Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on Mortality

Antimicrobial Pharmacodynamics: Concepts for Rational Selection and Dosing of Antibiotics

Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on Mortality
I want to start off by showing you this data from a study that compared in hospital mortality and other outcomes between patients with bloodstream infections who received adequate antimicrobial therapy vs those who did not. What they defined as adequate therapy was an antibiotic that showed to be active by susceptibility results. As we can see those patients who had inadequate therapy had a 2 fold greater risk of mortality. These results are not unique and several other studies are available to confirm these results in other types of infections as well (i.e. pneumonia). Ibrahim et.al. Study from Barnes Jewish Hospital Prospective cohort study with N = 492 Inadequate therapy = tx with an antibiotic that was resistant on susceptibility testing or no treatment with an effective antibiotic. Hospital mortality: 28.4% adequate vs 61.9% for inadequate. 2 fold greater mortality. Ibrahim E, et al. Chest 2000; 118:

Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on Mortality
In this study, nosocomial type organisms had the highest rates of inadequate therapy and there was a direct association for specific pathogens between inadequate therapy and hospital mortality rates. This was an observational study so this does not imply cause and effect but the relationship is interesting. OSSA=oxacillin-susceptible S. aureus; CNS=coagulase-negative staphylococci; VRE=vancomycin resistant enterococci Ibrahim E, et al. Chest 2000; 118:

What does “S” Mean? Susceptible - Isolates are inhibited by the usually achievable concentrations of antimicrobial agent when the recommended dose is used for the site of infection. Intermediate – Implies clinical efficacy in the areas where drugs are physiologically concentrated or when higher than normal dosages of drugs can be used Resistant – Isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules The determination of whether therapy is adequate takes into consideration several factors including patient specific, drug specific and bacterial specific factors. So based on how we defined adequate therapy we need to have some knowledge about the susceptibilities of the infecting pathogen in order to determine whether therapy is adequate. We most commonly define bacteria into 3 categories which are S, I , R based on the breakpoints defined by CLSI. If an organism is categorized as susceptible…therapy has a “good chance” of success at usual dosages. With “Intermediate” organisms, success may be achieved with higher than usual dosages The definition of “Resistant” means that there is a low chance of success with usual doses. However if we want to get more advanced than this we should think of susceptibilities in terms of actual MIC’s. By knowing the MIC of the organism and some pharmacokinetic data about the drug we are able to make better determinations about what will be adequate therapy for a specific infection. Keep in mind that resistance is a relative phenomenon and you may be able to successfully treat an infection with an antibiotic reported as resistant in the right setting. CLSI. M-100-S16. January 2006

However just knowing the pharmacokinetics of antimicrobials is not enough to make good choices in drug therapy. We also need to have some knowledge about the infecting pathogen, particularly the MIC’s. This picture shows the broth macrodilution technique for determining the MIC of an organism. We start off with test tube #1 which has 100mcg/ml of the antibiotic and each subsequent test tube has a two fold dilution. These are then inoculated with the bacteria and incubated. After that each test tube is visually inspected for bacterial growth. The test tube with the lowest concentration that inhibits bacterial growth is read as the MIC.

“PK is what the body does to the drug”
Pharmacokinetics Absorption Distribution Metabolism Elimination “PK is what the body does to the drug” In order to use antibiotics wisely we need to have an understanding of their pharmacokinetic properties. The pharmacokinetic parameters are the absorption, distribution, metabolism and elimination…or what the body does to the drug. Ultimately these factors all together determine the drug concentration profile for each individual drug.

Pharmacokinetics Serum/Tissue Concentrations Half-Life Pathogen Susceptibility MIC/MBC Pharmacodynamics Peak/MIC AUC/MIC Time > MIC Eradication/Cure

