HIV/Sexual Health Clinical Education Session

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1 HIV/Sexual Health Clinical Education Session About These Slide These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details. ASHM SSHC 2018 HIV/Sexual Health Clinical Education Centre 1

2 Pharmacokinetics and pharmacodynamics factors to consider for STI treatment Dr Fabian Kong Prof Jane Hocking Centre for Epidemiology and Biostatistics, Melbourne, University of Melbourne 1 Today Terminology key pharmacokinetic/pharmacodynamic measures Factors affecting AUC or Cmax Minimal inhibitory concentration (MIC) Local site effects including: protein binding site of infection urogenital, ano-rectal, oropharyngeal intra versus extracellular ph Research needed - oropharyngeal STIs 2 2

3 STI treatment what should we aim for? Few new antibiotics are expected within the next few years to address growing antimicrobial resistance for STIs We need dosing optimization of presently available antibiotics, relying on proper use and understanding of their pharmacokinetic pharmacodynamic (PK PD) relationships The objective is triple: (1) increase antimicrobial efficacy, (2) limit toxicity and (3) avoid selection and development of resistant mutants. 3 Key PK measures Key PK/PD measures Time drug concentration above MIC (T>MIC) Ratio max concentration to MIC (Cmax: MIC) Ratio area under concentration curve at 24h to MIC (AUC 0-24 : MIC) 2 major determinants of bacteria killing: 1 Time-dependent killing eg: beta-lactams (ceftriaxone) Concentration dependent killing eg: azithromycin, doxycycline 1. Barbour et al. Int J Antimicro Agents 2010;35:

4 PK following dosing maximum tolerated concentration Minimum Effective Concentration or MIC Area Under the Curve 5 T>MIC maximum tolerated concentration T >MIC eg: ceftriaxone Minimum Effective Concentration or MIC Area Under the Curve 6 4

5 AUC 0-24 : MIC ratio Ratio of AUC 0-24 : MIC Eg: doxycycline, azithromycin maximum tolerated concentration Minimum Effective Concentration or MIC Area Under the Curve t 24 7 C max : MIC C max : MIC eg: quinolones maximum tolerated concentration Minimum Effective Concentration or MIC Area Under the Curve 8 5

6 Factors affecting AUC and Cmax (1) Increasing dose will increase concentration and AUC A loading dose can Cmax, AUC and time to Cmax A single dose regimen of azithromycin gives a larger Cmax, but a similar AUC than longer courses of the same overall dose 1 1. Girard et al. J Antimicrob Chemo 2005;56: Factors affecting AUC and Cmax (2) Increasing dose will increase concentration and AUC A loading dose can Cmax, AUC and time to Cmax A single dose regimen of azithromycin has more rapid bacterial clearance than longer courses of the same overall dose 1 Hit hard, hit early 1. Girard et al. J Antimicrob Chemo 2005;56:

7 Factors affecting AUC and Cmax (3) Ideally need drugs that can penetrate all sites of infection Volume of distribution (Vd)1 Azithromycin 23L/kg, Doxycycline 50L/kg Ceftriaxone 0.2L/kg Benchmark (~blood) : Warfarin (blood thinner): 0.14L/kg Factors affecting AUC and Cmax (4) Amount absorbed from the gut dictates AUC and Cmax Diarrhoea can cause malabsorption Eg: rectal chlamydia treatment efficacy PK study of azithromycin in rectal tissue found lower tissue concentrations in those with diarrhoea and in those reporting rectal douching1 Measuring side effects is an important consideration when evaluating treatment efficacy Only 2 of 8 papers in meta-analysis of rectal CT treatment measured side-effects as factor potentially contributing to treatment success2 1. Kong FYS et al. PloS One 2017; 12: e Kong FYS et al.j Antimicrob Chemother 2015; 70:

