In critically ill patients with Gram-negative bacterial infection, continuous infusion of β-lactam antibiotics can achieve satisfactory PK/PD targets

*For medical professionals, the drug resistance situation of Gram-negative bacteria is severe, and it is imperative to optimize the treatment plan of β-lactam antibiotics
.

 Antimicrobial resistance is a growing global concern, and it is estimated that by 2050, the number of deaths due to resistance will exceed 10 million annually
.

The drug resistance situation of Gram-negative bacteria is particularly severe, including extended-spectrum β-lactamase-producing Enterobacter, carbapenem-resistant Enterobacter, multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii
.

In intensive care unit (ICU) patients, bacteremia caused by Gram-negative bacteria is the leading cause of death and disability
.

Beta-lactam antibiotics are often the mainstay of treatment for gram-negative infections in ICU patients
.

In addition to multidrug-resistant Gram-negative pathogens, inappropriate empiric or targeted therapy is currently considered a risk factor for mortality in ICU patients, and the course of therapy is also influenced by patient pathophysiological characteristics (eg, increased volume of distribution, drug clearance variability, etc.
), making the dose adjustment of β-lactam antibiotics more challenging
.

1.
Optimization of PK/PD characteristics is very important.
For the characteristics of antimicrobial drug metabolism in ICU patients, Kelly L.
Maguigan et al.
published in Antibiotics titled "Beta-Lactams Dosing in Critically Ill Patients with Gram-Negative bacterial Infections: A PK/PD Approach" review article to determine the optimal β-lactam antimicrobial regimen for Enterobacter and Pseudomonas aeruginosa based on the breakpoints established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST)
.

Beta-lactam antibiotics are recommended first-line agents for common infections including pneumonia, bacteremia, intra-abdominal infections, endocarditis, and urinary tract infections
.

Among them, penicillins, cephalosporins, carbapenems and monocyclic β-lactams are the four most commonly used β-lactam antibiotics in clinical practice
.

The optimization of pharmacokinetic/pharmacodynamic (PK/PD) profiles is crucial due to the significant reduction in the efficacy of β-lactam antimicrobials due to overuse of drugs and increased resistance of pathogenic bacteria
.

Because severe disease can significantly alter the PK/PD profile of β-lactam antimicrobials, achieving the desired PK/PD target is associated with microbiological treatment success, reduced clinical treatment failure, and improved prognosis
.

The most common contributors to PK/PD are changes in apparent volume of distribution (Vd) and clearance, so dosage, dosing interval, and infusion time must be adjusted
.

It should be noted that fluid resuscitation, hypoalbuminemia, renal replacement therapy (RRT), and extracorporeal membrane oxygenation (ECMO) all increase Vd, and a hypermetabolic state and enhanced renal clearance can lead to increased drug clearance and acute renal function.
Insufficiency (AKI) reduces drug clearance
.

The bactericidal effect of β-lactam antibiotics is time-dependent
.

Compared with non-ICU patients whose free plasma concentration is greater than the minimum inhibitory concentration (MIC) 40%-70% of the time, ICU patients may go from achieving a free plasma concentration greater than MIC 100% of the time (100% fT>MIC) or 100% of the time free plasma concentration greater than 4 times the MIC (100% fT > 4 × MIC) benefit
.

In addition, it has been found in some laboratory studies that prolonging the infusion time of β-lactam antibiotics can help to optimize PK/PD targets, thereby inhibiting the development of resistance
.

At present, although routine therapeutic drug monitoring (TDM) cannot be achieved in most medical institutions, most critically ill patients, especially those with low susceptibility to pathogens, are empirically treated with β-lactam antibiotics.
Administer medication with reference to known PK models
.

Based on the above background, in this review, the authors evaluated the antibacterial efficacy of Gram-negative bacterial infections by searching all published literature related to PK/PD of β-lactam drugs and based on the drug susceptibility breakpoints reported by EUCAST.
Medication dosing issues
.

2.
Search found: The PK/PD target can be achieved by the scheme of prolonging the infusion time.
Comprehensive search of PubMed and Medline databases, search terms: β-lactams, pharmacokinetics, pharmacokinetics, severe, including all medical and surgical ICU patients
.

All articles containing MIC values ​​for Enterobacteriaceae and Pseudomonas aeruginosa with reduced antimicrobial susceptibility or close to the EUCAST resistance breakpoint were included
.

The EUCAST data on MIC breakpoints for β-lactam antimicrobials are shown in Table 1
.

Table 1 The results of the EUCAST MIC breakpoint study on β-lactam antibiotics show that when severe patients are infected with Gram-negative bacteria with low susceptibility, the initial application of β-lactam antibiotics requires prolonged infusion or continuous infusion.
Drug strategies to optimize anti-infective goal completion rates, especially in patients with enhanced renal clearance
.

Patients with impaired renal function also usually require prolonged infusion time to achieve PK/PD goals, and it is recommended that therapeutic drug monitoring should be used to achieve individualized treatment
.

