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Towards sustainable and efficient therapeutic (antibacterial) strategies in Mediterranean
marine aquaculture
Andrea FabrisItalian Fish Farmers Association
George Rigos Hellenic Centre for Marine Research
INDUSTRY FORUM: SUSTAINABLE SOLUTIONS TO ADDRESS SEA BASS AND SEA BREAM FARMING CHALLENGES IN THE MEDITERRANEAN
➢Primary type is cage farming (small production is land-based or lagoons etc)
➢ large numbers of fish are kept together
➢There, fish subjected to several stressors for at least 12 months
➢Diseases are inevitable if management is problematic or not adequate
➢Parasites, viruses, bacteria and other pathogens
➢Infectious (bacterial) diseases in caged farming may become a substantial problem due to financial loss/mortalities, therapeutic costs, decrease of the performance of the fish and depreciation of product value
2
1. OVERVIEW OF SEA BASS/BREAM PRODUCTION
Characteristics & concerns
V. anguillarum
V. alginolyticus
A. veroni
T. maritimumM. marinum
Epitheliocystis
➢Vibrio anguillarum, Photobacteriumdamselae subsp. piscicida, Aeromonas veroni, Tenacibaculum maritimum, V. harveyi, V. alginolyticus
➢Βacterial outbreaks in ESB account for 30-40% (but in endemic with A. veroni areas this can up to 70%) of total disease cases
➢Less bacterial infections in GSB (<15%)
3
1. OVERVIEW OF SEA BASS/BREAM PRODUCTION
Overview of the main bacterial diseases
Use of antibacterials
Non use of commercial vaccines
2. ANTIBACTERIALS AND MANAGEMENT
Cases where antibacterial use may be necessary
Lack of any type of specific vaccines
New bacterial pathogens
Not adequate vaccination strategy
Improper management
Alteration of bacterial antigenicity
Low biosecurity measures
2. ANTIBACTERIALS AND MANAGEMENT
Antibacterial candidates for GSB & ESB
✓TETRACYCLINESOxytetracyclineChlortetracycline
✓(FLUORO)QUINOLONESOxolinic acidFlumequine
✓SULFONAMIDES Sulfadiazine Sulfamethazine
✓DIAMINOPYRIMIDINESTrimethoprim
✓PENICILLINS-B LACTAMAmoxycillin
✓PHENICOLSFlorfenicol
Registered for fish/animal use
✓(FLUORO)QUINOLONESSarafloxacinEnrofloxacinDanofloxacin
✓PHENICOLSThiamphenicol
Experimentally used/not registered
✓TETRACYCLINESDoxycycline
✓LINCOSAMIDESLincomycin
✓AMINOCYCLITOLSSpectinomycin
PFF antibacterials/not registered
(FLUORO)QUINOLONES are considered as antimicrobials critically important and with highest priority according WHO (2017), so probably their use forfarm animals will start to be reduced and eventually banned
*500 dd WT when used cascade principle
Antibacterial classPK/PD
interactionsOld PK/PD
models
Modern predictive indices of
PK/PD
Goal of therapy
Proposed values from
human medicine
Tetracyclines(codependent) conc. & time-
dependent killing
Cmax/MIC >4Cmax/MIC >8
AUC0-24/MICMax drug amount
>25
(fluoro)QuinolonesAminocyclitols
conc.-dependent killing
Cmax/MIC Max conc. >10
Sulfonamides & Diaminopyrimidines
PenicillinsPhenicols
Lincosamides
time-dependent killing
TC>MICMax duration of exposure
>50%
6
2. ANTIBACTERIALS AND MANAGEMENT
Important aspects of antibacterials for GSB & ESB
OTC19%
OA19%
FLU17%
SDZ12%
THI10%
TRIM7%
AMO5%
ENR5%
SAR2%
DAN2%
FLO2%
7
2. ANTIBACTERIALS AND MANAGEMENT
Number of published PK studies in ESB & GSB per drug
Drug MICs Kinetic profile Species
Proposed dosing
schedule based on PKs
WTs (h)-summer-
OTC
Low in V. anguillarum, big
variation in other
slow ESB, GSB1 meal/day-
sequential (winter)
<480
FLULow in almost all pathogens
fast ESB, GSB 1-2 meals/day >24
OA As above fast ESB, GSB 1-2 meals/day <24
SDZ Mixed fastGSB
PKs on ESB?>2 meals/day <144
AMO Mixed fast0.3% F in GSBPKs on ESB?
