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7.3 Optimization of antibiotics dosing based on their PK/PD parameters

7.3.1 Optimization of dosing of time-dependent ATB in the ICU

The published studies suggest that better results may be obtained in critically ill patients if the f T>MIC is more than 50%, ideally up to 90–100% of the dosing interval. This can be accomplished by administering ATBs at shorter dosing intervals, or better, by administering ATBs in extended or continuous infusions with an initial bolus that provides sufficient plasma concentrations quickly.

Extended/continuous infusion of beta-lactams

Beta-lactams are usually given in short infusions (15–30 min). By extending/prolonging the infusion to 3 hours or more, the f T>MIC can be significantly prolonged, thereby increasing the efficacy of beta-lactams. This effect is most pronounced with drugs with a short half-life; however, it can also be observed with drugs with a long half-life (e.g., ceftriaxone). In the case of continuous infusions, ATB concentrations are maintained above the MIC throughout the dosing interval. However, when beta-lactams are administered in this manner, the stability of a particular ATB in a specific carrier solution, as well as potential incompatibilities with other drugs, must be considered.

• Meropenem diluted in normal saline (NS) at a concentration of 20 mg/mL (2g meropenem in 100mL NS) has published stability of 10 hours at 21–26°C (source: stabilis.org). Is it possible to administer meropenem as a continuous 24-hour infusion?

  Yes, it is possible, but it is necessary to consider the above stability. Under these conditions, meropenem is stable for 10 hours, which means the patient should receive a newly prepared dose of ATBs after 10 hours at the latest. The total calculated daily dose must be divided into individual infusions, which will be consecutive. To simplify dosing, dividing the daily dose into 3 consecutive infusions over 8 hours or 4 infusions over 6 hours is appropriate. Due to the availability of 0.5g and 1g vials of meropenem on the market, it is appropriate to divide the dose to avoid forming residues that require disposal (economic and environmental impacts). At the same time, this manipulation does not require unnecessary recalculations, and thus the risk of potential error is reduced. Therefore, a 3g dose of meropenem can be prepared using three 1g vials, and each 1 g of meropenem will be infused over 8 hours, while a 4g dose is better divided into four daily doses (given over 6 hours). The specific method of dilution and stability of ATBs and compatibility with other drugs can be consulted with pharmacists. Pharmacists have a comprehensive knowledge not only of pharmacology but also of the physicochemical properties of drugs.

  (Simulated administration of the short/extended infusions will be shown and discussed in the lecture.)

In critically ill patients, a suitable procedure for initiating prolonged or continuous infusions should also be considered. In the case of sepsis, it is necessary to start effective ATB therapy as soon as possible; therefore, it is recommended to administer a loading dose of ATBs. With an LD omission, the increase in plasma drug concentrations would be gradual and usually too slow. The loading dose should be followed immediately by a prolonged/continuous infusion.

An example of a meropenem prescription as a continuous infusion might look like this:

• meropenem LD 2 g i.v. over 30–60 min and immediately after instillation, start the infusion at a dose of 125 mg/h

The exact schedule for nurses taking into account the stability of meropenem, could look like this:

• meropenem 2 g/50mL NS i.v. over 30 min and immediately after instillation, 1 g/50mL NS i.v. over 8 hours every 8 hours at …–…–…

The available PK/PD and clinical data suggest the beta-lactam prolonged infusion as a safe, effective, and potentially superior strategy for ATB administration compared to 30-min infusions. Advantageously, this method of administration can be used in critically ill patients in the case of pathogens with a higher MIC (Pseudomonas, Acinetobacter) or lung infections to increase the penetration of ATBs into the lungs. However, prolonged/continuous infusions cannot be recommended for all inpatients. Many departments do not have the necessary equipment for this method of ATB administration (injectors, multi-lumen venous catheters to prevent incompatibilities…). In addition, in patients with mild infections where standard intermittent infusions are sufficient, administration of ATBs by prolonged infusions is an unnecessary complication for caregivers, and it carries the risk of incompatibilities with other concomitant medications.

Comparison of cephalosporins

You already know from general pharmacology that cephalosporins are traditionally divided into five generations based on their microbiological effect. It is essential to emphasize that cephalosporins differ not only in the spectrum of action but also in the PK properties (see Table 7.3). Therefore, it is necessary to consider these facts when choosing the optimal ATB and to determine the dosage.