Table 2 shows the recommended initial dose of β-lactam antibiotics in the event of resistant Gram-negative infections
.

The recommended regimen is for patients with normal organ function, and when clinically feasible, the use of therapeutic drug monitoring to optimize the dosing regimen is recommended
.

Table 2 Recommended initial dosage of β-lactam antibiotics for drug-resistant Gram-negative bacteria infection in patients with normal liver and kidney function Note: 1.
It can also be adjusted according to renal function and body mass index; 2.
There is currently lack of stability data on continuous infusion.
3.
The review article on stability and safety issues mentioned that the physicochemical stability of β-lactam antibiotics should be considered when choosing extended or continuous infusion dosing regimens.
degradation, resulting in treatment failure
.

According to the U.
S.
Pharmacopeia, the loss rate of antibacterial drugs should not exceed 10% in 24 hours
.

The stability of β-lactam antibiotics varies greatly, carbapenems are the most unstable, and piperacillin/tazobactam and aztreonam are the most stable.
The recommended continuous infusion time of the drugs is shown in Table 3
.

Because meropenem is less stable than cephalosporins, piperacillin/tazobactam, continuous infusions at 12-hour intervals are necessary to reduce the risk of drug degradation
.

There are also few studies related to continuous infusion of ertapenem, and further studies are needed to evaluate the stability of continuous infusion of ertapenem
.

Table 3 Stability of continuous infusion beta-lactam antimicrobials For less sensitive pathogens, increased exposure to beta-lactam antimicrobial therapy is required by increasing the total daily dose and prolonging the duration of infusion, but increased exposure At the same time, there may be an increase in drug-related toxicity, including neurotoxicity, nephrotoxicity, liver toxicity and genotoxicity
.

Among them, the relative proconvulsant activity of β-lactam antibiotics is the most discussed among cefepime, meropenem and aztreonam, and nephrotoxicity is relatively rare, mainly manifested as acute interstitial nephritis, nephropathy caused by hemolytic anemia and Acute kidney injury
.

Acute interstitial nephritis is more likely to occur in penicillin and cephalosporin drugs, ceftriaxone and piperacillin are more likely to cause hemolytic anemia, and the incidence of AKI associated with piperacillin is relatively high, especially with vancomycin.
when used in combination
.

Of course, not all β-lactam antibiotics have a therapeutic effect that is related to toxicity
.

The clinical toxicity thresholds for meropenem, cefepime, and piperacillin alone were trough concentrations >44.
5 mg/L, 20 mg/L, and 361 mg/L, respectively
.

When the therapist pursues 100% fT>4×MIC, the risk of poisoning in patients with high MIC pathogenic bacteria also increases
.

For example, for a pathogen with an MIC value of 8 mg/L, when the treatment goal is set to 100% fT > 4 × MIC, when using cefepime treatment, a trough concentration of 32 mg/L needs to be reached, and this concentration only exceeds 20 mg/L.
L, it is possible to cause drug toxicity in patients
.

Therefore, other PK/PD targets, such as 100% fT>MIC, need to be carefully selected when the risk of β-lactam antibacterial poisoning is high and the resistance of the infectious pathogen is strong
.

IV.
LIMITATIONS OF THE REVIEW Some limitations of this review may have implications for clinical applicability
.

For example, renal function changes frequently in critically ill patients, making it extremely challenging to estimate renal function using predictive equations
.

It is estimated that the incidence of AKI in ICU patients is 20%-50%, and that of enhanced renal clearance is as high as 65%
.

Compared with traditional indicators such as urine volume and creatinine, the new markers are more accurate in assessing the severity of AKI, but they have not been used in the study of PK models, which is a challenge for drug dose adjustment in patients with fluctuating renal function, and may require more Monitor therapeutic drug levels frequently
.

With the exception of critically ill patients, this review does not provide recommendations for dose adjustment for other populations that may require special consideration, such as obesity, patients receiving ECMO or RRT
.

Obesity results in lower β-lactam exposure and treatment goal achievement rates, while drug adsorption and protein binding rates may lead to more unpredictable changes in drug concentrations in patients receiving ECMO and RRT
.

In conclusion, this review evaluates the use of β-lactam antimicrobials in the treatment of pathogens with low antimicrobial susceptibility, especially Pseudomonas aeruginosa, which usually require continuous infusion to achieve satisfactory PK/PD targets, and future needs More research to determine optimal dose targets for novel beta-lactam antimicrobials
.