Pharmacodynamic Interactions
Peak/MIC AUC/MIC Concentration By combining our knowledge of the pharmacokinetics of the drugs and the microbiological data we can come up with pharmacodynamic parameters and study the relationships of these parameters with bacterial killing and outcomes. This graph shows the most common pharmacodynamic parameters that have been studied. By knowing how these parameters are associated with outcomes we can then apply this knowledge to our therapeutic decisions to help optimized outcomes. The most common way to categorized the pharmacodynamics of antibacterial agents is as time dependent or concentration dependent. For time dependent drugs, the amount of bacterial killing is directly related to the duration of exposure of the bacteria to the antibiotic so with these drugs the goal is to prolong the time of exposure. There is no to minimal post antibiotic effect so once serum levels fall below the MIC bacterial growth resumes. For concentration dependent drugs the amount of bacterial killing is directly related to the amount of exposure of the bacteria to the antibiotic so with these drugs the goal is to maximize the amount of exposure. For these drugs there is a post antibiotic effect so even after the serum levels fall below the MIC the bacterial growth continues to be suppressed MIC Time>MIC Time

Concentration Dependent vs. Concentration Independent Bacterial Killing
Tobramycin Ciprofloxacin Ticarcillin Time (hours) Craig WA, et al. Scand J Infect Dis, 1991; Suppl (74)

Optimizing Antimicrobial Therapy
Concentration at Infection Site Host Factors PK PD Bacterial Killing Pathogen MIC/MBC Antibiotic Why is it important to understand pharmacodynamics? Why can’t I just pick an antibiotic with an “S” and use that? This slide shows how the antibiotic therapy, host factors and infecting pathogen interact to determine a clinical outcome. In normal healthy subjects with mild to moderate infections the antibiotic therapy contributes less to the outcome however when we are dealing with severe infections, relatively resistant bacteria or immune compromised hosts antibiotic therapy contributes more to the outcome. In these situations it becomes important to optimized the therapeutic regimen in order to tip the balance in favor of the patient and increase our chance for a good outcome. Outcome

Pharmacokinetic-Pharmacodynamic Indices Correlating with Efficacy
Antimicrobial Agent Bactericidal Pattern of in-vitro Activity PK-PD measure(s) Aminoglycosides Concentration AUC0-24:MIC, Cmax:MIC b-Lactams Penicillins Time T>MIC Cephalosporins Carbapenems Monobactams Glycopeptides/ Lipopeptides Daptomycin Oritavancin Vancomycin AUC0-24:MIC Fluoroquinolone Antimicrobial Agent Bactericidal Pattern of in-vitro Activity PK-PD measure(s) Macrolides Concentration AUC0-24:MIC, Cmax:MIC Azithromycin Time AUC0-24:MIC Clarithromycin Telithromycin Metronidazole Tetracyclines Doxycycline Tigacycline Clindamycin Oxazolidinones Linezolid There has been a lot of research in this area and this table shows the killing pattern and the pharmacodynamic parameters associated with efficacy for the different classes of antibiotics and for specific drugs. I will say that it is not all clear and that we still need a better understanding of the pharmacodynamics of some agents but the ones with the most research are beta-lactams, FQ’s, AG’s and vancomycin.

In-vitro Pharmacodynamic Models

Murine Thigh Infection Pharmacodynamic Model
Antimicrobial Cyclophosphamide Organism 107 CFU CFU determination Bacteriostatic dose Pharmacokinetic parameters A murine thigh infection model was used to investigate the pharmacodynamic/ pharmacokinetic relationship with Ketek. Mice were rendered neutropenic by cyclophosphamide injection. Approximately 107 colony forming units (CFU) of S. pneumoniae were injected into the thighs of neutropenic mice, and after 2 hours Ketek (or a comparator antibiotic) was administered every 3–24 hours. An Emax dose–response model was used to calculate the bacteriostatic dose of the antimicrobials over 24 hours (Vesga et al. 1997). Vesga et al. 37th ICAAC 1997 2 hours Vesga A, et al. 37th ICAAC

b-lactams

Correlation of PK/PD Parameters With Effect of Cefotaxime Against K
Correlation of PK/PD Parameters With Effect of Cefotaxime Against K. pneumoniae in Lungs of Neutropenic Mice Correlation of Pk/PD parameters with a reduction of bacterial counts in an in vivo murine model. Mice made neutropenic and lungs inoculated with fixed inoculum of bacterial via an aerosol. In this case K. pneumoniae. Then many different regimens of abx…this case cefotaxime where administered with varying dosages and frequencies. Mice are sacrificed and bactierial counts are done and plotted against different PD parameters. Each dot represents an individual mouse. For this bug/drug combo…found a linear relationship with cefotaxime and T>MIC for S. Pneumo. Dashed line is “the static” concentration. When you decrease the bacterial count down to the inoculum that you initially injected. T>MIC 40-50% gets you back to static concentration. This will become an important point Peak/MIC 24-Hr AUC/MIC T>MIC Craig WA. Diagn Microbiol Infect Dis 1995: 22:89-96

Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7
Relationship Between Time Serum Levels Exceed the MIC and Mortality for B-Lactams Against S. pneumoniae Penicillins Cephalosporins Obviously the next step is to see whether this actually has any effect on mortality. This slide shows data from animal infection models with S. pneumonia treated with penicillins and cephalosporins. As you can see when the T>MIC is less than 30% there is a high mortality rate but this drops off rapidly once T>MIC is 40% or higher. Find that that static concentration (~40-50% Time above MIC) is where you have decreased mortality and thus the goal for these drugs is to be achieve a T>MIC of greater than 50%. Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7

Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7
Animal data is nice but we would like to see if the same holds true in human infections. This graph shows the relationship between bacteriologic cure and T>MIC for PCN’s and Cephal’s in otitis media caused by S.pneumo and H.influenzea. As we saw in the animal models T>MIC of less than 30% are associated with poor outcomes. In order to get an efficacy rate of 80% or higher the T>MIC must be at least 40% or higher. Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7

Relation Between PD Parameters and Efficacy for Ticarcillin against P
Relation Between PD Parameters and Efficacy for Ticarcillin against P. aeruginosa We can also examine PK/PD for Beta lactams. This is a study looking at the relationship between certain PK/PD parameters and changes in CFU in a neutropenic mouse thigh model for Ticarcillin against PSA This is performed by making the mouse neutropenic and innoculating the thigh muscle with a given innoculm of bacteria and then giving many different doses and intervals of antibiotic. This case…TICAR vs PSA. Then the mouse is sacrificed and colony counts of bacteria in the thigh are performed and then plotted against the different PK/PD parameter. When plotting change in bacterial count relative to AUC/MIC for TC and PSA…you get a scattergram. No correlation. Same with PK/MIC ratio. However, with t>MIC and bacterial kill…there is a nice linear relationship…with maximum kill at 100% time above MIC 24-Hr AUC/MIC Peak/MIC T>MIC Vogelman B., et al. J Infect Dis (4).

What %T>MIC is our target for β-lactams?
“Static” dose 1 log 2 log 3 log Static Dose = 30% T>MIC. PD Parameter to maintatin starting innoculum. This endpoint has been associated with mortality data in murine pneumonia models. 1 log reduction at 50% T>MIC 2 log at 60% T>MIC 3 log at 70% T>MIC 24-Hr AUC/MIC Peak/MIC T>MIC Vogelman B., et al. J Infect Dis (4).

b-lactam Pharmacodynamics
Antibiotic Organism/Class Outcome Parameter and Value Source Cefazolin E. coli, Klebsiella T>MIC IVPDM Ceftriaxone S. pneumoniae T>MIC=100% Rabbit meningitis model E. coli T>MIC, max effect 4xMIC Cephalosporins Enterobacteriacae Streptococci S. aureus T>MIC 60-70% T>MIC 40-50% Animal data review Cefazolin, ticarcillin, penicillin P. aeruginosa T>MIC 100% T>MIC 55% Neutropenic murine thigh infection model Cefmenoxime Gram-negative T>DRC Human, nosocomial pneumonia Gunderson BW, et al. Pharmacotherapy Nov;21(11 Pt 2):302S-318S

Concentration Time Profile: Antibiotic Y
MIC=2 %T>MIC >90% DI Is it really necessary to administer b-lactams as continuous infusion? This graph represent the typical serum concentration versus time profile for a b-lactam like cefepime. We can see that against an organism with an MIC 2 or less the expected T>MIC far exceeds our target of >50% of the dosing interval. The enterobacteriacea such as E.coli, K.pneumonia, etc.

Concentration Time Profile: Antibiotic Y (q12h)
MIC=8 %T>MIC=50% DI However as the MIC of the infecting pathogen increases the T>MIC will decrease. The typical MIC of organisms such as Psuedomonas tend to be higher, in the 2 – 8 range. As you can see with an MIC of 8 we are at the boderline of efficacy with our q 12 hour regimen. Obviously even with an lower MIC in a large patient we may be at the borderline of efficacy because we will achiever lower levels secondary to the higher volume of distribution.

