Gunderson et al. (2008) reported in his study that so many antibiotics are marketed for resistant gram positive bacteria; no new antibiotic was available for many years. The medical practitioners require more effective ways to use the existing drugs. Colistin, an older antibiotic but the practitioners still consider it as a very effective antibacterial spectrum, especially for Pseudomonas and Acinetobacter spps. They plotted time kill curves for the 2 strains after treating with Colistin alone and its combination with other antimicrobial agents. They concluded that Colistin showed concentration dependent antibacterial response at concentration ranging 3 to 200 mg/L. They were unable to see the increased response at increasing the concentration above 18mg/L because of faster bactericidal activity. The data obtained from the experiment showed that bactericidal effect of Colistin in combination with ceftazidime can be maximized at peak concentration of less than eighteen mg/L.
Jin et al. (2010) investigated the factors affecting the transport of colistin across the blood brain barrier in mice and also to see the effect of systemic inflammation on the transport of colistin. Colistin sulfate was injected to the Swiss mice in multiple doses and analyze the relationship between brain uptake and plasma concentration of colistin. They also noted the effect p-glycoprotein on the blood brain barrier. They induced the inflammation by injecting lipopolysaccharides at the dose rate 3 mg/kg interaperitonealy and measured the transport of colistin through the blood brain barrier and also by in situ brain infusions. They reported that in healthy mice the transport of colistin through blood brain barrier was very low and transport was enhanced by systematic inflammation.
Li et al. (2004) studied the pharmacokinetics of colistin methanesulphate (CMS) and colistin after intravenous administration of methane sulphate in rats. They used 5 rats in their experiment; each rat received single dose intravenous of fifteen mg/kg of CMS. They determined the plasma concentration of colistin and CMS after the hydrolysis of CMS by HPLC. They calculated the pharmacokinetic parameters of CMS and colistin using the non-compartmental analysis. After analysis they concluded that sixty percent of the dose was eliminated through urine in twenty four hours. They observed that colistin appeared soon in the plasma after intravenous administration which showed rapid conversion of CMS. The high level of colistin in urine indicated the conversion of CMS in the kidney.
Quinn et al. (2005) reported in two cases of multidrug resistant (MDR) Pseudomonas aeruginosa meningitis and ventriculo-pertoneal shut (VPS) infection treatment with interathecal colistin ten mg/day after development of nepherotoxicity linked with interavenous administration. In one case a woman was admitted with VPS and meningitis. After CSF culture examination she was positive for P. aeruginosa susceptible only to colistin. The treatment was soon stopped due to the development of renal malfunction. There was clear improvement in the white blood cell count when they started interathecal colistin. After the treatment the CSF culture was negative and the renal function return to normal level. They concluded that interavenous colistin was the cause of renal dysfunction and the interathecal use of colistin was safe and effective against the resistant gram negative bacteria.
Montero et al. (2003) studied the toxicity and efficacy of the intravenously injected colistin in thirty five cases of ventilator associated pneumonia (VAP) due to resistant Acinetobacter baumannii. Through culture examination in twenty one patients the infection was susceptible to colistin. In fourteen patients the bacterial strain was susceptible to imipenem. In both cases treatment continued. Acute physiology and chronic health evaluation II scores were same a\both at the time of admittance and diagnosis. In both treatment cases cure rate was 57%. Four patients in the colistin treated group and six in the other group developed renal failure. Twelve patients were considered for neurological examination in the imipenem treated group but they found no sign of nervous dysfunction. They concluded that I/V colistin use was safe and effective relative to imipenem for the treatment of VAP caused by A.baumannii.
Ouderkirk et al. (2003) reported that nephrotoxicity reports resulting due to systematic use of polymyxin B had different conclusions. With increasing cases due to resistant gram negative bacteria, colistin was used to treat such infections. They determined the nephrotoxicity in the patients receiving systemic colistin from October 1999 to September 2000. Statistical and clinical information was obtained from sixty patients. The parameters of interest were renal toxicity, clinical and antimicrobial efficacy. Kidney failure was developed in 14% of cases. These were the patients who had normal renal function before the start of treatment. They concluded from their study that renal failure was independent of cumulative and daily dosing of polymyxin B but was found to be dependent on the age. The total mortality was 20% but increased in the cases with kidney damage to 57%. The bacteria were cleared in 88% of cases. They gave the conclusion that polymyxin B was highly effective in controlling the infection due to resistant gram negative bacteria and less associated to nephrotoxicity than previously reported.
