# Presentation: 535557

## Application of Pharmacokinetic and Pharmacodynamic Principles to Otitis Media and other Respiratory Tract Infections

**Professor of Pathology and Medicine**
**Case Western Reserve University**
**Director of Clinical Microbiology**
**University Hospitals of Cleveland**
**Cleveland, OH**

**Application of Pharmacokinetic and Pharmacodynamic Principles to Otitis Media and other ****Respiratory Tract Infections**

## Limitations of outpatient clinical studies in respiratory tract infections

- High-rate spontaneous resolution makes it difficult to show differences between agents
- Bacteriologic outcome studies are not often performed due to necessity for invasive procedure (ear, sinus or lung tap) to obtain specimen
- Most studies are therefore designed to show equivalent clinical outcome between established and new agents
- Inadequacies of agents studied are therefore often not apparent

**Jacobs. Clin Microbiol Infect 2001;7:589–96 **

## 1977 FDA Guidance on AOM

**“****In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug”**

## Objectives

- Define pharmacokinetics and pharmacodynamics
- Correlate serum pharmacokinetic parameters for various drug classes with outcome of infection in outpatient respiratory tract infections
- Show examples of these correlations in animal models and in humans
- Apply these principles to treatment of otitis media and other respiratory tract infections

## Impact of limited clinical data and increasing pathogen resistance on choice of antibacterial therapy

- There is a need for:
- accurate prediction of efficacy
- newer dosage regimens
- newer antibacterials
- revised susceptibility breakpoints
- statistically valid clinical studies

**Jacobs. Clin Microbiol Infect 2001;7:589–96 **

**Notes:**
There is a problem of increasing antibiotic resistance of pathogens
This, in turn, can lead to a reduction in efficacy of standard dosage regimens and hence, the need to re-assess treatment choices
There is a need for:
better prediction of efficacy to help doctors choose appropriate empirical therapies
newer dosage regimens, in cases where antimicrobial resistance can be overcome by increased levels of antibiotic (e.g. penicillin-resistant S. pneumoniae)
research to develop new antimicrobials
control measures to safeguard existing therapies

## Evaluating antibacterial efficacy using pharmacokinetics and pharmacodynamics

- Pharmacokinetics (PK)
- serum concentration profile
- penetration to site of infection
- Pharmacodynamics (PD)
- susceptibility – MIC (potency)
- concentration- vs. time-dependent killing
- persistent (post-antibiotic) effects (PAE)

**Jacobs. Clin Microbiol Infect 2001;7:589–96 **

**Notes:**
Pharmacokinetic (PK) and pharmacodynamic (PD) parameters are key to predicting the efficacy of antibiotics
MIC values provide us with a static picture of how a pathogen is affected by fixed concentrations of antibiotic in vitro
In the body, the antibiotic concentration is constantly changing – pharmacokinetic measurements can be used to estimate the dynamic situation within the body, at the site of infection
Different antibiotics kill pathogens in different ways – a knowledge of pharmacodynamic properties (concentration vs. time-dependant killing; persistent effects) together with the MIC enable us to interpret the dynamic picture and predict more closely what will happen during a clinical infection

## Pharmacokinetics

**GI Absorption**

**Blood**

**Renal**
**excretion**

**Pharmacokinetics**

**Extracellular**
** ****compartment**
** ****of tissues**

**Oral ingestion**

## Drug Pharmacokinetics in blood

## Pharmacokinetic Parameters

## Patterns of antibacterial activity

- Pattern				Pharmacodynamic					correlate
- Time-dependent killing 		         Time above MIC
- and minimal to moderate			     (T>MIC)
- persistent effects
- Time-dependent killing		          AUC/MIC ratio
- and prolonged persistent
- effects
- Concentration-dependent	                     AUC/MIC ratio
- killing and prolonged			        	      or
- persistent effects			         Peak/MIC ratio

**Jacobs. Clin Microbiol Infect 2001;7:589–96 **

## Time Above MIC:  -Lactams

- T>MIC (% of dosing interval) required for the static dose against most organisms in neutropenic mice vary from 25-35% for penicillins and from 30-45% for cephalosporins
- The presence of neutrophils reduces the T>MIC required for efficacy by 5-10%
- Free drug levels of penicillins and cephalosporins need to exceed the MIC for 35-50% of the dosing interval to produce maximum survival

## Relationship between Time above MIC and efficacy in animal infection models infected with S. pneumoniae

**0**

**20**

**40**

**60**

**80**

**100**

**0**

**20**

**40**

**60**

**80**

**100**

**Time above MIC (%)**

**Penicillins**

**Cephalosporins**

**Mortality after 4 days of therapy (%)**

- Craig. *Diagn Microbiol Infect Dis* 1996; **25**:213–217

**Relationship between Time above MIC ****and efficacy in animal infection models ****infected with *****S. pneumoniae***

