Optimizing the use of beta-lactam antibiotics

Optimizing the use of beta-lactam antibiotics

By, VAISHNAVI- MDCCC-138

Beta lactam (BL) antibiotics are the class of antibiotics that have a beta lactam ring and are hydrophilic. BL especially Cephalosporins are drug of choice for meningitis or meningoencephalitis and for penumonia caused by Typical bacterias. BL are the most commonly used drugs in Intensive Care Unit (ICU) patients. Though BL have specific dose for specific indication, it needs to be titrated for individualised Pk-PD status.

• The three principle Pk-PD indices are, Time dependent Antibiotics - %fT>MIC
• Concentration dependent Antibiotics - Cmax/MIC
• Time-concentration dependent - AUC 24hr/MIC

Changes in PK and PD status occurs in patients with, 

*increased volume of distribution

*Increased renal clearance

*Hypoalbuminemia

*Increased Cardiac Output

*Vasodilation

*Hemodialysis

*ECMO

*Obesity

*pediatrics

*Severe burns

PK changes is proportional to illness severity. BL act by binding and acylating the serine active site of the PBPs in the membrane which is involved in peptidoglycan incorporation and subsequent cell wall synthesis. Time dependent acylation occurs which is increased by affinity between BL & PBP and hardly by BL concentration. Acylation more than threshold value of 1 or more PBPs is necessary to inhibit cell wall synthesis. The more the Acylation occurs, more bactericidal effect is achieved, until the state of saturation.

It's necessary for an antibiotic concentration to remain more than MIC to exhibit its effect. After that, some antibiotics inhibit bacterial growth by post Antibiotic Effect (PAE). In BL, carbapenems are the only class that exert PAE against gram negative bacteria (GNB), due to its prolonged or irreversible acylation of PBPs.

Hypoalbuminemia, use of fluid resuscitation, Vasoactive medications, Augmented Renal Clearance (ARC) are some conditions of critically ill patients which may favor in increased Volume of Distribution (Vd). 

%fT >MIC is higher with continuous infusion and leads to resistance suppression. Mutation prevention Concentration (MPC) is the concentration of Antibiotics associated with maximum suppression of resistance. Maintaining Antibiotics concentration >MPC is always recommended.

Drug exposure of BL is high in extended infusion than in intermittent infusion. Interestingly, prolonged or continuous infusion may benefit only the critically ill patients, those with infections caused by more resistant bacteria & higher MIC values.

Loading dose with carbapenem evidenced increase cure rate & better clinical outcome with a decrease in overall mortality, recommending empirical treatment with carbapenem starting with loading dose followed by prolonged infusion. Characteristics of ideal BL is met by 1-2g Meropenem, which also have higher affinity with PBP. Meropenem is the first drug of choice for ESBL producing Klebsiella and E. coli. It has an extended spectrum and covers pseudomonas species also. Based on EUCAST criterion, the optimal Loading dose of Meropenem is 2g as 30 min infusion. Whereas, Extreme worst levels of albumin concentration, body weight and renal clearance suggests 0.5g of Meropenem as 30 min infusion.

 A study suggested no significant difference in toxicities between high and licensed dose groups. The risk of sub therapeutic levels in early phase of severe sepsis outweighs the risk of toxicity due to loading doses. High maintenance dose must be started within 1hr & 2hr of loading dose in patients with septic shock and without shock respectively. Dose adjustments may be done after 48-72 hrs to avoid toxicity.