Table 7.3: Cephalosporines' pharmacokinetic properties

	1st generation	2nd generation	3rd generation	4th–5th generation
representatives	cefazolin (iv), cefadroxil (po)	cefuroxime (iv), cefuroxime axetil (po),	cefotaxime, ceftriaxone, ceftazidime, cefoperazone,	cefepime, ceftaroline fosamil
absorption	good, 90%	good, 90%	poor, 25–40%	only iv
plasma protein binding	70–85% 15–20%	35–50%	15–40% 90–95% <10% 90%	20% 20%
cross blood-brain barrier		↑, cefuroxim	↑↑↑ cefotaxime ceftriaxone (only iv)	↑↑↑ cefepime (only iv)
metabolism	Minimal, <10%
excretion	renal	renal	renal: cefotaxime 40–60% ceftriaxone 40–60% ceftazidime 80–90% cefoperazone 20–30%	renal
T1/2	1–2h	1–2h	1–2h ceftriaxone approx. 8h	2h

Application exercise:

A 40-year-old woman with suspected bacterial meningitis was admitted to the ICU. Her bodyweight is 70 kg, height 170 cm. In the personal history, there is type 2 diabetes mellitus; renal and hepatic function are normal; except for the high inflammatory markers, no other significant deviations in the laboratory findings were observed. Antimicrobial therapy should be initiated as soon as possible.

• Design ATB therapy for the patient, including dosing.

  When selecting the optimal ATB, two main factors must be taken into account: the pathogen and the penetration of the ATB across the blood-brain barrier (BBB). The most common causes of bacterial meningitis are Streptococcus pneumoniae, Haemophilus influenzae, and meningococci. These pathogens are generally sensitive to cephalosporins; however, individual cephalosporins are not entirely interchangeable, and the choice depends primarily on the ability to permeate the BBB. The drugs of choice are thus the third generation cephalosporins cefotaxime and ceftriaxone or the fourth generation cephalosporin cefepime. Other cephalosporins cannot be used due to low concentrations in cerebrospinal fluid (CSF) achieved. This is because they are substrates for the efflux transport of P-glycoprotein located on the BBB, making it impossible to achieve sufficient concentrations of ATB in the CSF. To increase the likelihood of maintaining sufficient concentrations of the ATB in the CSF for an adequate period, it is advisable to administer prolonged infusions.

  A standard dosage of cephalosporins in meningitis vs. dosing of cephalosporins in other indications

  • Ceftriaxone – 2g every 8–12 hours 1–2 g every 12–24 hours
  • Cefotaxime – 2g every 4–6 hours 1–2 g every 6–8 hours
  • Cefepime – 2g every 6–8 hours 2 g every 8–12 hours

  The prescription could therefore look like this:

  • Ceftriaxone LD 2g/100mL NS/G5% i.v. over 30 min and immediately after instillation 2g/100mL NS/G5% i.v. over 3 hours every 12 hours

7.3.2 Optimalizace dávkování ATB závislých na koncentraci na JIP

7.3.2 Optimization of dosing of concentration-dependent ATBs in the ICU

When using the ATBs of this group, the aim is to achieve sufficiently high peak (c_MAX) concentrations. Therefore, the ideal dosing strategy is to administer high doses in longer time intervals. Typical representatives of concentration-dependent ATBs are aminoglycosides. The previously mentioned dosing strategy is also supported by the post-antibiotic effect (period after removal of the ATB during which the bacterial growth is suppressed) that is typical for aminoglycosides.

Methods of dosing aminoglycosides

There are two ways to administer aminoglycosides. In the conventional/traditional dosing – 2–3× a day in smaller doses, or a pulse dosing – once a day in a high dose. In intensive care units and beyond, once-daily dosing is preferred because of higher efficacy, lower toxicity and lower risk of resistance development; in other words, the "once daily" regimen is used almost always only with few exceptions (severe renal insufficiency, extensive burns, synergy with beta-lactams in the treatment of G+ infections). When administering smaller doses of aminoglycosides several times a day, critically ill patients are at risk of not reaching effective peak (c_MAX) concentrations. In addition, the patient is at risk of drug accumulation, which may lead to toxicity (see Figure 7.2). The dosing of aminoglycosides is summarized in Table 7.4 and Table 7.5. Aminoglycosides can be diluted in both NS and 5% glucose (G5%).