##  24-hr AUC/MIC and Peak/MIC RatiosCorrelation of serum pharmacokinetics with MIC (susceptibility) of an organism 

**Antibiotic concentration**

**MIC**** **

**Time**

**24-hr AUC/MIC is correlated with outcome of infection, the magnitude required for success and MIC at which this occurs becomes the PD breakpoint**

** ****24-hr AUC/MIC and Peak/MIC Ratios****Correlation of serum pharmacokinetics with MIC (susceptibility) of an organism**** **

## Relationship between 24 Hr AUC/MIC and mortality for fluoroquinolones against S. pneumoniae in immunocompetent animals

**Mortality (%)**

**24-hr AUC/MIC**

** ****1**

** ****25**

** ****10**

** ****5**

** ****2.5**

**0**

**20**

**40**

**60**

**80**

**100**

**100**

** ****50 **

## At dosing comparable to dosing in humans:
Azithromycin and clarithromycin were able to reduce inoculum by  3 log10 cfu/lung for macrolide susceptible S. pneumoniae 
Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms)

- Azithromycin and clarithromycin were able to reduce inoculum by  3 log10 cfu/lung for macrolide susceptible *S. pneumoniae *
- Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log10 cfu/lung for *H influenzae* or for macrolide non-susceptible *S. pneumoniae* (erm and mef mechanisms)

***S. pneumoniae***** and *****H.***** *****influenzae***** pneumonia in rats:****ED****50**** based on ******** 3 log****10**** reduction in cfu/lung**

- Mitten M. et al.* Antimicrob Agents Chemother* 2001; **45**: 2585–2593.

**Notes:**
At dosing comparable to dosing in humans:
Azithromycin and clarithromycin were able to reduce inoculum by  3 log10 cfu/lung for macrolide susceptible S. pneumoniae 
Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms) despite the high lung concentrations of these agents.
M. J. Mitten, J. Meulbroek, M. Nukkala, L. Paige, K. Jarvis, A. Oleksijew, A. Tovcimak, L. Hernandez, J. D. Alder,† P. Ewing, Y. S. Or, Z. Ma, A. M. Nilius, K. Mollison, And R. K. Flamm. Efficacies Of ABT773, A New Ketolide, Against Experimental Bacterial Infections. AAC 45:2585–2593, 2001

## Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Haemophilus influenzae (NTHI)

**Franz E. Babl, Stephen I. Pelton, and Zhong Li. Experimental Acute Otitis Media Due to Nontypeable *****Haemophilus influenzae*****: Comparison of High and Low Azithromycin Doses with Placebo. **Antimicrobial Agents and Chemotherapy, 2002, 46:2194-2199** **

**Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable *****Haemophilus influenzae *****(NTHI)**

## Relationship between Time above MIC and bacterial eradication with -lactams in otitis media

- Craig & Andes, Pediatr Infect Dis J, 1996
- Dagan et al studies

## Relationship between Time above MIC and bacterial eradication with -lactams in maxillary sinusitis

- Craig & Andes, Pediatr Infect Dis J, 1996
- Gwaltney & Scheld studies

## Levofloxacin PK/PD correlations134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5–14 days

**failure rate****	****   ****43%****	****11.5%****	****   1%**

**Levofloxacin PK/PD correlations****134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5–14 days**

**Jacobs. Clin Microbiol Infect 2001;7:589–96 **
**[Adapted from Preston et al. JAMA 1998;279:125–9]**

## 	PK/PD breakpoint
	ALL ORGANISMS
Amoxicillin	2
Amox/clav	2
Cefuroxime axetil	1
Cefprozil	1
Cefixime	0.5
Cefaclor	 0.5
Loracarbef	 0.5
Azithromycin	0.12
Clarithromycin	0.25

- 	ALL ORGANISMS
- Amoxicillin	2
- Amox/clav	2
- Cefuroxime axetil	1
- Cefprozil	1
- Cefixime	0.5
- Cefaclor	 0.5
- Loracarbef	 0.5
- Azithromycin	0.12
- Clarithromycin	0.25

**Pharmacodynamic breakpoints (μg/ml) for oral agents used for RTIs**

## 		NCCLS		PK/PD
	S. pneumoniae  		H. influenzae	ALL 					ORGANISMS
Amoxicillin	2		4	2
Amox/clav	2		4	2
Cefuroxime axetil	1		4	1
Cefprozil	2		8	1	
Cefixime	–		1	0.5	
Cefaclor	 1		8	0.5	
Loracarbef	 2		8	0.5	
Azithromycin	0.5		4	0.12
Clarithromycin	0.25		8	0.25

***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Amoxicillin****	****2****	****	****4****	****2**
**Amox/clav****	****2****	****	****4****	****2**
**Cefuroxime axetil****	****1****	****	****4****	****1**
**Cefprozil****	****2****	****	****8****	****1****	**
**Cefixime****	****–****	****	****1****	****0.5****	**
**Cefaclor****	**** 1****	****	****8****	****0.5****	**
**Loracarbef****	**** 2****	****	****8****	****0.5****	**
**Azithromycin****	****0.5****	****	****4****	****0.12**
**Clarithromycin****	****0.25****	****	****8****	****0.25**

**Pharmacodynamic vs. NCCLS breakpoints ****(values in μg/ml)**

- Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health Partnership. *Otolaryngol Head Neck Surg *2000; **123**(supp 1 part 2):S1–S32.