FLO Mixed fast ESB 2 meals/day 96
8
3. PHARMACOKINETICS /PHARMACODYNAMICS OF ANTIBACTERIALS
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25
Pla
sma
con
cen
trat
ion
(µ
g/m
l)
Tme (h)
D1
D2
D3
A. LINCOMYCINExp. Protocol PK
100 mg /kg fish for 5 days(23oC)5 ESB (93g) per time point3 samplings (D1,3,5)
Pathogen # strains MIC (μg/ml)
P. damselae piscicida 22 4-8
V. anguillarum 10 8-32
V. harveyi 10 32 -128
T. maritumum 7 0.12-0.5
•High plasma Linc levels•Drop fast during the 24h• 2 meals/day is suggested
9
3. PHARMACOKINETICS /PHARMACODYNAMICS OF ANTIBACTERIALS
B. DOXYCYCLINE
Exp. Protocol PK
100 mg /kg fish for 5 days(22oC)5 ESB (79g) per time point3 samplings (D1,3,5)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 5 10 15 20 25
Pla
sma
con
cen
trat
ion
µg/
ml
Time (h)
day 1
day 3
day 5
Pathogen # strains MIC (μg/ml)
P. damselae piscicida 22 0.125-0.5
V. anguillarum 10 0.125-0.5
V. harveyi 10 0.125-0.25
T. maritumum 7 0.25-0.5
•Low plasma Dox levels•Remain high during the 24h•1 meal /day or sequentialdosing is proposed
10
3. PHARMACOKINETICS /PHARMACODYNAMICS OF ANTIBACTERIALS
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 5 10 15 20 25
Pla
sma
con
cen
trat
ion
(µ
g/m
l)
Tme (h)
D1
D3
D5
C. SPECTINOMYCINExp. Protocol PK
50 mg /kg fish for 5 days (26oC)5 ESB (152g) per time point3 samplings (D1,3,5)
Pathogen # strains MIC (μg/ml)P. damseale piscicida 22 8 - 32
V. anguillarum 10 8 -16V. harveyi 10 16-64
T. maritumum 7 16-32
•Low plasma Spe levels•Drop fast during the 24h•2 meals/day is suggested
11
3. PHARMACOKINETICS /PHARMACODYNAMICS OF ANTIBACTERIALS
PKs:Cmax, AUC, TC
PDs:MIC / antibiogram
Data from clinical trials
Must be constantly updated
Ideal model for designing treatment schedule
•Consider evolution of the disease (proper early treatment)•Fish anorexia•Water temperature
12
4. ANTIBACTERIAL SELECTION
Ideal : early administration strategy
Prodromic Acute Chronic Resolution
Low infection-lossesHigh-medium appetite
High infection-lossesVery low appetite
Decreased populationResistant survivorsLow infectionMedium appetite
Naturally survivorsReduced riskMedium-high appetite
Phase 1 (prodromic) is the key phase when antibiotic administration has much sense and efficacy: all the stock are still eating and can
become protected by the medication
13
5. IMPLEMENTATION AND ESTIMATION OF MEDICATED DIET
Disease evolution phases
➢Most treatments in aquaculture are metaphylactic, in contrast to human and veterinary medicine; i) they are administered to particularly large population where a disease is being developed and thus include some infected and some uninfected animals ii) the main target in the metaphylactic treatments in aquaculture are not the affected or sick fish but those at considerable risk when an infectious agent cause an outbreak, iii) A metaphylactic treatment (control) should be clearly differentiated from therapeutic treatments (curative) and from prophylactic treatments (preventive)
➢Based on the above concept, when medicated diet is estimated, the whole population should not be included in the calculations. Periodical corrections should be implemented based on disease evolution phase and fish appetite. In some occasions, 50% of the initial estimation could be considered as overestimated
14
5. IMPLEMENTATION AND ESTIMATION OF MEDICATED DIET
Correct estimation of medicated dietsThe concept of metaphylactic treatments
•Financial loss•Environmental pollution(uneaten feed & drug)
improper timing of therapy/false calculation
of medicated diet
Mainly related to coated-medicated diets
15
6. ENVIRONMENTAL IMPACT
➢Rapid and proper diagnosis & selection of registered compound
➢Proper implementation of treatment; ideal to apply in prodromic phase not later; otherwise is it worthy to apply? Disease may be very progressive and most of the affected stock is anorectic or will eventually die
➢ Apply tailored Biosecurity measures and Vaccination strategies
➢Proper preparation of medicated diet. Consider unpalatable drugs. Use proper incorporation or coating techniques to enhance acceptance of medicated diets and reduce leaching. Masking also with attractants is advisable
➢Proper estimation of medicated diet. Adjustment/corrections based on metaphylactic concept; do not count all population in estimation of medicated diet
➢Accurate design of dosing schedule based on target species, target pathogen, environmental parameters (temperature etc). Use of published data when available from PKs on these species. Otherwise (not) extrapolate from other spp. Selection of single-double daily-sequential dosing. Completion of therapy
➢WTs should be considered when close to slaughtering
16
7. CONCLUSIONS & RECOMMENDATIONS FOR BEST PRACTICES
17
Contributors: HCMR: Kogiannou DimitraUAB-Francesc Padrós, Carles Cristòfol,UNIBO-Daniela Florio, Renato Giulio Zanoni, MarialetiziaFioravanti, SKRETTING-Carlos Zarza