Antibiotic Dosing Strategies-Clinical Background

I spent two rewarding weeks at the UQCCR and RBWH in Brisbane, Queensland, Australia as a part of  an observership programme in infectious diseases. I was assigned to prof.  Jason Roberts who is leading a team of researchers in the field of redefining antimicrobial use in order to reduce resistence. I took part in weekly rounds at the ICU unit discussing complex patients in terms of optimizing antimicorbial therapy. Attention is drawn to indications for antimicrobial use, the lenght of use and dosing. In terms of dosing I was faced with interesting approaches which are based on TDM of all antibiotics in clinical use.

University of Queensland, Centre for Clinical Research

Special attention is placed on critically ill because pharmacokinetic properties of antibiotics are greatly affected by critical ilness. To determine the influence that critical illness may exert on antibiotic pharmacokinetics it is prudent to split antibiotics into hydrophilic and lipophilic agents. Examples of hydrophilic antibiotics include widely used beta-lactams, aminoglycosides, lipopeptides (daptomycin), vancomycin, fosfomycin and other. In critically ill patients there are two major issues which we should consider. Volumen of distribution of these agents is limited to the extracellular enviornment meaning no reservoir within cells is available for retrograde diffusion into the interstitium. We know that in septic patients the volume of distribution increases greatly because of the sudden capillary leak, increased movement of albumin into tissues  and fluid shifts. Therefore the volume of distribution of hydrophilic antibiotics is increased greatly. The very first dose of hydrophilic antbiotics (loading dose) should therefore be higher than the one needed in clinically stable patients because the loading dose is directly proportional to the volume of distribution.  A proverb indicating ”there is only one opportunity to make a good first impression” states that an early adequate dosing is of crucial importance. Some practical examples. The need for higher than standard loading doses in septic patients was demonstrated for vancomycin. More than double loading dose compared to the standard (35 mg­/kg vs. 15 mg/kg) may be nedeed to quickly achieve the recommended target vancomycin concentration in septic patient (20 mg/l). For gentamicin a loading dose of 8mg/kg has been advised. The other important aspect in ctitically ill is maintenance dosing. Hydrophilic antibiotics are almost completely eliminated via the kidneys. The maintenance dose should therefore be adjusted to estimated or measured creatinine clearance. In ideal circumastancces this should be measured daily during critical illness because of frequent fluctuations. We should adjust dosing accordingly, but this is not limited only to decreased renal function!

The term I came across was ”augmented renal clearance (ARC).” Renal dysfunction is common in critical care settings, but the supra-normal function of the kidneys is infrequently considered by clinicians. ARC is defined as the enhanced renal elimination of circulating solutes as compared with an expected baseline. There are varying cut-offs to define ARC. Often this means renal clearance of serum creatinine greater than 130 mL/min/1.73m2 and 120 mL/min/1.73m2 for female gender. It is interesting that the majority of patients with ARC show levels of serum creatinine within the normal range. In comparison to patients with renal failure, where we see elevated levels of serum creatinine.

Centre for Clinical Research

The specific pathophysiology of ARC is far from being fully understood but factors like hyperdynamic circulation, increased cardiac output, diminished vascular resistence, administration of fluids and vasopresors seem like a good explanation though. From a practical point of view, whenever the estimated glomerular filtration rate values reported from the laboratory are considered normal, it is good to use the highest SMPC recommended doses of hydrophilic antibiotics in critically ill patients. Unless there is TDM available, but usually that is only the case for vancomycin and gentamicin.

Things seem somehow easier with lipophilic antibiotics. These include fluoroquinolones, macrolides, linezolid, tigecycline, rifampin, clindamycin and metronidazole. In the presence of critical illness, these agents often do not require any particular dosage adjustment in the presence of critical illness. Neither for the loading dose, nor the maintenance dose. The volume of distribution is already large due to lipophilic charachter and diffusion across the plasmatic membrane. Therefore, in the presence of increased volume of distribution, the intracelular compartment represents a reservoir for rapid equilibrium. There is no need to adjust the loading dose. Because they are eliminated mainly by the liver or other pathways (these metabolic pathways are usually preserved, although nonlinear), no dosage adjustments for the maintenace dose are usually needed in the critically ill. A notable exception is levofloksacin, which is renally cleared.