## Susceptibility of US Isolates at PK/PD breakpoints

**	****	****Percentage of strains susceptible**
**Agent****	*****S. pneumoniae    ******	******H. influenzae    ******	******M. catarrhalis***
**Amox/clav****	****90****	****97****	****100**
**Amoxicillin****	****90****	****61****	****14**
**Cefaclor****	****27****	****2****	****5****	**
**Cefixime****	****57****	****99****	****100**
**Cefpodoxime****	****63****	****99****	****64**
**Cefprozil****	****64****	****18****	****6**
**Cefuroxime****	****64****	****79****	****37**
**Cefdinir****‡**** ****	****61****	****97****	****100**
**Azithromycin****	****67****	****0****	****100**
**Clindamycin*****	****89****	****NA****	****NA**
**Doxycycline****	****76****	****20****	****96**
**Levofloxacin****	****99.8****	****100****	****99**
**TMP/SMX*****	****57****	****75****	****9**

- Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health Partnership. *Otolaryngol Head Neck Surg *2000; **123**(supp 1 part 2):S1–S32. **‡**Jacobs M. (unpublished)

**Notes:**
Few differences in proportions of strains of S. pneumoniae that are susceptible to these agents based on which breakpoints are used occur, and there are no NCCLS breakpoints for M. catarrhalis. However, there are several agents where PK/PD breakpoints indicate poor activity [0-2% susceptible], while NCCLS breakpoints show good activity [82-92% susceptible].

Data sources:
M100-S11, National Committee for Clinical Laboratory Standards, 2001
Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. 
‡Jacobs M. (unpublished)

## Amoxicillin-clavulanate

**Amoxicillin-clavulanate**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Amoxicillin****	****2****	****	****4****	****2**
**Amox/clav****	****2****	****	****4****	****2**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Cefaclor

**Cefaclor**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Cefaclor****	**** 1****	****	****8****	****0.5****	**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Cefuroxime axetil

**Cefuroxime axetil**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Cefuroxime axetil****	****1****	****	****4****	****1**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Cefprozil

**Cefprozil**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Cefprozil****	****2****	****	****8****	****1****	**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Cefixime

**Cefixime**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Cefixime****	****–****	****	****1****	****0.5****	**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Azithromycin

**Azithromycin**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Azithromycin****	****0.5****	****	****4****	****0.12**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Clarithromycin

**Clarithromycin**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Clarithromycin****	****0.25****	****	****8****	****0.25**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Clindamycin

**Clindamycin**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Clindamycin****	****0.25****	****	****NA****	****0.25**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Telithromycin

**Telithromycin**

**Nagai AAC 2002, 46:371-7; Pankuch AAC 1998, 42:3032-34**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Telithromycin****	****?****	****	****?****	****0.5**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Doxycycline

**Doxycycline**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Doxycycline****	****?****	****	****?****	****0.25**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Ciprofloxacin

**Ciprofloxacin**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Clarithromycin****	****NA****	****	****1****	****1**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Levofloxacin

**Levofloxacin**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Levofloxacin****	****2****	****	****2****	****2**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Trimethoprim-sulfamethoxazole

**Trimethoprim-sulfamethoxazole**

**Alexander Project USA 2000**

**  ****Susceptible breakpoint****	****	****NCCLS****	****	****PK/PD**
***	******S. pneumoniae  ******	******	******H. influenzae*****	****ALL ****	****	****	****	****	****ORGANISMS**
**Trimeth-sulfa****	****0.5****	****	****0.5****	****0.5**

**Notes:**
PIDJ Volume 19(5) Supplement             May 2000             pp S47-S56 Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on pharmacodynamic parameters[OTITIS MEDIA FORUM: PROCEEDING FROM A SYMPOSIUM HELD ON SEPTEMBER 23 TO 25, 1999 IN CARMEL, CA: Clinical and Epidemiologic Aspects of Acute Otitis Media]JACOBS, MICHAEL R. MD, PhD

## Conclusions: antibacterial choice for empiric use in RTI

- Most clinical studies do not show clinical differences between agents
- PK/PD parameters correlate with bacteriological and clinical outcome in animal models and in humans
- PK/PD parameters can be used to select agents with maximum potential for bacterial eradication
- Currently available agents vary significantly in achieving PK/PD parameters necessary for bacterial eradication

## 1977 FDA Guidance on AOM

**“****In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug”**

## New FDA Guidance on AOM

**Do we admit there is a problem?**
**What does it take to fix the problem?**
**Will we fix the problem?**
**When will this be achieved?**