ESCMID Online Lecture Library © by Author

Safety concerns and their relationship to dosing

Alasdair MacGowan Bristol Centre for Antimicrobial© Research by & authorEvaluation Department of Infection Sciences Lime Walk Building SouthmeadESCMID Hospital Online Lecture Library BRISTOL

North Bristol NHS Trust & University of Bristol Old antibiotics being used more frequently

Gram-positive infection Mixed Infection Gram-negative infection

Pristinamycin Fosfomycin Temocillin Fusidic acid Chloramphenicol Fosfomycin po Co-trimoxazole Mecillinam Teicoplanin Nitrofurantoin Aztreonam Clindamycin Colistin/Polymixin B Minocycline Isepamicin Amikacin

 Toxicodynamics Relationship of drug exposure to adverse events

 Risk of emergence of resistance Relationship of drug exposure to risk and degree of antibiotic resistance

Adverse Events

 Elevated serum creatinine

Trough concentration >60mg/L (14/43) 32.5% ↑creatinine

Trough concentration 20-40mg/L (4/36) 11.1% ↑creatinine

Protocol 109-019, Wilson and Gruneberg, 1997

 Thrombocytopenia

Dose: 30mg/Kg to treat IE

Trough concentration >60mg/L© by author (8/58) 13.8% had a fall in platelets

TroughESCMID concentration ≤60mg/LOnline Lecture Library (12/251) 4.8% had a fall in platelets

Association lost if patients with baseline platelet count >150,000 x 109/L Wilson and Grunberg, 1997 Teicoplanin SmPC recommendations

> trough concentrations should be measured at Steady State after use of a loading dose

Dose Indication Loading Maintenance

Skin and soft tissue 400mg (6mg/Kg) 6mg/Kg 24hly 12hrly for 3 doses

Trough >10mg/L Trough >10mg/L day 3-5 assay weekly

Bone and joint 800mg (12mg/Kg) 12mg/Kg 24hr 12 hrly for 3-5 doses Trough >15mg/L

Trough >15mg day© 3-5 by author

Infective endocarditis 800mg (12mg/Kg) 12mg/Kg 24hr 2 hrly for ESCMID Online3-5 doses LectureTrough Library >5-30mg/L

Trough 15-30mg/L Day 3-5

Chloramphenicol

Adverse events:-

 Bone marrow suppression

Mitochondrial effect, reduced Fe uptake, morphological changes in all cell lines – serum levels >25mg/L or total daily dose >4g/day. (Scott et al 1965)

 Gray Baby Syndrome

Occurs all ages: high mortality mitochondrial effect. Occurs at >40mg/L but most cases much higher >100mg/L. © by author (Thompson et al, 1975)

 Neurology ESCMID Online Lecture Library Peripheral & optic neuritis – related to duration.

(Yunis et al, 1989) Chloramphenicol

Pharmacokinetics

 Pro-drug – oral palmitate dose 0.5-1g, 6hrly po, high bioavailability serum concentration 6-11mg/L Lindberg et al, 1966

 Pro-drug – IV succinate dose 0.5-1g 6hrly IV highly variable bioavailability 6-82% lost by renal cleacine unhydrolysed

 Recommended range for TDM© 15 -25mg/L.by author ESCMID Online Lecture Library Co-trimoxazole

Trimethoprim-sulphamethoxazole

Evidence to link exposure to adverse events weak but

 Decreased potassium excretion in renal tubules cases hyperkalaemia at “high doses” Jung et al, 1994

 Leucopenia more common if serum sulphamethoxazole concentration >200mg/L Forg et al, 1988

 Unclear relationship between sulphamethoxazole serum concentration and nephrotoxicity, crystaluria suggested keep concentration pre-dose <100mg/L. © by author MacGowan et al, 1997

RecommendedESCMID ranges for Online TDM Lecture Library

Sulphamethoxazole pre <100mg/L; post dose 120-150 but less than 200mg/L.