We can see that dosing is in the spotlight. Adequate serum concentrations of antimicrobials prevent developmnet of resistance. We can still go further. Adequate serum concentrations are not just growth preventing concentrations. On this point there is still a possibility that a small part of a colony presents with diminished susceptibility and is able to develop resistance mechanism. So aiming for the highest reasonably safe serum concentration increases the chances of achieving a so called resistance preventing concentration and that is something we should aim for.

The daily rounds at the micro-lab were dedicated to interpretations of isolates from clinical samples. During my stay there was a rare case of neuroboreliosis (rare for Australia) in a returning traveller from Slovakia. I even got a chance to visit a microsampling symposium which was held in Brisbane this week. It seems that we will soon be able to get lab resuslt from dried blood spots, no iv. lines needed.    

I  have widen my horizons in any possible directions. It has been a privilege to stay in Australia.

One On One With Kangaroos

Saturday was reserved for kangaroos and koalas at Lone Pine. It is 12km from Brisbane on the outskirts of Queensland. Kangaroos are usually not aggressive towards humans but they can kick and scratch… well I got the impression that they only jump when absolutely needed, otherwise they prefer sun bathing. They are indigenous to Australia and, currently, there are probably more than 20 million of them here. Historically, they have been a source of food and there are still packages of meat seen in supermarkets today. Kangaroo meat is high in protein and low in fat (only 2 %), also exported to many countries around the world. Well, I will stop the meat writing right here since we have been cuddling wtih them the whole afternoon… No kangaroo meat for me.

One Sunny Winter In Brisbane

After an unexpectedly prolonged journey to southern hemisphere, now it is the time to enjoy Brisbane´s daily academic and research life at the University of Queensland. The journey from Zagreb to Frankfurt was almost smooth, excluding the fact that the lady at the check-in desk forgot to board me on a plane. Things got a bit complicated at Frankfurt airport where our flight was delayed due to technical issues with brakes. Consequently we were obliged to sit on a silent aircraft while they were performing repairment for three hours. Safety comes first. We missed our flight from Abu Dhabi to Brisbane and the airline arranged a one night stay at the airport hotel in UAE. We were scheduled to continue our journey to Sydney instead of Brisbane and to continue with a domestic flight from Sydney to Brisbane. But due to an unexpected delay, this time not due to technical issues, we missed this domestic flight…again. Luckily there are many domestic flights and we only had to wait for another hour. Brisbane was soaked in sun though it is winter time down here. The temperatures can be a bit low in the morning but it gets really warm during the day.

The first impression was really nice with an older volunteer helping us with the transportation from the airport to our place of stay – Raymont Residential College. We were kindly accepted and the vice principal took us around on a city tour showing us all the important locations for our stay here.

I took a chance to visit The University of Queensland St. Lucia Campus while Iztok signed in for his duties at Joyce Ackroyd Building. St. Lucia campus breathes with science, knowledge and youth. It is such an amazing place and you can not help yourself not to lay down on the grass in the campus park and read or discuss something. It is a place where the academic life happens with all the included facilities like UQ swimming pool and athletic stadium.

I took a short tour through the city center and I got there by CityCat. That is a small ferry which carries people downstream or upstream the Brisbane´s river. Such a convenient type of transportation. For public transportation means there is a »one card fits it all« system. This means you simply buy a GoCard, fill it up with some money and you are ready to go since you can use it for CityCat, bus and train.

Some UQ photos attached.

Ironman Tallinn, Estonia, 4.8. 2018

During the previous weekend Iztok and Dušan took part in Ironman Tallinn covering a classical 3,8 km swim, 180 km bike and 42,2 km run.  My sadness of not being able to take part in this event was at least partly diminshed by getting the best possible position for taking the finisher pics… a small blue chair in the finisher arena. I can only say that the water temperature was 15°C. But I had a chance to see Tallinn in detail, a lovely historic city centre indeed. I got to know one thing…Triahtlon Ironman is a way of life and we could never quit. It is an addiction.  At least once a year you have to go and shake yourself all day long!