8 Minimal Inhibitory Concentration-MIC MIC results vary - strain/assay/laboratory variability 1 MIC may differ depending on tissue type eg: chlamydia 2 MIC for macrolides/azithromycin higher in COLORECTAL vs ENDOCERVICAL cell line (~4 times) (regardless of genovar). MIC for doxycycline not different 1. Mouton et al. J Antimicrob Chemother 2018; 73: Foschi et al. J Antimicrob Chemother 2018; 73: Protein binding Only drug not bound to protein ( free drug ) is pharmacologically active Azithromycin 50% PB (at lower dose)- 7% at high dose 1 Doxycycline 90% PB 2 Ceftriaxone 90% PB 3 Illness can affect the amount of protein binding 4 binding is associated with disease 1. Foulds et al. J Antimicrob Chemo 1990;supplA.73: Agwuh et al. J Antimicrob Chemo 2006;58: Fraschini et al. Chemotherapy 1986;32: Schleibinger et al. Br J Clinical Pharm 2015;80:

9 Tissue concentrations High tissue concentrations do not equate to clinical efficacy 1 Relative distribution of drug into different tissue compartments including intra and extracellular Tissue concentrations often measured in homogenates 1 Ignores distinct compartments intra/extracellular Doesn't differentiate between free and bound drug Eg: PK of 1 g azithromycin in rectal mucosa 2 Found high levels of azithromycin in self collected rectal swabs, concluding that inadequate concentrations are unlikely to cause treatment failure BUT did not differentiate between free and bound drug nor intra/extracellular concentrations 1. Mouton et al. J Antimicrob Chemother 2008;61: Kong et al. PloS One 2017;12:e Potential impact of distribution of drug E.g. Azithromycin 1,2 majority of drug is confined to intracellular compartments, less available for extracellular antimicrobial activity. once it enters acidic compartments within cells, it becomes trapped, leading to slow release from the tissues (esp PMLs), contributing to long half life (~68 hours). Contributes to sub-inhibitory levels in extracellular space once drug discontinued -? contributing to macrolide resistance. 1. Zheng et al. Antimicrob Agents Chemother 2014: 58: Crokaert et al. Clin Drug Investigations 1998;16:

10 Site of infection Urogenital, oropharyngeal, ano-rectal organism/drug may behave differently at different sites drug efficacy can vary between different sites 1 17 ph Effects of local ph and degree of drug ionisation - only unionised form penetrates cells Azithromycin pka~8.51 At ph 8.5, 50% is unionised 1 unit increase in the ph results in 91% unionised drug 1 unit decrease results in only 9% being unionised Optimal ph for macrolides is ph 8 and worst when ph <6 Human rectum ph decreases due to inflammation (ph 8 to 7).2 PK of 1 g azithromycin in rectal mucosa found higher levels in those taking esomeprazole3 1. Pfizer Zithromax product information Bitterman W et al. Dis Colon Rectum 1969; 12: Kong et al. PloS One 2017;12:e

11 Other factors (1) Inflammatory response Uptake and concentration of antibiotics by phagocytes Immune response in gastro-intestinal tract is downregulated1,2 Hyperosmolar lubrication- induces greater epithelial denudation and luminal secretion than iso-osmolar gels3? Impact on drug concentrations/action at site Effects of douching (vaginal and rectal)? removal of drug, disruption of mucosa and microbiome Increased STIs associated with douching 4,5 1. Heiligenberg M et al. Clin Vacc Immunol 2013; 20: Rank et al. Infect Immun 2014; 82: Fuchs et al JID 2007;195: Tsai et al Am J Obstet Gynecol Jan; 200(1): 38.e1 38.e8. 5. Javanbakht BMC Infect Dis Feb 21;14:95 19 Other factors (2) What is the role of organism burden? e.g. Rectal chlamydia Higher organism load associated with repeat positivity following 1 g azithromycin (OR 1.7; )1 e.g. Urethral chlamydia Higher IFU associated with ciprofloxacin failure but not doxycycline (72% versus 0%)2 e.g. Mycoplasma genitalium (urogenital/rectal)3 Mean M. genitalium load in pre-treatment samples was 0.92 log10 higher in the 26 patients in whom pristinamycin failed (p<0.01) 1. Kong F et al. Epidemiol Infect 2016; 144: Hooton TM et al. J Am Med Assoc 1990; 264: Read et al. Emerging Infect Dis 2018;24:

12 Oropharyngeal STIs Penetration of antibiotics into pharyngeal mucosa is complex Oropharyngeal niche ideal environment for generating AMR through horizontal transfer of genetic material Inflammation penetration of antibiotics to infection foci E.g. Gonorrhoea Systematic review 96.4% cure overall, but cure rates were lower for pharyngeal NG in both men and women 1 1. Moran et al. STD 1995;22: Oropharyngeal STIs - Gonorrhoea Usually asymptomatic - inflammation Where does NG grow/replicate in pharynx? it has been found intracellularly in tissue sections of tonsils, in cellular debri in tonsillar crypts, in tonsillar exudate and in saliva. Gingivia, buccal mucosa, tongue are usually resistant to NG. 1 Similar organism load in pharynges (tonsillar fossae/ posterior oropharynx) and saliva 2 But is the saliva component important in sustaining infection? 1. Wiesner et al. NEJM 1973;288: Chow et al. J Clin Micro 2016;54:

13 Oropharyngeal STIs Tonsil versus saliva1-5 How important is penetration of drug into the saliva? Good saliva levels Azithromycin Saliva: plasma=6 (7-50% PB) Tonsil: plasma = 150 Gentamicin Saliva: plasma=~1.0 (<30% PB) Ofloxacin Saliva: plasma=0.9 (32% PB) Moderate saliva levels Ciprofloxacin Saliva: plasma=0.5 (30% PB) Poor saliva levels Ceftriaxone Saliva: plasma=<0.004 (90% PB) Tonsil: plasma=0.2 Doxycycline Saliva: plasma=0.11 (90% PB) Tonsil: plasma=1.0 References: 1. Soriano et al J Antimicrob Chemo 2002;50:Suppl S2:51-58; 2. Kiang et al. Clin Pharmacokinet 2016;55: Foulds et al. Eur. J. Clin. Microbiol. Infect. Dis 1991;10: Cunha et al. Therap Drug Monitor 1982;4: Fraschini et al. Chemotherapy 1986;32: Mouth and saliva Mean flow rate of saliva is 0:223±0:049 ml/min (18ml/hr) We swallow once a minute Surface area of epithelial cells and bacteria in saliva are replaced every 2.7 hours SO drugs get washed out from tissue and saliva very quickly. This means that the time a drug remains above the MIC is small (T>MIC) and the AUC is small in the mouth. After two cycles of saliva/epithelial cell replacement in the mouth, only low levels of ceftriaxone will remain. (t1/2=6 hours) Dawes C. Archives of Oral Biology 2003;48:

14 Oropharyngeal STIs - Gonorrhoea What s needed: Understanding about the microbiology of NG in the oropharynx where does it grow, replicate, how important is organism in saliva? Understanding about why some drugs appear to achieve suboptimal concentrations in tonsillar and other oropharyngeal tissues Need appropriate PK/PD studies and or optimised simulations with currently and future drugs for gono pharyngeal infection 25 Oropharyngeal STIs - Gonorrhoea Saliva, as anal lubricant contribute to ~50% rectal cases Modelling: mouth to mouth accounts ~72% incident NG infection Therefore it is vital that we understand and treat pharyngeal STIs effectively Chow EPF et al.sex Transm Infect 2016 Mar 3. Zhang L at al Sex Transm Dis 2017; 44:

15 Summary Select drugs based on: Site of infection PK characteristics of the drug distribution of free drug to those sites of infection Gaps in evidence Pharyngeal STIs their microbiology, epidemiology PK/PD of drugs in mouth PK/PD of drugs in anorectum Role of behaviour factors/microbiome/non-antibiotic drugs 27 Contact Dr Fabian Kong Prof Jane Hocking Centre for Epidemiology and Biostatistics, Melbourne, University of Melbourne No conflict of interest to declare 28 15