Concentration Time Profile: Antibiotic Y (q8h)
MIC=8 %T>MIC>90% DI By administering the antibiotic more frequently we can increase our T>MIC in increase our chance of a good clinical outcome. This is why for organims such as psueudomonas we will usually increase the doses or frequencies of the adntibiotics.

Continuous Infusion Beta-lactams
Intermittent Beta-lactam Serum Concentrations Continuous MIC Well based on the data we’ve seen so far it would make sense then to administer B-lactams in a way that will optimize our T>MIC. Some investigators have proposed administering B-lactams as a continuous infusion to do so. With continuous infusion we achieve lower peaks but we are able to maintain levels above the MIC for longer periods of time. MIC Time (h)

Cefamandole: Continuous vs. Intermittent infusion
This is data from an older study but there are several other studied that have addressed the same issue and have shown similar results. This study showed that the method of administration, either continuous infusion or intermittent infusion, did not make a difference in the outcome of infected patients overall when treated with cefamandole. p=NS Bodey, GP, et al. Am J Med

Cure Rate of Infections in Persistently Febrile Neutropenic Patients
However when the investigators looked at the results in neutropenic patients there was a difference in cure rate favoring the administration of cefamandole via continuous infusion. It seems logical that in these patients with compromised host defenses optimizing the antibacterial activity would make a difference because in these patients antibiotic therapy contributes more to the clinical outcome. However we don’t use continuous infusion antibiotics very much. Why not? Well there are several reasons such as most of us are not trained to dose antibiotics this way, this type of administration can be a little more tedious because it will require a dedicated line or lumen, and a infusion pump. However we may use continuous infusion when dealing with a highly resistant pathogen in order to overcome the resistance. p=0.03 Bodey, GP, et al. Am J Med

Fluoroquinolones

Correlation of PK/PD Parameters With Effect of Levofloxacin Against S
Correlation of PK/PD Parameters With Effect of Levofloxacin Against S. pneumoniae in Thighs of Neutropenic Mice Switch to quinolones In vitro: Linear relationship between auc/mic. As AUC/MIC increases…bacterial colony counts decrease linearly. 24-Hr AUC/MIC Peak/MIC T>MIC Handbook of Experimental Pharmacology. Vol 127: Quinolone Antibacterials. 1998

Relationship Between 24-Hour AUC/MIC and Mortality for Fluoroquinolones Against S. pneumoniae
In vivo…animal model…0% Mortality when AUC/MIC approaches 30%. This is very controversial. Some individuals believe that the AUC/MIC should be higher. Currently lacking human studies to confirm this however several experts accept this as the pharmacodynamic goal for the FQ’s against gram positives. Craig, WA 37th IDSA, 1999 Clin Infect Dis. (in press)

Relationship Between 24-Hour AUC/MIC and Mortality for Fluoroquinolones Against Gram-Negative Bacilli in a Murine Model This is a murine pneumonia model looking at % mortality for GNB pneumonia relative to the AUC/MIC ratio for fluoroquinolones achieved in mice. One can immediately notice a nice linear relationship between increasing AUC/MIC and decreasing mortality until reaching an AUC/MIC of ~100 where the mortality rate drops to 0. Nice for mice…however… Craig, WA 37th IDSA, 1999 Clin Infect Dis. (in press)

Relationship Between AUC24/MIC and Efficacy of Ciprofloxacin in Patients with Serious Bacterial Infections When you look at the work by Alan Forrest and his colleagues where they looked at ciprofloxacin in critically ill patients, mainly nosocomial pneumonia in ventilated patients. They plotted AUC/MIC relative to % efficacy: resolution of S/S ass w/ infection. They found that once one achieved an AUC/MIC ratio of 125…there was a statistically significant difference in those patients exhibiting both a clinical and microbiological cure. This is the study that set the goal of an AUC/MIC ratio of >125 for FQ’s against GN’s. Very similar results to what Craig and his colleagues found in the animal model. Forrest A, et al. AAC, 1993; 37:

Fluoroquinolone Pharmacodynamics: S. pneumoniae
Antibiotic Outcome Parameter and Value Source Levoflooxacin, ciprofloxacin, trovafloxacin AUC:MIC > 35 IVPDM Ciprofloxacin, levofloxacin AUC:MIC 30-35 Ciprofloxacin, ofloxacin, trovafloxacin AUC:MIC 44-49 Ciprofloxacin, levovfloxacin AUC:MIC 32-64 Quinolones AUC:MIC > 40 Sitafloxacin AUC:MIC = 37 Murine thigh and lung infection model Gatifloxacin AUC:MIC = 52 Gemifloxacin AUC:MIC = 35 Gunderson BW, et al. Pharmacotherapy Nov;21(11 Pt 2):302S-318S

Fluoroquinolone Pharmacodynamics: Gram Negative Bacilli
Antibiotic Organism/Class Outcome Parameter and Value Source Enoxacin P. aeruginosa, E. coli Cmax:MIC>8 IVPDM Ciprofloxacin P. aeruginosa Ciprofloxacin, ofloxacin AUC:MIC>100 Lomefloxacin Cmax:MIC>10 Neutropenic rat sepsis model Gatifloxacin Enterobacteriacae AUC:MIC=48 Murine thigh and lung infection model Sitafloxacin AUC:MIC=43 GNR, mostly LRTI AUC:MIC>125 Human, retrospective GNR, vent dependent Gunderson BW, et al. Pharmacotherapy Nov;21(11 Pt 2):302S-318S

Aminoglycosides

Max Peak/MIC Ratio and Clinical Response with Aminoglycosides
This study showed the relationship between plasma concentrations, the MIC, and therapeutic outcomes in patients with gram-negative bacterial infections in four clinical trials of gent, tobra, and amikacin. The peak/MIC ratios were associated significantly with clinical response. Peak/MIC ratios of > 10 were associated with a 90% response rate. Moore,et al. J Inf Disease, 1987; 155(1): 93-98

Aminoglycoside Pharmacodynamics: Human Studies
Antibiotic Organism Outcome Parameter and Value Gent, Tob, Amik GNR(63% E. coli, 27% Klebsiella); UTI, LRTI, bacteremia, SSI Cmax:MIC>10 GNR; UTI, LRTI, URTI, SSI, Sepsis Cmax:MIC>8 Gent, Tob GNR Moore,et al. J Inf Disease, 1987; 155(1): 93-98 Deziel-Evans LM, et al. Clin Pharm 1986; 5: Nicolau DP, et al. Antimicrob Agents Chemother 1995; 39:650-5

Methods for AG Dosing This graph shows the serum concentration vs time profiles that you can expect when administering an aminoglycoside via traditional dosing (administering smaller doses several times per day) vs high dose extended interval dosing (higher dose less frequently). As we already mentioned AG’s are concentration dependent killing agents and as we increase the peak to mic ratio for these drugs we will increase bacterial killing and hopefully achieve more favorable outcomes.

Single Daily Dosing Aminoglycosides: Efficacy
Bailey TC, et al. Clin Infect Dis 1997; 24: Zaki M, Goetz MB. Clin Infect Dis 1997; 24:

Single Daily Dosing Aminoglycosides: Toxicity
Bailey TC, et al. Clin Infect Dis 1997; 24: Zaki M, Goetz MB. Clin Infect Dis 1997; 24:

Extended Interval Dosing of Aminoglycosides
Clin Infect Dis 2000 Mar;30(3):433-9 National survey of extended-interval aminoglycoside dosing (EIAD). Chuck SK, Raber SR, Rodvold KA, Areff D. 500 acute care hospitals in the United States EIAD adopted in 3 of every 4 acute care hospitals 4-fold increase since 1993 written guidelines for EIAD in 64% of all hospitals rationale 87.1% : equal or less toxicity, 76.9% : equal efficacy 65.6% :cost-savings dose: > 5 mg/Kg 47% used extended interval in case of decline in renal function (38% with Hartford nomogram)

Optimal Pharmacodynamic Indices
Drug Class % T>MIC AUC/MIC Peak/MIC Cephalosporins 60 – 70% Penicillins 40 – 50% Carbapenems 30 – 40% Fluoroquinolones Gram + Gram - 125 Aminoglycosides 10 Craig WA. Infect Dis Clin N Am : Gunderson BW, et al. Pharmacotherapy : 302S-318S