Tam et al. (2005) investigated that although limited data is available on polymyxin B (PB) but still its use was increased because it was the last treatment option against the multi drug resistant (MDR) gram negative bacteria. They tested the in vitro pharmacodynamics of PB against 4 strains of Pseudomonas aeruginosa. Time kill studies were done using different minimum inhibitory concentrations of the PB. They performed their experiment using in vitro pharmacokinetic model and MDR strains. They used 3 regimes and studied steady state unbound PB pharmacokinetics using dose rate of 2.5mg/kg and 20mg/kg. From the analysis of their data they suggested that the antibacterial activity of the polymyxin B was dependent on the concentration regardless of the dosing time and also related area under the curve and minimum inhibitory concentration.
Naesens et al. (2011) reported in their studies that colistin was the last therapeutic option for the pneumonia caused by MDR Pseudomonas spp. Using the case history of twenty ICU patients with pneumonia caused by MDR P.aeruginosa who had received colistin sulphomethate sodium from 2007 to 2009. They stated that a strain is MDR if it was resistant to these six antibiotics piperacillin-tazobactum, ceftazidime, cefepime, meropenem, aztreonam, ciprofloxacin and amikacin. They studied drug administration mode and predicted mortality using simplified acute physiology score III (SAPSIII) and sequential organ failure assessment score (SOFA) at the start of the colistin therapy, at the clinical and microbicidal outcome of the disease. In six cases colistin was given by inhalation, in five cases by injection and in nine cases by combination of both. All cases were receiving β-lactam therapy. The results showed 100% cure rate in inhalation mode and 40% in parenteral mode. In combination mode the cure rate was 78%. Mortality in pareteral mode was 100%, 0% in inhalation mode and 33% in combination mode. Results showed that inhalation colistin combination was effective in the treatment of MDR bacterial pneumonia.
Dalfino et al. (2012) studied the infection acquired in hospital due to gram negative bacteria were colistin only susceptible (COS). But best administration mode needs to be sorted out. They included the cases in their experiments with sepsis and treated with I/V colistin. They included 2 dosing schedule in the study 9 MIU and 9 MIU twice daily. After sampling the cases were subjected to different kidney function tests, bacterial clearance tests and clinical cure rate was determined. They processed 28 cases of infection due to COS gram negative bacteria. The major infections were ventilator associated pneumonia (35.7%) and blood stream infections (64.3%). Acute renal injury developed in five cases (17.8%), but they did not require renal therapy and injury cured within 2 weeks after stopping the treatment and infection cured in twenty three cases (82.1%). Serum creatinine levels showed no clear changes in their level from baseline to peak. From this study they concluded that in dangerous infections due to COS bacteria, high dose extended period colistin dosing criteria had good results, without high level of renal damage.
Hartzell et al. (2009) investigated the incidence of acute kidney failure in a medical centre named as Walter Reed. They studied sixty six cases of intera-venous therapy of colistimethate sodium (CMS) and characterized by RIFLE (Risk, Injury, Failure, Loss and end stage kidney disease). These were the clinical characters analyzed demographically. In 59 cases CMS was given I/V, in 5 cases I/V and inhalation therapy and in 2 cases I/V and interathecal route. In I/V treatment cases higher levels of creatinine and on urine examination muddy brown casts were seen. The current study showed that 45% cases showed the renal dysfunction and treatment was abandoned due to nephrotoxicity. They gave the idea that results of nephrotoxicity should be compared using the RIFLE method in future.
