoznačně předjímat absolutní eliminaci amikacinu. ...
Renální insuficience je významným faktorem ovlivňujícím schopnost organismu udržovat vnitřní prostředí. V klinicky definovaných případech je u pacientů nutná náhrada eliminační funkce ledvin. Technické metody umožňují eliminaci toxických metabolitů, dochází ovšem také k eliminaci některých léčiv. Z tohoto pohledu je významné posouzení rizika kumulace léčiv u renální insuficience, stejně tak jako vlivu eliminační metody na clearance látek a přizpůsobení dávky, případně intervalu dávkování. Pro odhad eliminace léčiva je nezbytné zohlednit jak vlastnosti použité eliminační metody, tak farmakokinetické parametry léčiva.
... There is little data on the use of such a large dose of amikacin. The study of Brasseur et al. investigated high amikacin doses combined with renal replacement therapy (RRT) in order to accelerate amikacin elimination for the treatment of infections caused by multidrug-resistant (MDR) bacteria in ICUs (29). In 11 patients under amikacin therapy, the initial dose ranged from 25 to 37 mg/kg, and the maximal daily dose over therapy ranged from 26 to 67 mg/kg. ...
Amikacin is commonly used for probabilistic antimicrobial therapy in critically ill patients with sepsis. Its narrow therapeutic margin makes it challenging to determine the right individual dose that ensures the highest efficacy target attainment rate (TAR) in this setting. This study aims to develop a new initial dosing approach for amikacin, by optimizing the a priori TAR in this population. A population pharmacokinetic model was built with a learning dataset from critically ill patients who received amikacin. It was then used to design an initial dosing approach maximizing a priori TAR for a target peak concentration over the MIC ratio (Cmax/MIC) ≥ 8 or daily area under the curve over the MIC ratio (AUC 0-24h /MIC) ≥ 75.
In the included 166 patients, 53% had Cmax ≥ 64 mg/L with a median dose of 23.4 mg/kg. A two-compartment model with creatinine clearance and body surface area as covariates best described the data and showed good predictive performance. Our dosing approach was successful in optimizing TAR for Cmax/MIC, with a rate of 92.9% versus 67.9% using a 30 mg/kg regimen, based on an external subset of data and assuming a MIC = 8 mg/L. Mean optimal doses were higher (3.5± 0.5 g) than with 30 mg/kg regimen (2.1± 0.3 g). Suggested doses varied with the MIC, the target index and desired TAR threshold. A dosing algorithm based on the method is proposed for large range of patient covariates. Clinical studies are necessary to confirm efficacy and safety of this optimized dosing approach.
