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PD-targets for Voriconazole and Posaconazole

Based on the estimates of the PD-targets for voriconazole and posaconazole we can now determine if there remains a role for voriconazole or posaconazole in the management of azole-resistant disease. The integration of all above information is given in Table 5 for voriconazole and Table 6 for posaconazole. The underlying resistance mechanisms are provided for each MIC-value. Based on the estimates of the PD-target, the exposure can be calculated that is needed to achieve the PD-target for each MIC. The exposure corresponds with plasma levels, which are typically higher than those needed for treating infection due to wild-type isolates. The feasibility of achieving higher exposure depends on characteristics of the drug related to absorption and clearance, but is limited by toxicity.
For voriconazole, a total drug AUC/MIC ratio of 21.96 was associated with 50% probability of success (EI50 ) to suppress galactomannan concentrations in a dynamic in vitro model of the human alveolus (Jeans et al., 2012). Using an immunocompetent murine model of invasive aspergillosis, we observed that achieving a serum total AUC0–24 /MIC ratio of 17.61 was the PD-target linked to halfmaximum antifungal effect predicting therapeutic success (Table 4) (Mavridou et al., 2010b). Although, the calculated pharmacodynamic index (using total drug) is similar for both studies, one should consider that in vitro simulation of in vivo protein binding by adding serum proteins in the in vitro models is difficult since complex phenomena may take place (Smith et al., 2010). Given the qualitative and quantitative differences between human and bovine serum, the unbound fraction of various drugs was markedly different between human and bovine serum (Finlay and Baguley, 2000). Such differences were found for voriconazole in the serum of human and different animals (Roffey et al., 2003). It is generally accepted that only the unbound fraction of drug is pharmacologically active and therefore when in vitro concentrations are correlated with in vivo concentrations, in vivo drug exposures should be corrected for the protein binding (Zeitlinger et al., 2011). This can alter the PD of voriconazole depending on the protein-binding differences between 2% fetal bovine serum and 100% human serum.
Recently, Pascual et al. performed a population pharmacokinetic analysis (NONMEM) on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended voriconazole doses in order to describe factors influencing the pharmacokinetic variability, to assess associations between plasma concentrations and efficacy or neurotoxicity/hepatotoxicity, and to define intravenous and oral doses required for achieving drug exposure with the most appropriate efficacy/toxicity profile (Pascual et al., 2012). A logistic multivariate regression analysis revealed the therapeutic target with a clinically appropriate efficacy-safety profile, close to that recently reported by others (Seyedmousavi et al., 2013e). An independent association between voriconazole trough concentrations and probability of response or neurotoxicity was identified for a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300–400 mg twice-daily oral doses and 200–300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68–78% for the oral regimen and 70–87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19–29% for the oral regimen and 18–37% for the intravenous regimen (Pascual et al., 2012). Apparently, patients achieving higher concentrations of voriconazole may show higher exposure and a better response to therapy, but they are at higher risk for toxicity. In contrast, patients achieving lower concentrations may have reduced therapeutic response but subsequently a lower risk for adverse events.
Whereas the Pascual study is based on trough levels as a measure of exposure (Pascual et al., 2012), because it is much easier to determine than the AUC, all preclinical models are AUC based (Jeans et al., 2012; Mavridou et al., 2010b; Seyedmousavi et al.,2013a). However, voriconazole trough levels correlate well with AUC as determined in several studies. Estimates of total AUC0–24 in sixty-four healthy subjects showed that standard dose on the basis of 200 mg twice daily oral voriconazole results in a total AUC value of 18–23 mg.h/L (Purkins et al., 2003). Population PK modeling of voriconazole in 21 healthy volunteers, and 43 patients with proven or probable invasive aspergillosis, (Hope, 2012) and other PK studies in allogeneic haematopoietic stem cell transplant recipients (Fig. 1) (Bruggemann et al., 2010a), revealed that the trough concentration are well correlated with the AUC, and a drug level of 1 and 4.5 mg/L corresponded with a total AUC0–24 of 43 and 151 mg h/L, respectively.