I have the pics and congrats ready!

 

 

Ironman 70.3 Jeju, South Korea

It was one hot day at Zagreb airport and we were ready to start the journey towards Doha and South Korea. Our bikes were packed in a practical fashion and our luggage was minimized. Afer flying for 14 hours in two parts we landed at Incheon International Airport in Seoul. Transfering our bike bags to a Hotel in Incheon, getting a very hot spicy dinner and having a prolonged sleep were the last tasks in that day. The next few days were spent hanging around in Seoul and visiting Korea University for Iztok`s talk. We had a lot to see, though in comparison to other Asian cities, Seoul does not offer much diversity.  The race was held on a small island called Jeju so we had to transport our bikes once again for a short flight with their national airway Korean Air. The impressive thing was that we had a chance to fly with an enormous Boeing 747 aircraft for a one hour flight. Well, but getting from the airport to our guesthouse was an achievement. We decided for a bus ride and had some troubles explaining the luggage to a non-English speaking bus driver. We were also suggested to unpack our bikes and ride down the highway to the southern part of the island in the middle of the night. The latter suggestion sounded attractive but dangerous so a bus ride was a way to go.

Our host was highly hospitable and we were offered a ride from his guesthouse to anywhere we  wished. We did no have to take care for small organizational worries like getting to the race registration point or supermarket for example. Let me say a few words about our traditional breakfast. A rice bowl, sea grass, greasy fish and sometimes pork. After few days we decided to switch on a traditional European breakfast and dinner – cereals with soy milk.

Pasta party, a traditional carbohydrate dinner before long endurance events, was held two days before the race at the registration point. The food was delicious; pasta, sweet potato, kimchi, pumpkin soup, green tea desserts any many more. There is a myth about Koreans eating dogs`s meat. Well, I hope I did not accidentally mix sweet potato for this mythical meal.

Race day was about to come and we checked for a weather forecast more often. The typhoon was coming in and on a race day we had many troubles fighting the winds, first when coming to the swim start at the Pyoseon beach. The water was warm but not too much so we were still allowed to wear swim suits. We had a rolling start meaning there were three person at the line for a start. Jumping into the water poured all the adrenaline into the blood and the race was on.

Coming out of the water I was feeling good and ready to continue. I spent a few minutes in the transition zone to unchange my clothes and get ready for a wet and windy bike ride. Using brakes on a wet surface is a skill for itself. To be honest we did not have much to see during the 90,1 km bike ride since the rain and the fog were so dense. Well I was feeling fantastic anyway, like finally getting loose after a long year. Somewhere there was a thought that this was my last long endurance triathlon event for a few years, therefore the main goal was to have as much fun as possible. The winds were changing directions and on some rare occasions the winds came from the back…the speed on a flat ground approached 60 km/h.

I started guessing my position. I did not see many women in my age group getting by. When fnishing the bike ride and getting to the bike-run transition area, I saw there was only one who came in faster. Well, that was a chance of a lifetime. I put on my running shoes and started running the 21 km distance ahead. I was running as fast as I possibly could and I did not realize that somewhere in between I had passed the remaining competitors in my age group…

We all did extremely well…1st place, 2nd place and a slot for Nelson Mandela Bay… I will let the pictures do the talking…

Mt. Kilimanjaro, September 2017

At the time of writing this post I am still overflowing  with joy and wonder brought back home from the Kilimanjaro ascent. It was legendary, mentally and physically demanding… but so fulfilling, touching the core…I just can not find the words to describe it. Since the beginning of the year 2017 we had a black and white picture of Mt. Kilimanjaro  on our refrigerator waiting to see it in colors…and on September 8th when the plane took off heading for Istanbul and therefrom to Kilimanjaro International Airport we felt  excitement accompanied by some doubts, adrenaline and, to be honest, some fear too.  Mt. Kilimanjaro is a dormant volcano in Tanzania, the highest mountain in Africa and it rises 5895  meters above sea level.  It was first summited by Meyer and  Purtscheller way back in 1889…