Vaara et al. (2008) reported that due to unavailability of drugs against gram negative bacteria had made the polymyxin an important drug for the control of MDR infections. But there use is limited or even discontinued due to nephrotoxicity of polymyxins. They stated that toxicity of these antibiotics might be due to their highly cationic nature of the molecule. Colistin and polymyxin B cary 5+ve charges. They said that the new polymyxin derivative carrying 3+ve charge was an efficacious microbicial agent. The derivative named as NAB was found to be identical to polymyxin B (PB) but it had less cationic charges as compared to PB. This derivate was also identical in MICs of PB. It was tested against seventeen strain of E.coli, Enterobacteriaceae and other PB susceptible bacteria and it showed similar results. They also concluded that even its lower concentration sensitize the different MDR resistant bacteria for the effect of other antimicrobial agents. The activity of this NAB derivative for rat kidney brush border was also lower than that of PB.
Ozkan et al. (2012) studied the rhabdomyolysis and muscular weakness associated with the colistin therapy. This condition was associated with kidney failure in almost 40% of cases. This might be due to some muscular injury or any other reason. This might be due to colistin toxicity. In their results they mentioned that colistin was nephrotoxic because it increased the membrane permeability, cause cellular inflammation and even lysis. They showed the toxic effect of colistin by acute tubular necrosis leading to renal failure.
Lim et al. (2010) reported that the fact behind the reappearance of colistin and excellent treatment choice for the management of resistant gram negative bacteria. The critical nature of these MDR infections was due to high morbidity and mortality caused by them. This had made colistin an efficacious drug to treat them. But in all reports the main problem was the development of resistance and resistance development mechanism had not been clear. It was purposed that that it was due to genetic regulatory mechanism. They told that to coop with this problem colistin dose must be optimized. Under dosing might be linked with this problem. The pharmacology studies and universal conversion of dose units both were lacked. In critical illness cases the pharmacology of colistin might be changed so dose modification was very important for maximal results. They reported that the colistin toxicity is reversible and less common. They concluded that there was a need of more studies on dosing of colistin and mechanism of development of resistance.
Sarkar et al. (2007) reported that the structure and pharmacological characteristics of colistin and polymyxin B and other member of this class were similar. Colistin had bactericidal effect on almost all strains of gram negative bacilli. But resistance development was main problem. But it was not discussed in literature often. Orally the colistin was not absorbed through GI tact, mucus membranes or through skin. In series of case reports it was discussed that colistin must be given parenterally. Colistin gave best results in terms safety and efficacy when used parenterally. In 3 reports cure rate was 58-78% with this route. In previous studies it was reported that colistin was little effective and more nephrotoxic. In recent studies it was shown that it was not much toxic but had good efficacy. They suggested that normal dose of colistin was 2.5 to 5mg/kg/day. This dose must be regulated according to renal dysfunction. But dose regimes were not given for the individual having renal therapy. From all this study they concluded renal functions had to be monitored and neurotoxic drug combination must be avoided for favorable outcomes in colistin therapy.
Yousef et al. (2012) investigated the nepheroprotective effect of vitamin C and they used the colistin high dosing to induce the nepherotoxicity. They injected mice twice daily with the total dose of 36.5mg/kg and vitamin C 50-200mg/kg for a week. Colistin induced the renal tubular damage in rat in vitro using proximal tubular cellular lines without vitamin C. Latter on they investigated that combine effect of these two. Their results showed that increased levels of sensitive marker of tubular injury in colistin only treated groups and low level of these indicators in colistin/vitamin C treated groups. In histological studies renal tubular changes were very evident in colistin group with high percentage of apoptotic cells. In vitro same changes were seen in cell cultures in the presence of colistin alone. But in the presence of vitamin C the apoptotic bodies were significantly reduced in both cases in rat kidney and in vitro studies. They showed vitamin C altered the pharmacological properties of colistin and total body clearance is decreased. They draw the conclusion that co-administration of colistin with ascorbic acid had great potential to increase the therapeutic index of colistin.
Yousef et al. (2011) performed a study on rats to see the nephroprotective effect of melatonin against the colistin high dose toxicity. They divided rats in different groups each having seven rats. In 1st group they injected .5-4mg/kg colistin in saline solution I/V and in 2nd melatonin 5mg/kg and in other group both melatonin and colistin for seven days. Both the groups were examined for histological and biochemical changes. After the biochemical analysis they reported that there were very low levels of renal tubular damage indicator at day 1. Plasma level of creatinine was higher at day 6 in colistin only group. Histological examination revealed clear changes in the renal tubules. Melatonin changed the pharmacology of the colistin. This change was manifested by decreased clearance of combination group. They concluded from their work that high dose colistin toxicity was the result of oxidative injury and melatonin as antioxidant to minimize the toxicity and to maximize the therapeutic characteristics of colistin.