Colistin

Adverse event

 Nephrotoxicity (1)

Prospective observational cohort study (n=102) Cmax/Cmin measured by HPLC AKI defined by RIFLE criteria (serum creatinine and GFR) AKI related to colistin concentration at D7 and End of Therapy (EoT) in multi-variable analysis:-

D7 Cmin OR 4.6 (2.3 - 9.2) EoT Cmin OR 2.4 (1.3 - 3.4) Charlson score OR 1.3 (1.0 - 1.6) Nephrotoxicity OR 2.6 (1.0© - 6.8)by author

Critical values D7 ≤3.3mg/L ESCMID EoT ≤2.4mg/L Online Lecture Library

Sorli et al, 2013 Colistin – nephrotoxicity (2)

 Prospective observational study 2011-15 (n=64)

 Assay by HPLC

 Cmin was measured

 70% male; 17% UTI; 14% pneumonia; 33% bronchia infection; 10% bacteraemia, 17% other

 Cmin > 2.4mg/L associated with nephrotoxicity at D7 and EoT Luque et al, 2015

ESCMID Online Lecture Library Colistin

Dosing and pharmacodynamics for efficacy

Recommended dosing:-

Load 9MU IV; maintenance 3M-4.5MU 8hrly IV

Nephrotoxicity varies 10-30% in critical care

TDM difficult – LCMS but no EQA

Recommended reference ranges – efficacy colistin

2-4mg/L satisfactory © by author ≤ 1mg/L low ≥ 6mg/L high ESCMID 1-<2; >4-6 early repeat Online Lecture Library Couet et al, 2014 Isepamicin/amikacin

Adverse events  Nephrotoxicity  Ototoxicity

Data from: BSAC literature review on Therapeutic Drug Monitoring Amikacin

17 studies (22 reports), 1677 participants, 1977-2011; doses 11-15mg/Kg/day, 13 studies used 15mg/Kg/day

Overall:- Nephrotoxicity 5.9% (60/1025) Auditory toxicity 7.1% (49/690) Vestibular toxicity 2.0% (9/448) © by author Amikacin serum concentrations measured in 15 studies – in 11 doses modified according to pre-clinical target concentrations ESCMID Online Lecture Library Dose Troughs Peaks

7.5mg/Kg BD 5mg/L 25-30mg/L 15mg/Kg OD 1-2mg/L 40-45mg/L

Dosing regimens for amikacin toxicity – studies that included target concentrations

Author Dose Nephrotoxicity Ototoxicity Target concentrations (mg/L) Bock, 1980 7.5mg/Kg BD 27.6% (8/29) 24.1% (7/29) Trough <5 then Peak 15-25 tailored Chen, 2005 500mg daily 16.7% (3/18) - Trough <30 then tailored Giamarellou, 1991 7.5mg/Kg BD 6.7% (4/60) 3.3% (2/60) Trough <5 or 15mg/Kg OD Peak >40 then tailored Holm, 1983 7.5mg/Kg BD 6.1% (3/49) 7.9% (3/38) Trough <10 then Peak >35 tailored Maller, 1993 7.5mg/Kg BD 6.4% (20/311) 1.6% (5/316) Trough <5 (OD) or © by author Trough <10 (BD) 15mg/Kg OD then tailored Noone, 1989 7.5mg/Kg BD 4.2% (4/96) 13.2% (7/53) Trough <10 ESCMIDthen Online Lecture LibraryPeak 20-30 tailored Smith, 1977 8mg/Kg 14.5% (9/62) 5.9% (2/34) Peak 20-40 then tailored

Amikacin

Conclusion

- Insufficient data to recommend reference ranges for TDM

- Use expert opinion

Recommended dosing: 15mg/Kg,24hr, trough <5mg/L

Example: Minocycline vs Acinetobacter baumannii (1)

fAUC/MIC for:- 24h 48h Strain MIC Static -1 log -2 log Static effect -1 log -2 log (mg/L) effect drop drop drop drop 33980 0.5 14.2 26.1 >350 15.4 24.9 >350 35406 3.0 19.2 24.8 >100 25.2 46.0 >100 34958 4.0 15.8 19.1 >80 18.0 20.3 >80 © by author 16.4±2.6 23.3±3.7 >80 19.5± 5.1 30.4±13.7 >80

ESCMID Online Lecture Library Emergence of Resistance

Example: Minocycline vs Acinetobacter baumannii (2)

Changes in population profiles at 72h Growth on MIC x 4 plates Growth on MIC x8 plates Number Mean bacterial Number Mean bacterial fAUC/MIC of count of count experiments (10mg CFU/ml) experiments (log CFU/ml) 0 0/3 <2 0/3 <2 1-5 1/3 3.6 1/3 3.2 >5-10 2/3 7.2 2/3 5.5 >10-15 2/3 ©7.6 by author 0/3 <2 >15-20 0/3 <2 0/3 <2 >20 0/3 <2 0/3 <2 ESCMID Online Lecture Library fAUC/MIC minocycline relationship to antibacterial effect for Acinetobacter baumanii 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