The AUC levels required for efficacy as derived from the trough levels in the Pascual study (Pascual et al., 2012), correspond well with the AUC levels required for efficacy in preclinical models. The threshold was consistent with minimum inhibitory concentration required to inhibit the growth of 90% of organisms and epidemiological cutoffs of most VRC-susceptible fungal species, as well as clinical reports (Espinel-Ingroff et al., 2010; Pfaller et al., 2011; Verweij et al., 2009a) (Arendrup et al., 2012a; Hope et al., 2013; Rodriguez-Tudela et al., 2008).
Assuming no resistant strains in the Pascual study (Pascual et al., 2012), the ECOFF of voriconazole (1 mg/L) can be used as the upper value of the MIC distribution and the denominator in the AUC/MIC. In addition, using EUCAST methodology, Jeans et al. reported that the trough concentration/MIC values that achieve optimal efficacy was 1 (Jeans et al., 2012). However, considering both wild-type and mutant population of A.fumigatus, higher ECOFF is required for voriconazole (2 mg/L) (van Ingen et al., 2014). Given this, the upper value of denominator will be 2 mg/L and the AUC/MIC ratio required for optimal treatment is 43. It follows that the AUC/MIC ratio required for optimal treatment is very close to the pharmacodynamic targets derived from preclinical models (EI50 EUCAST: 17.61–21.96) in order to achieve therapeutic success considering the differences in voriconazole disposition between human and mouse.
Therefore, it can be expected that isolates with a MIC that is classified as susceptible can be treated with voriconazole, with a probability of exposure attainment of over 90% according to population pharmacokinetics modeling of Hope et al. using licensed doses of voriconazole (Hope, 2012; Hope et al., 2013). For isolates with a voriconazole MIC of 2 mg/L, classified as intermediate susceptibility by Verweij et al. (2009a), the plasma level should exceed 1.03 mg/L which is well attainable. Voriconazole MIC of 4 mg/L is classified as resistant, and in order to achieve the PD-target a higher exposure is needed (?2.65 mg/L). Higher exposure of voriconazole can be achieved using dose escalation, but will be associated with increased probability of toxicity. Clearly if voriconazole would be used in this setting intravenous administration would be required as well as close monitoring of plasma levels. For isolates with a MIC exceeding 4 mg/L very high plasma levels exceeding 5.30 mg/L are needed, which are in a range where toxicity can be anticipated.
Posaconazole is currently not licensed for the primary therapy of invasive aspergillosis, but may be used for salvage therapy. Similar to the other triazoles, posaconazole displays concentrationdependent with time dependence pharmacodynamic characteristics, for which a total AUC0–24 /MIC ratio ranging 167–178 was the value predictive of success associated with half-maximal efficacy. Estimates of the total AUC0–24 for patients infected with A. fumigatus with a posaconazole MIC of 0.125 mg/L receiving 800 mg/day are 13–17 mg.h/L, corresponding to the best response rate (AbuTarif et al., 2010; Ullmann et al., 2006). Our calculation (Table 6) also showed that similar exposure (AUC0–24 10.43–11.12 and AUC0–24 20.87–22.5) are required to achieve optimal response for the isolates with MIC 0.64 and 0.125 mg/L, respectively. On the other hand, optimal outcome could be achieved with posacona- zole plasma concentrations of ?0.7 mg/L when administered for prophylaxis. However, for purpose of salvage therapy, Walsh et al. showed that an average concentration of 1.25 mg/L was associated with a higher probability of a clinical response for patients with invasive aspergillosis receiving posaconazole 800 mg/day (Walsh et al., 2007), corresponding to an AUC of approximately 30 mg h/L. Therefore, with fixed dosing of 800 mg/day (200 mg four times a day), drug exposures may not be high enough to cover the entire wild-type distribution, reliably in persistently neutropenic hosts with invasive aspergillosis. The patients infected with an Aspergillus strain with a MIC of 0.25 mg/L, will need to obtain an AUC0–24 of ?40–50 mg.h/L, which corresponds with trough concentrations of >1.25 mg/L, as shown in Fig. 1 (Bruggemann et al., 2010a,b).