Ko et al. (2011) discussed that renal toxicity of colistin had been reported. It was stated that acute kidney injury (AKI) resulted after 2 weeks on an average. But they had seen it early. They observed the clinical picture of the cases with AKI after colistin treatment. They observed the case histories in four hospitals from 2007 to 2009. They selected 119 cases with I/V therapy for 3 days. They compared the groups with early AKI and late AKI. In 54% cases AKI developed within a week and 45.4% cases after a week. The mortality was high in early AKI then in late AKI.
Paul et al. (2011) studied the efficacy of colistin relative to other drugs such as imipenem, meropenem, amicillin in treating the infections. All cases from May 2006 to July 2009 were included in the study. They studied the mortality rate for thirty days. They treated 200 patients with colistin and 295 with other drugs. The mortality percentage was 39% in colistin treated group and 28.8% for other antibiotics. Renal toxicity with the colistin treated group was high as compared with other group. They reported that colistin was linked with higher mortality and higher toxicity in comparison with other antibiotics.
Falagas et al. (2005) reported renal toxicity and neuronal toxicity after the use of colistin. This was the main cause of exclusion of colistin from antibiotic therapy for twenty years. But resistant development against most of antibiotic had lead to its re-inclusion in therapy. They performed the study in a large hospital. They included the cases of resistant infections due to gram negative bacteria that had been injected with colistin for four weeks. They studied the serum biochemical tests associated with kidney function and neurological symptoms of the cases. The analysis of data showed that the cases where colistin was used for longer duration the kidney toxicity was evident by increased level of creatinine and no nervous sign was seen as compared to the cases where colistin was not used. But level of creatinine returned to baseline after discontinuation of the therapy. They concluded that no clear toxicity was associated with continuous use of colistin.
Garonzik et al. (2011) reported that new drugs against the new resistant gram negative organism were not available. This was the reason behind the reuse of colistin against these organisms. Colistin methansulphate was used in the critical cases and the cases with ongoing with kidney therapy. They studied the pharmacokinetics data that was previously recorded to develop a population pharmacokinetic model. They included one hundred cases and twelve cases on hemodialysis and four on renal therapy. Creatinine clearance showed wide variation among the patients. Each case was treated with different dosage schedule. They studied the 2 compatment and 1 compartment of colistin. The results showed that colistin had best results in combination in the cases with moderate to good kidney function with MICs of more than 1 mg/ liter.
Ozyilmaz et al. (2011) demonstrate colistin toxicity and the nephro-protective effect N-acetylcysteine (NAC) and oxidative stress induced by this toxicity on lungs. They used colistin to induce the nephro-toxicity. They selected 18 rats in 3 groups 1st group was control, 2nd received .3 million IU/kg/day of colistin injection and the 3rd group received .3 million IU/kg/day of colistin and 150 mg/kg of NAC for 6 days regularly. They measured different kidney function parameters like blood urea nitrogen (BUN), creatinine, urinary creatinine, plasma tumor necrosis factor alpha levels, kidney specific enzymes and immune-cytological techniques were evaluated. Colistin toxicity was resulted and clarified by increased level of BUN and creatinine levels and elevated kidney function enzymes. NAC did not show any effect on above mentioned parameters but decreased the other renal enzymes. They also demonstrated that in colistin only group there was increased oxidative injury to the lungs.
Landman et al. (2000) studied the effect of colistin sulphate on the nervous system in young ostriches at the doserate of 39.5mg/kg body weight. At this dose rate when colistin was injected subcutaneously results in rapid mortality within 1 to 3 hours in ostriches. At this dose rate the birds showed the signs of apathy, lethargy and hypotonia which shows that the drug has clear on the nervous system. When the birds were examined at postmortem examination, they showed vascular congestion of brain vessels. When the brain samples were examined histologically they showed severe acute edema in the epicardium and the serosa of intestine. They also showed congestion of villi, swelling and vacuolization of the plexus of Auerbach and intramuscular and perivascular edema of the heart.Afterviewing the above mentioned observation in ostriches and other species it was concluded that a dose of polymyxin E more than 5mg per kg body weight is not considered safe for parenteral administration in young ostriches.