Aminoglycoside dosing and TDM

Table 7.4: Conventional dosing of aminoglycosides

CrCl (mL/min)	>50	20–50	<20
amikacin	7.5 mg/kg every 12 h	7.5 mg/kg every 24 h	7.5 mg/kg every 48 h
gentamicin, tobramycin	2 mg/kg loading dose, followed by 1.7 mg/kg every 8 h	1.7 mg/kg every 12–24 h	1.7 mg/kg every 48 h

Table 7.5: Pulse dosing of aminoglycosides

CrCl (mL/min)	>60	40–59	20–39	<20
amikacin	15 mg/kg every 24 h (in severe infections up to 30 mg/kg)	15 (up to 30) mg/kg every 36 h	15 (up to 30) mg/kg every 48 h	conventional dosing
gentamicin, tobramycin	5–7 mg/kg every 24 h	5–7 mg/kg every 36 h	5–7 mg/kg every 48 h	conventional dosing

Due to the interindividual differences in the PK of aminoglycosides and an increased risk of nephrotoxicity, plasma concentrations should be monitored from the start of therapy, and the dose should be subsequently individualized.

Critically ill patients have higher V_D, and it is usually necessary to administer a higher initial dose to achieve a sufficiently high peak (c_MAX) concentration. The first dose of gentamicin (7 mg/kg) and amikacin (20–30 mg/kg) should provide a sufficient bactericidal effect. Subsequently, it is necessary to monitor plasma concentrations and adjust the therapy according to the measured levels. Reference limits for aminoglycosides are given in Table 7.6 and Table 7.7.

Table 7.6: Target concentration for aminoglycosides in conventional dosing

	Trough concentration	Peak (cMAX) concentration
amikacin	4–8 mg/L	20–30 mg/L 25–35 mg/L in severe infections
gentamicin/tobramycin	1–2 mg/L	5–8 mg/L 8–10 mg/L in severe infections

Table 7.7: Target concentration for aminoglycosides in pulse dosing

	Trough concentration	Peak (cMAX) concentration
amikacin	<4 mg/L	40–60 mg/L 60–80 mg/L in severe infections
gentamicin/tobramycin	<1 mg/L	>15 mg/L 20–30 mg/L in severe infections

Application exercise:

Patient, male, 35-year-old, 86 kg and 185 cm in septic condition, mechanically ventilated, on vasopressors (catecholamines) and boluses of crystalloids given. Gentamicin was added to previous ATB therapy at an initial dose of 600 mg once daily as a 15-min infusion. Laboratory: urea 5 mmol/L (normal range 3.2–7.4 mmol/L), creatinine 74 µmol/L (normal range 64–104 µmol/L).

• Was the selected dose appropriate?

  Yes, it is clear from the above information that the patient is in a life-threatening condition; the volume of distribution for hydrophilic drugs may be increased due to fluid resuscitation and mechanical ventilation. In addition, he is a young man with a generally higher proportion of body water. His renal function is good, and the dose corresponds to the recommended dose of 7 mg/kg of body weight.

The trough concentration of gentamicin was taken before the second dose. The value was <1 mg/L. The attending physician decided to continue treatment with the same dose of gentamicin. With continued ventilation, the patient does not need fluid and catecholamine administration from the second day. A control sample over the next two days revealed an increasing trough concentration – 2.1 mg/L.

• What may be the cause of gentamicin accumulation? Was this accumulation preventable?

  One cause of the increased trough concentration may be an initial and transient increase in V_D for gentamicin. The first dose was high enough to ensure efficacy despite the increased V_D. Still, even after the cessation of fluid administration and circulation stabilization, the same dose was continued, which may have been too high at this point. For critically ill, unstable patients, it is precisely for this reason that it is advisable to control drug levels every day and prevent serious adverse effects. The patient's condition often changes from hour to hour in the ICU.