According to available data shown in Table 6, the exposure needed to treat infection due to isolates that are classified as susceptible can only be achieved with a low probability of exposure attainment in isolates with the MIC ranging 0.31–0.125 mg/L (Arendrup et al., 2012a; Verweij et al., 2009a). Given the current problems of increasing the exposure of the drug due to its formulation and limited absorption, there appears to be no room for posaconazole for the treatment of isolates that are not within the wild type distribution. However, a new oral tablet and intravenous formulation are under development and soon to be brought the clinical practice (Krishna et al., 2012b). The tablet is designed to release the entire dose of solubilized posaconazole in the small intestine, maximizing systemic absorption. In an exploratory study, this new solid oral formulation significantly increased exposure to posaconazole relative to the oral suspension in fasting healthy volunteers (Courtney et al., 2004; Krishna et al., 2009, 2012a). Following single and multiple doses of posaconazole solid oral tablets (200 and 400 mg) in healthy subjects, the exposure increased in a dose-related manner. When the dose was increased in a 1:2 ratio, exposure increased in 1:1.9 and 1:1.8 ratios for days 1 and 14, respectively. On day 1, the dose-normalized posaconazole exposure (AUCtau ) was substantially higher than for the oral suspension under both fasted and fed conditions (Krishna et al., 2012a). Notably, a novel cyclodextrin formulation of posaconazole is under development for intravenous (i.v) use. In a phase 1B study, the pharmacokinetics of two doses of i.v. posaconazole was investigated in 55 patient volunteers (Maertens et al., 2012). The higher protective blood level of posaconazole was found for the 300 mg given once daily, for which the average blood concentration at 14 days was 1.43 mg/L. The minimum effective concentration was seen in 95% of patients. Recently, Cornely et al. reported that 300 mg posaconazole i.v. was well tolerated and resulted in higher exposure compared to the oral suspension (Cornely et al., 2013). A lowest mean Cmin value of 1297 mg/L was achieved for posaconazole i.v 300 mg vs. 751 mg/L for posaconazole oral suspension. Although our calculations indicate that a posaconazole exposure of ?3.33 mg/L wouldbe required to treat infection due to isolates with a posaconazole MIC of 0.5 mg/L, we believe that this might be achievable using the i.v. formulation. Given that a significant proportion of isolates harboring an azole resistance mechanism exhibit a posaconazole MIC of 0.5 mg/L, this approach requires further investigation in experimental models.

Snake Venom Effects on the Human Body

Snake venom is adapted saliva that is formed by distinct glands of only certain species of snakes. The gland which secretes the zootoxin is an alteration of the parotid salivary gland of other vertebrates, and is usually located on each side of the head underneath and at the back of the eye, capitalized in a muscular case. It is offered with large alveoli in which the venom is stored before being transported by a vessel to the base of the fang across which it is expelled. Snake venom is a mixture of different enzymes and proteins which many of it not harmless to humans, but some are very toxic. Snake venoms are ordinarily not dangerous once ingested
Chemistry:
Snake venom involves enzymes, proteins and substances with a cytotoxic, neurotoxic effect and coagulants:
Phosphodiesterases are used to affect the target’s cardiac system to decrease the blood pressure.
Phospholipase A2 lysing the cell membranes of red blood cells leads to hemolysis
Snake venom hinders cholinesterase causes loss of muscle control.
Hyaluronidase enhances permeability of tissue that boosts the rate of incorporation of other enzymes into the target’s cells.
Snake venom frequently contains ATPase which promote the hydrolysis of ATP
Amino acid oxidases responsible for the yellow color of the venom of some species
Some are Neurotoxins: Fasciculins Dendrotoxins α-neurotoxins
And other is Cytotoxins: Phospholipases Cardiotoxins Haemotoxins
(Snake venom)
Uses of snake venom:
Hemostasis
Snake venom contains molecules with hemostatins (coagulation modifiers) that may be activators or inhibitors of coagulation process and some are basis for hemostasis tests
Such as Prothrombin Activators which are the best considered snake venom hemostatins. They are presently termed according to the taxonomic name of the snake of origin and advanced classification according to their cofactor condition
Group
Snake
Uses
Group A (no cofactor requirement)
Echis Carinatus
Ecarin A
Group B (requires calcium)
Echis Carinatus
Carinactivase B
Group C (requires calcium and phospholipid)
Pseudonaja textilis
Oxyuranus scutellatus
Pseutarin C
Oscutarin C
Group D (requires calcium and phospholipids and Factor Va)
Pseudonaja textilis
Pseutarin D
Less Common Uses:
Thrombin-like enzymes (SVTLE) snake venom is used for fibrinogen breakdown assay and for the fibrinogen dysfunction detection. SVTLE are not repressed by heparin and therefore used for assaying antithrombin in heparin-containing testers. (Snake venom uses)
Effect of Snake Venom on Human Body
When human is bitten with hemotoxic venom by a snake, the venom decrease blood pressure and increase blood clotting. The venom also hits the heart muscle may causing death.