Sapapen et al. (2011) reviewed in his work that colistin is an antibiotic that has two main groups A and B. It was not in medical practice since 1970s due to its toxicity to kidneys and nervous system. They reviewed that it is major antibiotic to combat against the multi drug resistant bacteria. Colistin had been used in different doses and durations but it has better results in treating the infection than other antibiotics. Colistin has damaging effect on kidneys but this effect can be decreased by decreasing the treatment duration. Factors that may increases its side effects decreased blood albumin, shock and combination therapy. Brain damage does not happened to be a major toxic effect of colistin therapy. By studying pharmacokinetics of colistin in patients with major kidney damage is a good tool to device dose, higher antibacterial action and lower nephrotoxicity.
Deryke et al. (2010) studied the adverse action of colistin by injecting intravenously in 30 adult patients. Patients were given colistin intravenously at 5.1±2.4milligram per kg per day. Results showed that 33% of treated patients had higher rate of nephrotoxicity at 80%.
Wallace et al. (2008) investigated the relativeincidence ofneurotoxicity and nephrotoxicity of colistin sulphate by injecting intravenously in rates. They injected mice once and twice daily with clinically same dose as for humans. Microscopically the kidneys showed severe lesions.
Falagas and Kasiakou (2006) worked on ability of colistin for the treatment of sensitive gram-negative bacteria. They concluded from their work that colistin was used mainly in the patients of cystic fibrosis and the other uses in human had been stopped.
Durant et al. (1981) conducted a study on the frog to see the adverse effects of polymyxin B on neuromuscular junction. They used the voltage clamp and conventional electrophysiological techniques. They confirmed that polymyxin decreases quantal release and causes variable degree of blockade at the post junctional receptors and complete acetylcholine channels blockage. They showed their results that polymyxin B has induced the neuromuscular blockade which is non competitive in nature.
Harritova et al. (2003) demonstrated in his studied the pharmacokinetics of colistin in chicken at different ages. From there investigation they found that there is no significant difference on the calculated pharmacokinetic parameters in 4 age groups. There was ten times decrease in the bioavailability of colistin after 30 days of the age and these were close to previously investigated valve.
Bozorgmehri et al. (2004) designed an experiment to see the effect of colistin sulfate on decreasing Salmonella enteritidisinfection in broilers birds. The infection was thought to be originated from the contaminated broiler carcass. They divided forty thousand birds in two separate houses. Colistin sulfate was added in to the feed of the test group as 100g containing 1,200,000IU/ton of feed for the whole period (56 days). The results also indicate that due to addition of colistin sulfate, the live weight gain increases by 14% and the feed conversion rate improves by 8% in this study.
Kasiakou et al. (2005) reported the clinical use of colistin against resistant gram negative bacteria. They concluded from their report that drug development was not there for these resistant bacteria. To see the affectivity and safety of injecting the colistin intravenously alone and with other microbicidal agents, in curing serious infections excluding cystic fibrosis. They designed an experiment in a four hundred and fifty bed hospital that was located in Athens, Greece. In this experiment 50 patients were given I/V colistin at the dose rate of 4.5 million IU for the treatments of fifty five repetitions of infections due to multi drug resistant gram negative bacteria. The major infectious diseases were pneumonia thirty three percent, bacteremia twenty eight percent, infection of excretory and intra abdominal infection eleven percent each. The main infectious agents were Acinetobacter baumannii fifty two percent, Pseudomonas aeruginosa forty two percent, and Klebsiella pneumoniae four percent. The mortality rate was twenty four percent in that medical centre. Kidney function damage was eight percent. The few major limitations of this experiment were that they did not have control group and combination therapy in this study. They found that the intra venous administration of colistin was very safe and efficacious in combating the multi drug resistant gram negative bacteria.
