Two or more antimicrobials prescribed in large doses for prolonged duration of treatment can lead to drug resistance, superinfection. HPLC serves as a validated method for measuring the PK/PD(Pharmacokinetic/Pharmacodynamic) ratio.

Cumulative measure of pharmacokinetic is done by comparing Peaks in Chromatography with baseline as zero or mean of 1^st readings of plasma concentration of individuals.

Concentration- response or time-curve is PK-PD relation that starts with binding of ligand(drugs) with receptors- to response we measure. Antimicrobials are ligands (L) that binds with receptors [R] microbial proteins like penicillin binding protein (PBP) in cell wall of microbes such as bacteria clostridium tetani, anaerobes Bacteroides fragilis, fusobacterium etc. [1]. AMR (antimicrobial resistance) stewardship program endeavoring on rationale use of antimicrobials [2]. The prolong duration of treatment by antibiotics leads to administration of large dose antibiotics. Simultaneous quantitative measure of antibiotics concentration both at plasma and wound fluid can provide evidence for relation of appropriate dosage for clinical outcome. In patients with mixed infection, larger doses of two or more drugs are given simultaneously, resistant strain multiply to cause superinfection [3].

MATERIAL AND METHOD:

Source of information: -- BHTs of different wards at Medical Record Department, RIMS, Ranchi. Data collected from Medical Record Department to focus on rationale use of antimicrobials, difference in dosage regimen, multiple antimicrobial prescribing trends, use of various combinations of AWaRe group antimicrobials.

Step 1- Method development mentioned by using columns for – 1. Serial number, 2.I Indoor unique ID number.,3. Demography and personal details of patient. 4. Date of admission. Provisional diagnosis/final diagnosis with date .5. Treatment started with date and dosage regimen of antibiotics. 6.Date of stopping the antibiotics, 7. Total days spent in hospital,8. Investigations, 9. Address

Added drug prescribed on admission selected were N=240[ Surgical ward BHT n=60; Gynaecology ward BHT n=60; Medicine ward BHT n=60; Orthopedics’ ward BHT n=60.]

Step 2. Random collection of data by filling the tables mentioned.

Step 3.  of BHTs with lowest and highest dosage regimens of most frequent antibiotics administered in treatment chart of different patients of different wards.

Step 4. Compilation of most frequent administered antibiotics as total amount antibiotic consumption in one episode of dosage regimen for longer duration hospital stay, Table-1. Cefoperazone and ceftriaxone are 3^rd generation cephalosporins, being empirically prescribed are Watch group drugs, Table-2, polytherapy-Table-3.

Antimicrobial prescription variability also is due to patient’s attitude as some patients leave against medical advice. Following are the headings covered to compiled table data-

• Variations in dosage regimen antibiotics administered in post -operative patients.
• Variation choice from AWaRe group, dosage regimen and trends in prescribing antimicrobials.
• Trends in prescribing multiple antimicrobials with variable dosage regimen.

Antimicrobials characterized by 3 basic parameters:

• Efficacy=Emax [Full bactericidal response elicited at some concentration of drug]
• Potency= EC50 or IC50[Inhibitory concentration the plasma concentration of drug producing bacteriostatic effect]

Drug with greater efficacy is more therapeutically beneficial than one that is more potent.

• H or Hill factor or slope of curve.

Econ Control bacterial microbes log 10 CFU /ml in X axis of a sigmoid curve without treatment. Minimum Inhibitory Concentration (MIC) is the lowest concentration antibiotic after 24 hours Incubation Period with inoculation of 10⁴ to 10⁵ CFU/ml causing complete destruction or survival of less than 0.1% of inoculum.

The pharmacokinetic basis of antimicrobial therapy

In clinical trials, the following are the two most important factors in predicting successful clinical and microbiological outcomes in patients.

1.C _MAX at C 1 central compartment maximum plasma concentration of drug in plasma,12Xmic (12 times the MIC, minimum inhibitory concentration).