Cytotoxic venom causing death of tissues. Many cytotoxic types of venom also extent through the body increasing permeability of muscle cells.
Neurotoxic venom interrupts brain function and nervous system it produces paralysis or deficiency of muscle control.
Some animals have normal protection to snake venom, and immune bodies can be brought through cautious applications of managed venom; this technique is used to make the anti-venom treatments. (Effect of Snake Venom)
Types of snake venom
As mentioned, snake venom is modified saliva which contains a variety of proteins and enzymes. Not all snake venoms are dangerous to humans as they contain phosphodiesterase, cholinesterase, hyalurinodase, ATPase. The venom is a clear, limpid fluid of a pale straw or amber colour, or it can be greenish, but very rarely and sometimes with a certain amount of suspended matter. The snake venoms that exist are categorized into several types such as hemotoxic venoms, neurotoxic venoms, cytotoxic venoms and myotoxic venoms. These venoms will be discussed in the next few paragraphs.
1-neurotoxics
One of the major families of snake venom is the neurotoxins venoms; which means it’s the venom which attacks the central nervous system and brain. What happens when a snake bites? An exchange of ions across the nerve cell membrane sends a depolarising current towards the end of the nerve cell. When the depolarising current arrives at the nerve cell terminus, the neurotransmitter acetylcholine (ACh), which is held in vesicles, is released into the space between the two nerves (synapse). It moves across the synapse to the postsynaptic receptors.
If ACh remains at the receptor, the nerve stays stimulated, causing incontrollable muscle contractions. This condition is called tetany. So an enzyme called acetylcholinesterase destroys the ACh so tetany does not occur. It is subdivided into three groups: Fasciculins, dendrotoxins and α-neurotoxins.
1) Fasciculins:
These toxins attack cholinergic neurons (those that use ACh as a transmitter) by destroying acetylcholinesterase (AChE). ACh therefore cannot be broken down and stays in the receptor. This causes tetany, which can lead to death.
Snake example: Black Mamba
2) Dendrotoxins:
Dendrotoxins inhibit neurotransmissions by blocking the exchange of and – ions across the neuronal membrane ==> no nerve impulse. So it paralyses the nerves.
Snake example: Mambas
3) α-neurotoxins:
α-neurotoxins also attack cholinergic neurons. They mimic the shape of the acetylcholine molecule and therefore fit into the receptors †’ they block the ACh flow †’ feeling of numbness and paralysis.
Snake examples: 1- Kraits use erabutoxin (the Many-banded krait uses Bungarotoxin)
2- Cobras use cobratoxin.
They often result in respiratory paralysis and heart failures. Their effect can range between mild seizures to death. Cobras, mambas, sea snakes, kraits and coral snakes are known to possess this venom. The king cobras (ophiophagus hannah) are the most infamous carriers of this venom. Neurotoxic venom is essentially nerve destroying. Hence, one can see speech and swallowing difficulties, drooling, difficulty in breathing, respiratory arrests, convulsions and sometimes even prolonged unconsciousness in the victims. The milder symptoms are dizziness, tunnel vision, blurred vision and increased sweating. This venom causes a very fast degeneration of the synaptic nerves and this is the reason for the blockage of nerve impulses sent to and from the brain to the muscles.
2- Cytotoxics
1) Phospholipases:
Phospholipase is an enzyme that transforms the phospholipid molecule into a lysophospholipid (soap) ==> the new molecule attracts and binds fat and rips a hole in the cell membrane. Consequently water flows into the cell and destroys the molecules in it. That is called necrosis.