Falagas and Kasiakou (2005) in this work reviewed the literature. They reported that the toxicity resulted from the administration of polymyxins were of two types nephrotoxicity and neurotoxicity associated with blockade of nerve impulse to muscles. They reported that the nephrotoxicity incidence was less common in recent studies in comparison with old studies. They also reported mildness of neuro-toxic effects and these effects subsides when the therapy was stopped. They also added that apnea and neuro-muscular blockade was not reported recently in literature. So they enlighten the fact that polymyxins are less toxic than previously reported. They highlighted that by avoiding combination therapy of neurotoxic and nephrotoxin drugs and cautious dosing and minimizing abnormalities associated with electrolytes and use of ICU may be considered responsible for the discrepancy between old and new literature.
Lewis and Lewis (2003) studied the effect of colistin on the mammalian urolithium. They used the male New Zealand white rabbits in this study. They found the direct toxic effect of colistin on the excised urolithium due to prolong exposure of colistin.
Turkoglu et al. (2011) reported that colistin was used recently used more frequently in critically ill cases due resistant infections resulted from gram negative bacteria. They studied the efficacy of colistin in these cases with kidney failure. They included ninety four cases from 2008 to 2010. In 1st group thirty nine patients were suffering from chronic kidney failure and 2nd group was control with no such problem. Both the groups were similar except 1st group had more males. In the 1st group where colistin was given the cure rate was eighty seven percent and in the 2nd group was ninety five percent. The mortality was similar in the both groups. Concomitant dosing or the daily dosing did not affect the development of nephrotoxicity. Death due to nephrotoxicity was 38% that was similar to the other group. They concluded that in critically ill patients and with kidney damage the use of colistin was efficacious as in the cases without kidney damage.
Gauthiera et al. (2012) studied the association between colistin and nephrotoxicity development in overweight patients. There was scarcity of data related to toxicity in such cases. The time period of the experiment was about 3 years. They included the obese patients that were receiving colistin parentrally through I/V route for 72 hours. They used acute renal injury assessment criteria called RIFLE (Risk, Injury, Failure, Loss and End stage renal disease. Dose rate and toxicity development was secondary parameter. Total 42 cases were included in the study. Fourth eight cases showed renal toxicity, fifteen percent risk, five percent injury, and eighty percent showed renal failure. In the study period of 1 month mortality in toxicity group was forty percent and in others was fourteen percent. They concluded from their experiment that the overweight patients would be monitored for acute renal damage for best results from colistin I/V therapy.
Korbila et al. (2010) studied re-emergence of intravenous colistin against resistant bacteria causing ventilator associated pneumonia (VAP). Combination of intravenous colistin along with inhalation therapy was common. In their study they included the cases with VAP. They divided cases in two categories, 1st group receiving I/V colistin only and 2nd group receiving combination of colistin I/V and inhalation therapy. In 1st group dose rate was 7.0 ± 2.4 million IU and 2.1 ± 0.9 million IU of inhaled colistin. Total 121 cases were enrolled in the study. From these 78 were in first group and 43 were in second group. The cure rate was significantly higher in the 2nd group where combination therapy was done. The mortality was similar in the both groups. Their study showed that more work needs to be done on this combination therapy.
Karabinis et al. (2004) reported a case of Klebsiella pneumonia induced sepsis. Teyhis bacterium was not responding to any treatment available. There was no data available on previous colistin therapy against this organism. This patient had developed septic shock due to an injury. He was given 2.5mg/kg of body weight colistin in 3 divided doses. After 2 days he started recovering from the disease. They observed no sign of toxicity.
Westerman et al. (2006) demonstrated the use of colistin sulphomethate and tobramycin through pulmonary route to improve the lungs condition in cystic fibrosis (CF). They used a new technique of administration, dry powder inhalation. They used a newly manufactured device to inhale the colistin in the healthy individuals. They inhaled a single dose of 25 mg/kg as dry powder in 8 individuals with no clinical disease. Pulmonary function was tested before the start of the experiment, five minutes and thirty minute intervals and the serum samples were collected 8 times in a 24 after the start of experiment. In their results they showed that dry powder was well tolerated by healthy persons and lungs, kidneys and liver function tests were normal.