e2019209.
24.
Kuhn,D.
; Metz, C.
; Seiler, F.
; et al.
Antibiotic therapeutic drug monitoring inintensive care patients treated with different modalities of extracorporealmembrane oxygenation (ECMO) and renal replacement therapy: A prospective,observational single- center study.
Crit.
Care 2020, 24, 1–11.
This article is only used to provide scientific information to medical and health professionals, and does not represent the platform's position 2.
4 times higher risk than CP-CRE! 2.
In-depth analysis of the 2021 SSC guidelines, focusing on anti-infective treatment of sepsis 3.
Carbapenem-resistant Enterobacteriaceae infections make treatment more difficult.
What are the advantages of combined therapy? 4.
The demand for combined application of antibacterial drugs is becoming more and more urgent.
Do you know all four kinds of in vitro combined drug susceptibility tests? 5.
Meropenem and therapeutic drug monitoring, these issues are worth knowing! 6.
The use of antibiotics in severe infections and the monitoring of therapeutic drugs are worthy of attention! 7.
What is the in vitro efficacy of antibiotic combination therapy on carbapenem-resistant Gram-negative bacteria? See what this review has to say? 8.
The in vitro antibacterial activity monitoring report of meropenem is here! Take a look at the latest monitoring data together Health professionals better understand the latest developments in related disease areas Antibiotic therapeutic drug monitoring inintensive care patients treated with different modalities of extracorporealmembrane oxygenation (ECMO) and renal replacement therapy: A prospective,observational single-center study.
Crit.
Care 2020, 24, 1–11.
Professionals provide scientific information and do not represent the platform's position.
Review of past highlights: 1.
The latest research shows that the risk of death from non-CP-CRE infection is 2.
4 times higher than that of CP-CRE! 2.
In-depth analysis of the 2021 SSC guidelines, focusing on anti-infective treatment of sepsis 3.
Carbapenem-resistant Enterobacteriaceae infections make treatment more difficult.
What are the advantages of combined therapy? 4.
The demand for combined application of antibacterial drugs is becoming more and more urgent.
Do you know all four kinds of in vitro combined drug susceptibility tests? 5.
Meropenem and therapeutic drug monitoring, these issues are worth knowing! 6.
The use of antibiotics in severe infections and the monitoring of therapeutic drugs are worthy of attention! 7.
What is the in vitro efficacy of antibiotic combination therapy on carbapenem-resistant Gram-negative bacteria? See what this review has to say? 8.
The in vitro antibacterial activity monitoring report of meropenem is here! Take a look at the latest monitoring data together Health professionals better understand the latest developments in related disease areas Antibiotic therapeutic drug monitoring inintensive care patients treated with different modalities of extracorporealmembrane oxygenation (ECMO) and renal replacement therapy: A prospective,observational single-center study.
Crit.
Care 2020, 24, 1–11.
Professionals provide scientific information and do not represent the platform's position.
Review of past highlights: 1.
The latest research shows that the risk of death from non-CP-CRE infection is 2.
4 times higher than that of CP-CRE! 2.
In-depth analysis of the 2021 SSC guidelines, focusing on anti-infective treatment of sepsis 3.
Carbapenem-resistant Enterobacteriaceae infections make treatment more difficult.
What are the advantages of combined therapy? 4.
The demand for combined application of antibacterial drugs is becoming more and more urgent.
Do you know all four kinds of in vitro combined drug susceptibility tests? 5.
Meropenem and therapeutic drug monitoring, these issues are worth knowing! 6.
The use of antibiotics in severe infections and the monitoring of therapeutic drugs are worthy of attention! 7.
What is the in vitro efficacy of antibiotic combination therapy on carbapenem-resistant Gram-negative bacteria? See what this review has to say? 8.
The in vitro antibacterial activity monitoring report of meropenem is here! Take a look at the latest monitoring data together Health professionals better understand the latest developments in related disease areas 4 times! 2.
In-depth analysis of the 2021 SSC guidelines, focusing on anti-infective treatment of sepsis 3.
Carbapenem-resistant Enterobacteriaceae infections make treatment more difficult.
What are the advantages of combined therapy? 4.
The demand for combined application of antibacterial drugs is becoming more and more urgent.
Do you know all four kinds of in vitro combined drug susceptibility tests? 5.
Meropenem and therapeutic drug monitoring, these issues are worth knowing! 6.
The use of antibiotics in severe infections and the monitoring of therapeutic drugs are worthy of attention! 7.
What is the in vitro efficacy of antibiotic combination therapy on carbapenem-resistant Gram-negative bacteria? See what this review has to say? 8.
The in vitro antibacterial activity monitoring report of meropenem is here! Take a look at the latest monitoring data together Health professionals better understand the latest developments in related disease areas 4 times! 2.
In-depth analysis of the 2021 SSC guidelines, focusing on anti-infective treatment of sepsis 3.
Carbapenem-resistant Enterobacteriaceae infections make treatment more difficult.
What are the advantages of combined therapy? 4.
The demand for combined application of antibacterial drugs is becoming more and more urgent.
Do you know all four kinds of in vitro combined drug susceptibility tests? 5.
Meropenem and therapeutic drug monitoring, these issues are worth knowing! 6.
The use of antibiotics in severe infections and the monitoring of therapeutic drugs are worthy of attention! 7.
What is the in vitro efficacy of antibiotic combination therapy on carbapenem-resistant Gram-negative bacteria? See what this review has to say? 8.
The in vitro antibacterial activity monitoring report of meropenem is here! Take a look at the latest monitoring data together Health professionals better understand the latest developments in related disease areas
.

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