Snake example: The Japanese Habu snakes (low toxicity)
2) Cardiotoxins:
Actually cardiotoxins are muscle venoms. They bind to particular sites on the surface of muscle cells causing depolarisation ==> the toxin prevents muscle contraction. For example the heart muscle: the heart will beat irregularly and stop beating, which will cause death.
Snake example: King Cobra and some other cobras
3) Haemotoxins:
The toxin destroys red blood cells (erythrocytes). This symptom is called haemolysis. As it is very slowly progressing venom it would probably not kill a human – another toxin in the snake’s venom would most certainly have caused death by then.
Snake example: most Vipers and the members of Naja genus
This is milder venom that generally causes only localized symptoms at the location of the bite. This is a cell destroying venom that destroys everything in it’s path – blood vessels, cells and tissues. The symptoms of the invasion of this venom are generally seen around 10-15 minutes after the snake encounter (I meant bite, not the spotting). The results are generally localized pain accompanied by severe swelling and bleeding. One can easily spot the formation of red blisters near the bite area. This venom causes blue/black spotting due to limited blood circulation. The body often revolts against the invasion of this venom by causing nausea and vomiting. If this venom is not treated within four hours, it generally needs an amputation. Puff adders (bitis arietans) are the snakes to be avoided if one is pain phobic.
3-hemotoxic venoms
They are toxins that destroy red blood cells, disrupt blood clotting, and/or cause organ degeneration and generalized tissuedamage. The term hemotoxin is to some degree a misnomer since toxins that damage the blood also damage other tissues. Injury from a hemotoxic agent is often very painful and can cause permanent damage. Loss of an affected limb is possible even with prompt treatment.
Hemotoxins are frequently employed by venomous animals, including pit vipers. Animal venoms contain enzymes and other proteins that are hemotoxic or neurotoxic or occasionally both (as in the Mojave Rattlesnake, the Japanese mamushi, and similar species). In addition to killing the prey, part of the function of hemotoxic venom for some animals is to aid digestion. The venom breaks down protein in the region of the bite, making prey easier to digest.
The process by which a hemotoxin causes death is much slower than that of a neurotoxin. Snakes which envenomate a prey animal may have to track the prey as it flees. Typically, a mammalian prey item will stop fleeing not because of death, but due to shock caused by the venomous bite. This venom causes the poisoning of blood and affects the blood clotting mechanism to such a grave extent, that the victim can die of internal bleeding. Usually, neither pain nor any other symptoms can be observed for almost 1-3 hours (sometimes even 8). This makes it deadlier, as the victim is usually beyond medical help, by the time the cause is even ascertained. The effects of this venom can be seen as lethargy, headaches, nausea, vomiting, etc. The most scary observations of the outcome of a snake bite of this kind are bruising or blood spots beneath the victim’s skin. In extremely bad cases, blood is known to ooze out from all possible bodily openings. It is these venoms that usually cause excessive (and hideous) scarring, gangrene and permanent or temporary loss of motor skills. Worst cases can even result in the amputation of the affected limb. Dependent upon species, size, location of bite and the amount of venom injected, symptoms in humans such as nausea, disorientation, and headache may be delayed for several hours. Hemotoxins are used in diagnostic studies of the coagulation system. Lupus anticoagulans is detected by changes in the dilute Russell’s viper venom time (DRVVT), which is a laboratoryassay based on-as its name indicates-venom of the Russell’s viper.
4-myotoxic
This venom is found in the ‘bothrops moojeni’ snakes, commonly known as the Brazillian lancehead snakes. This venom is known to cause muscular necrosis. Its symptoms are a thickened-tongue sensation, dry throat, thirst, muscular spasms and convulsions. It also causes the stiffness of the jaw, neck, trunk and limbs along with severe pain in movement. The victims often start with drooping eyelids and then turn to more austere results like loss of breath and blackish brown urine discharge. Myotoxic venom contains peptides that destroy the muscle fiber proteins and result in myonecrosis (muscle destruction).
In the very later stages (when treatment is delayed) of the spread of this venom, the muscle proteins enter the blood stream. The kidney overworks in trying to filter out this junk and often gives up trying. This kidney failure is the reason for the dark coloration of urine.
Signs

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