It was 1.00 AM and warm night with light breeze at Kilimanjaro International Airport at the time of arrival. Despite the promising name of the airport it is actually a small building with 2 terminals…and a runway somewhere in between the fields, but obviously enough to land an extended version of Boeing 737. After bureaucratic procedures we left the building in hope to find our prearranged transportation to Moshi town where we should sleep for the rest of the night until our guide would come in the morning to pick us up. But there was no one waiting for us so we made a call and the guy said he would be a bit late. It turned out that a bit meant 1,5h. When he finally came we packed our things in a van and drove outside the airport facilities into the night. We got a first sense of Tanzania, no traffic lights by the road, bumpy roads and dangerous ultrafast drivers who like to overtake into scissors. But the overall energy felt in the air was somehow nostalgic,  like we had been there once before. And after all the inconvenience with the delay, the driver still had the guts to ask for a tip.

After two hours of sleeping we were prepared to meet our local guide. He was a professional with several years of experience in climbing Kilimanjaro. We collected the staff and made an one hour drive up to the rainy forest where the journey had started. The Marangu gate, an entry point into Kilimanjaro and the start of the Marangu hiking trail. We started walking through the rainy forest and the humidity was extreme. We were soaked and the nature was amazing as we passed many waterfalls. After 4-5 hours we reached the Mandara hut where we spent the first night.  Some pumpkin soup and popcorn for dinner. We unfolded the sleeping bags in the hut and went to sleep. The night was really cold and in the morning we woke up covered in morning dew. I undressed all the additional layers of clothes and we were ready to eat some breakfast (fruit soup). We started the journey towards 3700 m.a.s.l., the Horombo hut. The path lead us up through the habitat called moorland and is characterized by low-growing vegetation.  When getting to high altitudes you can see a plant called Dendrosenecio kilimanjari and can only be seen on Kilimanjaro-a pretty amazing plant to see.  We walked for 6-7 hours and the tropical sun was starting to get really strong so we got sunburned  on some forgotten exposed parts of the skin. The night at Horombo hut was cold and clear.  The hut we stayed in was small and had four mattresses and therefore we shared the room with a couple from South Korea. The morning came early and I got a weird nausea feeling in my stomach and I had no real appetite for breakfast. So we kept on walking for 8 hours through the Alpine desert in which we felt like Martians.

The previous evening we had a prolonged conversation with our guide who proposed that we skip the acclimatization day meaning we skip a day at high altitude 3700 m.a.s.l. and go directly to 4700 m.a.s.l. He said that our general condition is good and staying long at hight altitude might decrease the options for successful last ascent. We knew that that there was a lot at risk but we decided to go for it. So we reached the Kibo hut at 4700 m.a.s.l. in the evening and after a short dinner we had a few hours of sleep until 2 a.m. in the night. It was time to go for the final ascent.  I slept for one hour, again it was too cold to sleep and when waking up I felt my heart bumping at 100 beats per minute while adapting to altitude and low partial pressure of oxygen.  My stomach was not in the mood for eating so we started the ascent at -20°C as soon as possible. It was an incredible night and those memories have no value in money… while ascending up the steep mountain slope in slow zig-zag movement we had an opportunity to see the night sky over Equatorial Africa… billions of Milky Way stars. The most astonishing night sky ever. At the dawn the temperature was even lower and the strong wind started blowing uphill. At the sunrise we reached the Gilman`s point at 5700 m.a.s.l. And from there we had an app. 1 hour of ascent left to the Uhuru peah. So we kept on fighting. The sun was coming out of the night and as we passed the first glaciers we saw some people turning around and going back down… a young woman needed an oxygen supply and another one was lying on the ground vomiting. They were all headed back down… as they should. The helicopter rescue was available at 3700 m.a.s.l. and I had nothing to help with in that specific situation. The Uhuru peak was seen in distance together with glaciers and volcanic crater. After passing the Stella point there were only ten minutes to the top.  We walked slowly and when reaching the Uhuru peak there was an immense amount of adrenaline flushing through the veins. By getting too excited you could easily feel the lack of oxygen so we took the pictures in hypoxic euphoria and saved some last memories from the Uhuru peak… some paths in life will probably never be walked again.