Azzopardi et al. (2012) reported in his study the past and future status of colistin. They stated that colistin was a valuable antimicrobial agent. Their study design was based on the studies conducted in 50 years. They divided the literature in three periods: first, 1940-1975; second, 1975-2000; third, 2000-post 2000. In first period there was a trend of increasing publications, followed by toxicity publications. Second period quick decrease in research articles and third period there was re-emergence of colistin as only feasible option for the treatment of resistant gram negative bacteria. This era was also considered important in drug development techniques. They showed two trends, dose regulation was due to the development in period second. Second trend was re-development of colistin through its utility in current infections and unavailability of effective antibiotics.
Kim et al. (2009) reported that there were solid evidences that polymyxin E had showed renal toxicity but still it was used clinically due to its spectrum of activity against the major resistant gram negative micro organisms. They designed a study to see the possible harmful effects and renal toxicity associated with its clinical use. Time period of the experiment was 22 months. Forty seven cases 32% showed signs of renal toxicity and 20% received replacement therapy. After one month some cases re-examined for renal function and ninety percent recovered from renal injury. They also used NSAIDs and antibiotics along with regular colistin treatment. They also found that use of other hypoalbuminaemia and use of NSAIDs had major role in development of renal dysfunction.
Strenger et al. (2011) designed his work to see the activity of colistin against the extended spectrum β-lactamase producing Enterobacteriaceae (ESBL-E) that was wide spread problem in new born children. During their study period of 18 months 3 outbreak of ESBL-E were observed. Before this cases were receiving 15mg/kg/day gentamicin orally as a preventive measure. During study period they replaced it with colistin with oral dose rate of 8mg/kg/day. After that all the cases were examined clinically for ESBL-E organisms. Genetic relationship among the positive cases was accessed by PCR. During study thirty patients of 667 were found positive. They found that the rate of development of resistance was more in the colistin treated group when they found both colistin susceptible and resistant organism in the same colony which was a solid indicator of resistance development. The result of the experiment was the given dose of oral colistin did not prevent the infection but instead lead to development of resistant organisms.
Perez et al. (2012) studied the efficacy of colistin and tigecycline in model of pneumonia caused by E.coli and Klebsiella pnemoniae. They adopted microdilution method for the determination of susceptibility. They used immuno-competant mice in the experiment. The dose rate for colistin was 60 mg/kg/day and for tigecycline were 10 mg/kg/day. Bacterial load, fatalities and bacteraemia were the study parameters. Colistin had good protective effect these strains. They concluded from their experiment that both these antibiotic hah excellent efficacies against these strains of Enterobacteriacae.
Westerman et al. (2004) studied the use colistin in combating resistant infection due to Pseudomonas aeruginosa in the cases with cystic fibrosis (CF). They stated that inhalation route was best route for treatment but the only side effect was constriction of bronchioles in CF. They planned their study to investigate the minimum dose required for single inhalation therapy without any toxic effect. They administered colistin sulphate and colistin sulphomethate in the cases with chronic CF. After that they conducted the pulmonary function tests and found the colistin sulphate significantly decrease the pulmonary function as compared to other. Its administration was not done in the seven patients with tracheal irritation and sever cough. They concluded that use of colistin sulphate was not better for the treatment of CF through pulmonary route and colistin sulphomethate was safer for inhalation therapy.
Gales et al. (2001) worked on polymyxin E and polymyxin B due to their importance in treating the resistant infections. National committee for clinical laboratory standards (NCCLS) did not clarified evaluation methods for the two antimicrobials. They planned their study to evaluate efficacy of these antibiotics. They used 2 hundred bacteria collected from blood through a surveillance program. After performing all standard tests according to NCCLS standards they showed that these 2 antibiotics had similar antimicrobial properties. After performing different tests regarding its MIC they concluded that laboratories had to use MICs as standards. Until NCCLS modified tests are published.