  The second reason for the accumulation may be the development of acute renal failure, which has so far gone unnoticed. With toxic ATBs, it is necessary to monitor the development of organ functions daily and, in the event of renal and/or liver failure development, to respond adequately by adjusting the ATB dose. For aminoglycosides, the availability of TDM makes our work much more manageable. So we do not have to worry about underdosing the patient by adjusting the doses because we can easily check the levels. Thus, the accumulation mentioned above could be prevented by more rigorous monitoring of the patient's clinical condition and more frequent collection of gentamicin levels.

Checking the laboratory findings, it was evident that AKI had developed: urea 18 mmol/L (normal range 3.2–7.4 mmol/L), creatinine 195 μmol/L (normal range 64–104 µmol/L).

• What would be your next step, and how would you adjust your gentamicin dosage?

  In the case of our patient, the best option is to keep the current dose and extend the dosing interval of gentamicin from 24 hours to 36 hours. It would be advisable to control trough concentrations before each subsequent administration of gentamicin.

  The modified gentamicin prescription could therefore be as follows:

  Gentamicin 600 mg/100mL NS/G5% i.v. over 15 minutes every 36 hours. Ideally, the specific day and time of dosing should be recorded in the prescription to avoid incorrect timing of administration at this not entirely standard interval. It is advisable to state in the note the time of the control sampling TDM.

  Pharmacokinetic software (e.g., MwPharm) is a helpful tool in optimizing aminoglycoside dosing, facilitating an individualized ATB dose calculation for a particular patient based on population data and simulation models. Under this link for gentamicin TDM, you can try such simulations.

7.3.3 Optimization of dosing of exposition-dependent (concentration-time dependent) ATBs in the ICU

For this group of ATBs, the optimal PK/PD parameter is the 24-hour AUC relative to the MIC, with the difficulty of determining the most appropriate dosing schedule in general. The dose and frequency of administration vary from one ATB to another, and therapeutic monitoring of ATB levels would be ideal. This ATB group includes glycopeptides (vancomycin, teicoplanin), fluoroquinolones, tigecycline, colistin, and linezolid.

Vancomycin

Vancomycin is a glycopeptide ATB with antibacterial activity on gram-positive organisms, including MRSA and Staphylococcus epidermidis. It is mainly used in the treatment of severe staphylococcal and enterococcal infections. It has a narrow spectrum of activity; it is ineffective in infections caused by gram-negative pathogens.

It has minimal bioavailability after oral administration, therefore i.v. infusion is necessary to achieve systemic exposure. Vancomycin is administered orally only in the indication of Clostridioides difficile infections.

Doses of up to 1 g can be administered within 60 minutes via a central venous catheter (CVC), with higher doses within 90 or 120 minutes. This is to prevent the adverse effect of vancomycin – the so-called red-man syndrome, which can be avoided if the ATB is given by slow infusions. The usual problem in the hospital is the correct dilution of vancomycin – when administering vancomycin via a central vein, the dilution may be a maximum of 10 mg/mL, but when administered via a peripheral vein, the dilution should not exceed 5 mg/mL. These dilutions are recommended to minimize infusion-related adverse effects such as thrombophlebitis or the above-mentioned red-man syndrome. Vancomycin can be diluted in both NS and G5%.

Vancomycin dosing strategies in the ICU

There are three crucial points to keep in mind when administering vancomycin to critically ill patients:

• Determine the appropriate loading dose (LD).
• Determine the appropriate maintenance doses.
• Adjust the dosage based on vancomycin TDM.

Intermittent (traditional) dosing of vancomycin

1. A loading dose of 25–30 mg/kg (serious infections). Doses for individual weight categories are given in Table 7.8.

   Table 7.8: The recommended loading doses of vancomycin considering the patient's body weight

   Bodyweight	Recommended loading dose	Length of the infusion
   25–35 kg	750 mg	60 minutes
   36–45 kg	1000 mg	60 minutes
   46–55 kg	1250 mg	90 minutes
   56–65 kg	1500 mg	90 minutes
   66–75 kg	1750 mg	120 minutes
   ≥76 kg	2000 mg	120 minutes

2. Maintenance dose – it is necessary to take into account the renal parameters (see Table 7.9)

   Table 7.9: Recommended maintenance vancomycin dosing considering the renal functions.