ESCMIDchange in viable count at 24hrs Online Lecture Library 0 10 20 30 40 50 60 70 80 90 100 fAUC/MIC Emergence of Resistance

Amikacin vs P.aeruginosa (1)

fAUC/MIC for:- 24h 48h Strain MIC Static -1 log -2 log drop Static -1 log -2 log drop (mg/L) effect drop effect drop 41961 2.0 23.6 56.2 102.8 31.0 74.3 147.9 41959 6.0 25.0 55.8 113.9 24.7 55.8 112.2 41957 32.0 19.5 24.8 33.1 34.7 57.3 100.00 © by author 22.7±2.9 45.6±18.0 83.3±43.8 30.1±5.1 62.5±10.3 120.0±24.9

ESCMID Online Lecture Library Emergence of Resistance

Amikacin vs P.aeruginosa (2)

Changes in population profile at 24h Number Mean bacterial Number Bacterial mean fAUC/MIC of count of count experiments (log CFU/ml) experiments (log CFU/ml) 0 0/3 <2 0/3 <2 1-20 5/6 4.2 ± 1.0 2/6 3.2 >20-40 2/6 © by4.7 author 2.6 4.5 >40-60 1/3 2.8 0/3 <2 >60-80 1/3 2.7 0/3 <2 >80 0/6 >2 0/6 <2 ESCMID Online Lecture Library fAUC/MIC amikacin relationship to antibacterial effect P.aeruginosa

-1

-2 log cfu/mL

-3

-4 © by author 0 50 100 150 200 250 fAUC/MIC ESCMID Online Lecture Library Impact of antibiotic exposure on bacterial kill and risk of emergence of resistance

Size of PDI for Agent Pathogen Pharmacodynamic 24h static 24h Maximum Index effect -1 log drop amplification of (PDI) oin count resistant population

Razupenem MRSA T>MIC 5±1.5 13±6 2.5-10 Daptomycin MRSA AUC/MIC 37±16 41±18 30-40 Telavancin MS/RSA AUC/MIC 43±38 50±40 1-10 Ceftaroline MS/RSA T>MIC 27±10 31±12 15-40 Minocycline MRSA AUC/MIC 12±7 22±12 No resistance Razupenem Enterobacteriaceae T>MIC 34±18 42±8 30-39 Ceftaroline E.coli T>MIC 35±6 37±7 20-40 K.pneumoniae T>MIC 36±8 44±9 1-30 Amikacin K.pneumoniae AUC/MIC 36±18 58±20 10-20 Doripenem P.aeruginosa T>MIC 25±11 30±11 12.5-25 Ceftolozane-tazobactam P.aeruginosa T>MIC 25±3 26±4 10-30 Amikacin P.aeruginosa AUC/MIC 51±15 70±14 1-20 Piperacillin-tazobactam P.aeruginosa T>MIC 39±8 51±13 20-60 Doripenem A.baumanii ©T>MIC by author20±11 25±10 12.5-25 Minocycline A.baumanii AUC/MIC 16±3 23±4 5-15 Telavancin Enterococcus sp AUC/MIC 15±8 40±30 3-10

ESCMID Online Lecture Library General situation: reduction in bacterial load and emergence of resistance

high

emergence bacterial of resistance load

low high ESCMID Onlinepharmacodynamic Lecture index Library

 Risk of emergence of resistance maximal just below 24hr static effect exposure Combination therapy

Fosfomycin 4g 8hrly and colistin sulphate 2MU 8hrly against NDM producing E coli and Klebsiella sp

10 9 10 8 10 7 10 6 10 5 10 4 10 3

Viable count CFU/ml count Viable 10 10 1 © by author 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (hrs) ESCMIDGrowth Control OnlineFosfomycin Lecture only Colistin onlyLibrary Colistin (sensitive) + Fosfomycin(sensitive) Colistin (sensitive) + Fosfomycin(resistant)

Albur (in press) Conclusions:

 For some “older” agents drug exposure is linked to adverse events (teicoplanin, chloramphenicol, co-trimoxazole, colistin, aminoglycosides)

 Clinical evidence is usually weak and no evidence TDM helps (except aminoglycosides)

 TDM likely to have some role especially for colistin and aminoglycosides

 Risk of emergence of resistance for “old” agents follows same course as “developmental”. Potential© mitigating by factorsauthor are short duration, high exposure, front loading, combinations. ESCMID Online Lecture Library