It was time to get back down again and it took us about 5 hours to reach the 3700 m.a.s.l., the Horombo hut. It would be dangerous to sleep at Kibo hut because of the high altitude, so despite the tiredness we kept on walking. When reaching the Horombo we could get some sleep and despite the cold I did not wake up the whole night. The next day we did the last part of the descent back to the entry point… and it was time to board a plane for our next stop, Zanzibar…

Kilimanjaro… in one sentence…It was an experience of a lifetime!

Understanding Information

It is my great pleasure to announce the book “Understanding Information – From the Big Bang to Big Data” (link). The motivation of this book is to understand  the subject of information from many different perspectives.  The book includes contributions ranging from biology, neuroscience, computer science, artificial intelligence, quantum physics, big data, information society and philosophy. I would like to say many thanks to the respected editor Dr. Schuster from Tokyo for an invitation to contribute to this amazing and futuristic work. It was an honor to experience that sort of commitment and creative feedback. Our contribution covers the potential of plants and seeds in DNA-based information storage;full description of the experiment and its futuristic applications.

Ford Challenge Prague, 29.7. 2017

It was a challenging triathlon in the center and on the outskirts of the, so called, the most beautiful city in the hearth of Europe. On the race morning, the sun was already high in the sky and was announcing one hot day in the city. The temperatures were rising and the race was due to start at noon. We tried to get some good sleep the previous night but we had some loud Chinese neighbors who were very talkative in the morning hours. After breakfast we prepared our bikes and took a one mile stroll down to the center.

Swim start in Vltava (source: Challenge Prague)

The swim was held in the Vltava river with refreshing 17 degrees. The first impression was amazing though the water is not clean and there is some rubbish swimming allover. Anyway, through my goggles I was able to see nothing, not even my hand in front of me. The swim start was explosive and it took me by surprise while I was still polishing my goggles. It was time to start swimming. We took two U-turns and swam under two bridges. First part of the swim was against the flow and it felt harder than the other part going in the opposite direction.

Swim start in Vltava (source: Challenge Prague)

After coming out of the muddy river bank, we were getting ready for the bike part. The transition was busy and you had to took the stairs up on the bridge to get your bicycle. Cycling was held on the highways and country roads outside Prague. There were two laps to be ridden and the heat was already taking its toll. We tried to drink a lot and one big banana was my energy provider.  It was nice but I could not wait for the run to start because I did not manage to get the optimal cycling training distance in the previous months. I was counting on some experience from the past three years.

The cycling part (Source: Challenge Prague)

Finally, the running part. It is a part when you can relax knowing that somehow you will probably manage to get to the finish line. I enjoyed running and whenever there was a chance I took some watermelon for refreshment. The evening was approaching and it was time to pass the finish line. I always get emotional when this happens because you never know when your last amazing triathlon finish line will be passed. Therefore, not even one should be taken for granted.

My darling”s legendary picture. Dušan and I were too fast to be caught on tape… 🙂 (Source: Challenge Prague)

Afterwards… pizza, salmon, salad and a glass of local beer. It was a mild beer with a gentle taste, especially appropriate for women. 🙂 Though I rarely drink it and I am not really familiar with European beers. For dessert… an ice cream and one long, deep sleep. I guess we finally deserved it… the Chinese were quiet.