2.Site of infection (drug penetration at the site of infection through anatomical compartment depends on the physical barriers such as epithelial layers ,membrane transporters, drug’s chemical nature).Orally administered drug absorbed through GI Tract (g) absorption constant (ka) and passes through Multicompartmental Pharmacokinetic; drug concentration are different in central ,C 2 site oof infection, and C 3 compartment other tissues of the body change.[4]

Basic PK Parameters-Therapeutic Drug Monitoring

   1.Bioavailability (f) is fraction of administered drug reaching the systemic circulation.

F=AUC oral route/AUC by IV route (F is 100% for IV drug,0-100% for non -IV drugs).

2. Clearance [CL] rate at which drug is removed per unit time from plasma.

CL=K_e (Rate of elimination / Volume of distribution mg per minute/mg per ml.

After reaching the plateau phase, five t_1/2 CL can be derived also from steady state

Concentration.

C_{SS =} K_e *V d and K_e (elimination constant) = 0.693/t_1/2.

3.Vd (L)= D/C (total drug administered / plasma concentration), estimates total amount of drug in the body at any time and loading dose (Loading Dose=V d* desired concentration) [CL Renal =Rate of secretion -Rate of absorption /plasma concentration].

4.Elimination half-life. time duration in which plasma concentration of drug fall by 50% [t_1/2 ]=0.693xVd/CL [0.693 is log 2, representing exponential rate of Elimination.]

5.AUC Total amount of drug concentration in plasma at any point of time.

Important parameters derived from CL and Dose. AUC=D/CL.

Common AUC estimates are AUC _exact , AUCO, AUCO₂₄ area can also be calculated by adding area of discrete set of blocks set up by dose and interval on axis X concentration X concentration, axis Y called Trapezoid method.

C_ss (Steady state concentration) is attained when rate of,

Rate of administration=Rate of elimination, for fixed time interval regimen50% of C_ss achieved in 1*t^1/2,

90% 0f C _SS achieved in 3.3*t_1/2.,

95% of C_ss achieved in 4-5* t_1/2

Stronger relationship exists between the plasma concentration (C_SS) of drugs and effect, than between dose and effect. Timely communication of results to clinicians is important and the clinicians should interpret the C_ss in context of patient’s status.{4}.

DISCUSSION:

We should endeavor to improve antibiotic safety. Cefoperazone and ceftriaxone are 3^rd generation cephalosporins. being empirically prescribed are Watch Group Drugs. Optimization of dosage-based 3^rd Generation Cephalosporines based on evidence by TDM will save drug from large amount being administered, drug-resistance. Evidence differentiating between possible Adverse Drug Reaction (ADR) from toxicity, therapeutic from sub therapeutic dose. Pharmacokinetic data obtained by TDM of patient will contribute relevant data from for ICMR-AMR surveillance program of this region.

Acknowledgements:

I should be grateful for all MRD staff, nurses who made treatment practically administered, and doctors and patients who remain unsung.

Funding Statement

  No funding.

Conflict Of Interest

  None.

Author’s contribution:

1. Conceptualizing, Writing. ---- Dr Kavita Topno.
2. Proof Reading, Data Analysis--Dr Marshall Daud Kerketta
3. Analysis---Dr Shadab Alam
4. Data Collection—Dr Nidhi Ekka, Dr Aman Kumar Gupta, Dr Sidyant Singh
5. Data Correction and Analysis- Dr Ankit Kumar.

REFERENCES: -

1. Wallenburg E, Ter Heine R, Schouten JA, et all: An integral pharmacokinetic analysis of piperacillin and tazobactam in plasma and urine in critically ill patients. Clin. Pharmacokinet.2022,61:907-18,10.1007/s40262-022-01113-6.
2. Access, watch, reserve classification of antibiotics; WHO-EMP-IAU-2019.11-eng.
3. Satoskar RS, Rege NN, Bhandarkar SD: Pharmacology and Pharmacotherapeutics,24^thElsevier,2015.
4. K, Heil EL, Tam VH: Optimizing pharmacokinetics-pharmacodynamics of antimicrobial management in patients with sepsis: a review. J Infect Dis.2020, 222: S132-41.10.1093/ infdis/ jiaa118