Conclusions There are associations between antibiotic concentrations and microbiologic effects. “WHAT CONCENTRATION AM I GOING TO ACHIEVE WITH A GIVEN DOSE AND HOW DOES THIS CONCENTRATION RELATE TO THE CONCENTRATION NEEDED TO INHIBIT/KILL IN VITRO” These associations are dependent on the organisms and the antibiotic class. GN vs GP CEPHALOSPORINS/PENICILLINS/CARBAPENEMS Investigations have led to new knowledge and application of these principles to optimizing antibiotic doses. NEW DRUGS COMING TO MARKET WHAT ABOUT OLDER DRUGS?? AMINOGLYCOSIDES CONTINUOUS INFUSION B-LACTAMS Organisms can be susceptible (by MIC) to an antibiotic that can not kill the organism. P. AERUGINOSA FLUOROQUINOLONES & PIPERACILLIN/TAZOBACTAM Additional studies evaluating the outcome of patients are needed to refine these principles.

Selection of Antimicrobial Therapy
I think your patient needs Imipenem 1gmq6h

* May be unlikely to achieve optimal PD targets
Impact of PD on Outcomes Examples of Drug-Bug Combinations with Low Conc:MIC Ratios Staphylococcus sp. cephalosporins, FQ, vancomycin Streptococcus sp. FQ, oral beta-lactams Enterobacter sp. 3rd Generation cephalosporins Pseudomonas sp. Beta-lactams, FQ, aminoglycosides Acinetobacter sp. Beta-lactams, FQ * May be unlikely to achieve optimal PD targets

Mathematical Expression of Pharmacodynamic Indices
Dose t1/ AUC24/MIC = * * Vd * MIC DI Dose t1/ %T>MIC = ln * * Vd * MIC DI Dose (mg) DI = Dosing Interval (q6h, DI=6) t1/2 = Half life of the Drug (hr) Vd = Apparent Volume of Distribution (Liters/kg) MIC = Minimum Inhibitory Concentration (mg/L)

Pharmacokinetic Changes in Critically Ill
Normal Patients Vd (L/kg) T1/2 (hr) Vd (L/kg) 0.31 2.5 Cefepime 0.22 2 1.5 P/T 0.14 0.75 0.4 Imipenem 0.16 1 0.27 Meropenem 0.17 3.3 Ciprofloxacin 1.3

Cefepime Pharmacokinetics in Critically Ill Adults with Sepsis
13 patients with CrCl>50 Received Cefepime 2gm x 1 dose Vd Mean: L Range: 16.2 L – 31.4 L t1/2 Mean: hours Range: 1.5 – 5.6 hrs

Monte Carlo Simulation: Applied to Pharmacokinetic-Pharmacodynamic Models
Random pharmacokinetics and MIC values from data set AUC MIC Calculate pharmacodynamic parameter Plot results in a probability chart AUC:MIC Dudley MN, Ambrose PG. Curr Opin Microbiol. 2000;3:

Pharmacodynamics of Ciprofloxacin 400mg IV q8H Against P
Pharmacodynamics of Ciprofloxacin 400mg IV q8H Against P. aeruginosa in Critically Ill Patients CLSI BP =1 ug/ml 69% Susceptible 56% Ciprofloxacin Optimized MIC Distributions adapted from Mystic Surveillance Network, Ciprofloxacin PK adapted from Lipman J, et al. Antimicrob Agents Chemother 1998; 42(9): Craig WA. Infect Dis Clin N Am :

Pharmacodynamics of Cefepime 2gm q12h against P
Pharmacodynamics of Cefepime 2gm q12h against P. aeruginosa in Critically Ill Patients CLSI BP = 8 ug/ml 84% Susceptible MIC Distributions adapted from Mystic Surveillance Network, Cefepime PK adapted from Lipman, et al. Antimicrob Agents Chemother 1999; 43: Craig WA. Infect Dis Clin N Am :

Probability of 50% T>MIC (Free) for Piperacillin/Tazobactam
Lomaestro BM, Drusano GL. 41st Annual ICAAC Abstract A-2190

Optimizing b-lactam Antibiotics
Meropenem Cefepime Lomaestro BM, Drusano GL. Antimicrob Agents Chemother 2005; 49:461-3. Mohr JF, et al. 41st IDSA Abstract# 34.