He et al. (2007) discovered a new bacterial strain that had broad bactericidal activity on wide range of bacteria. It was Paenibacillus polymyxa. The chemicals produced by this bacterium by fermentation and analyzed chromatography technique. They separated 2 antimicrobial agents: first chemical was polymyxin E1 and an unknown chemical highly active against gram positive bacteria. The unknown chemical was separated and its potency and its chemical structure were clarified. This chemical was named as paenibacillin. It was very potent against many food poisoning and spoilage causing bacteria. After evaluating of this chemical by different modern laboratory techniques, this chemical was considered as excellent lantibiotic. Combination of these 2 antimicrobial was reported first time. They highlighted its application in food and medical industry.
Li et al. (2003) studied stability of colistin methanesuphate (CMS) in water using HPLC technique. They found that at four and thirty seven centigrade for approximately 2 months and 5 days it remained unchanged in water. They also observed that changes occurred when it was kept in plasma and phosphate buffer solution at 37 ͦ C. Un-degradability was thought to be due to heavy cationic properties. They measured the hydrolysis of CMS by HPLC in these three mediums and in a broth medium. The formation of colistin from CMS was measured. They showed that there were different abilities of CMSs for the formation of colistin. These conclusions were very useful in the further study of pharmacology of colistin in animals and humans.
Imberti et al. (2010) studied the rediscovery of colistin as novel antibiotic for treating gram negative infection. There were very less studies conducted on the pharmacology of colistin in critically ill cases. Thirteen cases with pneumonia were selected. These were injected with two MIU of colistin through intravenous route for 48 hours. Blood samples were taken from the injected cases after equal period of time. Colistin concentration was measured by HPLC procedure. They found MIC after each period and no sign of renal injury was observed. They concluded that pharmacological parameters of CMS were not well known and this level gives suboptimal plasma concentration of colistin. They highlighted the need of dose optimization.
Plachouras et al. (2009) reported that CMS which is converted into active drug but information regarding this limited. They designed the present study to evaluate the pharmacology of CMS in cases with terminal disease. Cases with resistant infections were included in the experiment; each of them received 3 MIU of CMS intravenous after eight hours. They took the blood sample after injection, after fixed intervals and after 4th injection. They measure the concentration of CMS and colistin with HPLC quickly to avoid the metabolism. They selected 18 cases in the study with known creatinine levels. They found the plasma half life of colistin was long with respect to dosing. But still the pharmacological parameters were not fully evaluated. Another point was aroused that whether loading dose would benefit terminally ill cases.
Gobin et al. (2010) stated that HPLC and mass spectrometry were the techniques used to determine the concentrations of colistins in urine and plasma. They used H2 SO4 treatment to determine the concentration of CMS and pro drugs by hydrolyzation. Their quantification was effectively determined by this method. They pointed out that more studies were needed for validation of quantification methods.
Koomanachai et al. (2007) investigated the efficacy of colistimethate sodium for treating the resistant infections. The duration of the research was 15 months. They included the cases of resistant infections in the study. They were injected 5 mg/kg/day of colistin through I/V route. The study parameters were clinical outcome, number of fatalities, antibacterial activity and side effects within 1 month of treatment. Total 93 cases enrolled in the study and divided into 2 groups. In first group 78 patients were given colistin and remaining patients were given other antibiotics. They found that clinical favorable outcome in colistin treated group along with low fatality rate and good antimicrobial response. Renal toxicity was observed twenty four patients most of them had previous renal malfunction and nephrotoxicity was no observed in any case.
Markou et al. (2003) stated that historically colistin had been used in emergency medical centers for the treatment of gram negative bacilli. They investigated the parenteral administration of colistin in terminally ill patients. They included ICU center in the study and 24 cases were injected colistin twenty six times in their treatment course. They determined the cure rate from the infections. They observed that control group was not present in their study so results were not satisfactory on clinical efficacy of colistin. But the margin of safety was acceptable for the colistin. They recommended its use in clinical practice.
Price and Graham (1970) studied the use of high doses of colistin in the treatment of lung and urinary system. They also noted the renal injury caused by high doses of colistin. They included 14 cases of infection in the study and treated with high doses of colistin. They concluded from their experiment that colistin cause acute renal damage and acute renal tubular necrosis leading to renal failure and death in some cases, but they found that major cause of death was neurological injury.