   Creatinine clearance (mL/min)	Dose and frequency
   >90	15–20 mg/kg every 8–12 h
   51–89	10–20 mg/kg every 12 h
   30–50	10–15 mg/kg every 12 h or 20 mg/kg every 24 h
   10–29	10–15 mg/kg every 24–48 h
   <10	10–15 mg/kg once, then according to the levels

   However, practical experience suggests that in patients with creatinine clearance >90 ml/min, trough (c_MIN) concentrations are subtherapeutic with a 12-hour interval between doses. Therefore, an 8-hour interval seems optimal.

   ×
3. TDM.

   Vancomycin target concentrations have been changing over the years. It is currently recommended to maintain higher levels of vancomycin than it used to be in the past. The trough concentration of vancomycin (i.e., a sample taken before the next dose) is best to monitor efficacy. However, new guidelines were published in 2020, mentioning AUC as a more appropriate parameter. However, in clinical practice, the calculation of AUC is more complicated because it requires PK software, so the use of trough concentrations still persists. Levels should be taken ideally at the time of steady-state (before the 4th or 5th dose); however, in critically ill patients with sepsis, it is recommended to measure the concentration as early as 24 hours after the start of therapy. Steady-state cannot be expected in these patients due to changing organ functions. Ideally, vancomycin levels should be taken daily in septic patients, and the dosage adjusted according to the measured value.

   The optimal effect of vancomycin occurs at AUC/MIC>400, which can be achieved by maintaining the trough concentrations listed in Table 7.10.

   Table 7.10: Target vancomycin trough concentrations for TDM

   Target trough concentration	Indication
   10–15 mg/l	Skin and soft tissue infection
   15–20 mg/l	Pneumonia, bacteremia, endocarditis, osteomyelitis

Continuous administration of vancomycin

Administration of vancomycin in this way is not more effective than intermittent infusion. However, it has several advantages in ICUs. One of them is the fact that target concentrations (15–25 mg/L, for life-threatening conditions up to 30 mg/L) can be achieved using lower daily doses. For continuous administration, sampling can also be performed to determine vancomycin levels at any time during the day, which reduces the risk of incorrect sampling timing and subsequent misinterpretation of the measured vancomycin levels. The dosage can then be adjusted very quickly according to the measured concentration by decreasing/increasing the infusion rate, administering a bolus re-loading dose, or stopping the infusion.

Application exercise:

A 56-year-old male patient, 72 kg, 185 cm, was admitted to the ICU in septic shock. See the following laboratory results: CRP 380 mg/L (<5 mg/L), urea 14 mmol/L (normal range 3.2–7.4 mmol/L), creatinine 192 µmol/L (normal range 64–104 µmol/L), elevation of liver enzymes. The patient's condition requires the administration of fluids, catecholamines, and artificial lung ventilation. It was decided to use the ATB combination of vancomycin + meropenem as the initial empiric therapy.

• Think about the combination of ATBs used. Why were these two drugs chosen? Suggest vancomycin dosing based on the available data.

  From the above information, it is clear that the patient has reduced renal function. However, as mentioned earlier, in critically ill patients, there is a greater risk of underdosing than overdosing at the beginning of therapy; therefore, reducing the initial doses of ATBs is not recommended. Thus, we will use an unreduced loading dose for a toxic ATB such as vancomycin. According to the calculation, we can round it to 2 g according to the patient's weight (25–30 mg/kg). We try to adjust the maintenance doses to renal function. The calculated creatinine clearance for the patient is approximately 40 mL/min. We know that glomerular filtration rate assessment equations are challenging in acute conditions, so we use them only for basic orientation. According to the above dosing table, the patient falls within the range of 30–49 mL/min, and the doses should be in the range of 15–20 mg/kg every 12–24 hours. Since 40 mL/min is in the middle of the interval, the resulting empirical maintenance dose may look like this: 15 mg×72 kg every 12 h=1080 mg every 12 h – rounded to 1 g every 12 hours.

  Do not forget sufficient dilution and infusion time – vancomycin concentrations should not exceed 10 mg/mL, and the infusion rate 60 min for every 1 g of vancomycin via a central vein.

  The final dosage will therefore look like this:

  • Vancomycin LD 2 g/200mL NS/G5% i.v. over 120 min, then 1 g/100mL NS/G5% i.v. over 60 min every 12 h

  Further development of the case report, including dose adjustments based on TDM, will be presented at the lecture.