In-vitro Pharmacodynamic Models

Piperacillin/ Tazobactam
Minimum-inhibitory concentrations (MICs) of P. aeruginosa tested in an in-vitro Pharmacodynamic Model Organism # Cefepime Meropenem Piperacillin/ Tazobactam 2 32 (H) >32 (H) >256 (H) 25 2 (L) 0.25 (L) 4 (L) 29 8 (M) 64 (M) 31 4 (M) 8 (L) 35 64 (H) 40 0.5 (L) 32 (M) 53 16 (H) 62 1 (L) 68 H = “Resistant” strains M = “Moderately Susceptible” strains L = “Susceptible” strains Mohr et al, Submitted ICAAC 2007

Effect of meropenem 1 gm q8h on P
Effect of meropenem 1 gm q8h on P. aeruginosa that are resistant (MPM-H), moderately susceptible (MPM-M) and susceptible (MPM-L) in an in-vitro pharmacodynamic model Mohr et al, Submitted ICAAC 2007

Effect of cefepime 2 gm q12h on P
Effect of cefepime 2 gm q12h on P. aeruginosa that are resistant (CPM-H), moderately susceptible (CPM-M) and susceptible (CPM-L) in an in-vitro pharmacodynamic model of bacteremia.

Effect of piperacillin/tazobactam 4. 5 gm q6h on P
Effect of piperacillin/tazobactam 4.5 gm q6h on P. aeruginosa that are resistant (PT-H), moderately susceptible (PT-M) and susceptible (PT-L) in an in-vitro pharmacodynamic model of bacteremia.

Pharmacokinetic Parameters
Peak (Cmax) Concentration Whenever you give an antibiotic…you achieve a maximum concentration. Over time…that antibiotic is eliminated and we achieve a minimum concentration just before we decide to redose. We can get very fancy and then use the trapezoidal rule we all learned in calculus and quantify this area underneath this concentration time curve…or the AUC. Because the minimum inhibitory concentration is also a concentration and these two are related by how much drug is available in the systemic circulation…one can draw in the MIC Cmin AUC (Area Under the Curve) Time

AUIC Peak/MIC AUC/MIC Cmax/MIC MPC T>MIC PAE AUC>MIC PALE PA-SME
There are many different pharmacodynamic relationships…and more and more are being coined with each national meeting. This is my pharmacodynamic alphabet and as you begin to try to go through the alphabet soup of pharmacodynamics… AUC>MIC PALE PA-SME

One’s next reaction is to just scream.

“PD is what the drug does in the body”
Pharmacodynamics Describes the relationship between drug concentration and pharmacologic effect “PD is what the drug does in the body” Pharmacodynamics, on the other hand is what the drug does in the body. The relationship between drug concentration and the pahrmacologic effect. The B-blocker on the heart…decrease in heart rate. The antibiotic on the bacteria…decrease in bacterial growth

Antimicrobial Therapy: Appropriate vs. Adequate
Appropriate therapy—antimicrobial treatment selected for efficacy based on: Presumptive identification of causative pathogen Antimicrobial agent’s spectrum of activity Local microbial resistance patterns Adequate therapy—microbiological documentation of an infection that was being effectively treated at the time of its identification You are going to here the terms “appropriate therapy” and “adequate therapy” frequently and interchangeably but it is important to differentiate between these terms. The definition of appropriate therapy is treatment with an agent that includes the presumed pathogen in it’s spectrum of activity (i.e. cefepime for a presumed pseudomonas pneumonia). Adequate therapy is treatment with an agent that is shown by culture and susceptibility results to be active against the infecting pathogen (cefepime for a pseudomonas which is cefepime resistant is not adequate). We can even take it one step further and say that adequate therapy is treatment with an agent administered in a way that achieves the necessary pharmacodynamic parameter associated with efficacy (i.e. cefepime 1gm q8 is appropriate for a cefepime susceptible pseudomonas infection with an mic of 2 in a 70kg person but not in a 150kg person). Kollef MH. Clin Infect Dis. 2000;31:S131–S138.

Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on Mortality

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