Finisher medals (Source: Challenge Prague)

Napredne metode zdravljenja hemofilije

Sicer mi področje ni ravno blizu, a ker se je bilo v zadnjem meecu potrebno nekoliko poglobiti v teorijo genskega zdravljenja, tukaj nekaj o naprednih metodah zdravljenja hemofilije, o katerih pred leti v študentskih knjigah ni bilo ne duha ne sluha.  Hemofilija je recesivno dedna bolezen, ki nastopi zaradi pomanjkanja specifičnega faktorja strjevanja krvi, pri kateri nastanejo same od sebe ali po neznatni poškodbi krvavitve v koži, mišicah, sklepih, dlesnih, jeziku, telesnih votlinah in krvavitve iz sečil. Ločimo dve po vzroku različni obliki hemofilije, ki se dedujeta recesivno preko kromosoma X, in sicer hemofilijo A, ki nastane zaradi pomanjkljive aktivnosti faktorja VIII (antihemofilnega globulina), in hemofilijo B, ki je posledica pomanjkljive aktivnosti faktorja IX (Christmasovega faktorja).

Source: nature.com

Pomemben napredek v zdravljenju hemofilije predstavlja genska terapija. Glavni namen genske terapije je popravek oziroma zamenjava problematične genske sekvence z namenom, da se prepreči manifestacija patološkega fenotipa. Fokus večine današnjih genskih terapija je dodajanje neokvarjenega gena brez odstranitve oz. deaktivacije okvarjenega gena. Hemofilija A in B sta med najbolj raziskanimi boleznimi za genetsko zdravljenje. Gre za in vivo prenos gena v jetra preko AAV (adeno-associated viral) vektorjev. AAV vektorji so transgenski produkti, pridobljeni s pomočjo parvovirusov. AAV vektor ima tropizem za številna tarčna tkiva, med njimi tudi jetra in skeletne mišice. Edina prava omejitev omenjenih vektorjev je, da ne morejo “nositi” sekvenc, ki so daljše od 5 kilobaznih parov. AAV ima kratko, enojnovijačno, krožno DNK molekulo, ki kodira kapsido in drug strukturne proteine virusa, hkrati pa kodira tudi proteine, ki spodbudijo integracijo virusa v specifično okvarjeno mesto na kromosomu 19. Doslej so aplikacijo AAV v človeški prganizem poskušali intravenozno (cilj jetra) in intramuskularno (skeletne mišice). Metode dostave so bile torej ali z intramuskularno injekcijo ali preko portalne ali periferne vene. Ker imamo na voljo več serotipov AAV vektorjev, lahko vplivamo na tropizem injiciranih vektorjev. Tako lahko pojasnimo dejstvo, da je aplikacija serotipa AAV8 preko periferne vene povsem učinkovita zaradi močnega hepatotropizma navedenega serotipa. Ko AAV vektorji enkrat dosežejo svoj cilj, katerega prepoznajo po serotipsko specifičnih membranskih receptorjih, z endocitotskimi vezikli vstopijo v notranjost celice. Kapsida se odstrani in nukleinska kislina vstopi v celično jedro. Nukleinska kislina nato perzistira v jedru. Pri visokih dozirnih koncentracija pride do integracije v gostiteljev genom. Doslej je bilo objavljeno eno poročilo o razvoju hepatocelularnega karcinoma pri miškah, katerim so injicirali AAV. Zdravljenje z AAV vektorji je že bilo opravljeno tudi na ljudeh, in sicer za hemofilijo B v obliki intravenoznih in intramuskularnih injekcij. Koncentracije faktorja FIX v plazmi prično naraščati po 2-6 tednih, in sicer dosežejo vrednosti 2-10%. To se na prvi pogled zdi relativno malo, vendar je z vidika hemofilije že minimalen porast v aktivnosti koagulacijskega faktorja znatnega pomena. Še vedno poteka sledenje pacientov, ki so bili zdravljeni z gensko terapijo, zato zaenkrat še ni mogoče napovedati, kako dolgo povprečno traja učinek enkratne apliakcije. Po doslej znanih podatkih je pri 1/3 pacientov 3,2 leta po enojni aplikaciji vektorja v periferno veno nivo faktorja FIX še vedno med 1-5%.

Na kratko, biotehnologija je prihodnost!  🙂