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Paper text:
a 92-year old male resident in a nursing home was admitted to our tertiary care center in riyadh , saudi arabia , with a general deterioration . he had a past history of diabetes mellitus , systemic hypertension and stroke .
the physical examination revealed a temperature of 34c , blood pressure of 70/30 mmhg , pulse rate of 115 per minute , respiratory rate of 22 per minute and a glasgow coma scale of 8 out of 15 .
a temporary diagnosis of urinary tract infection and septic shock was made and he was transferred to the intensive care unit , where he received intravenous fluids , vasopressors and mechanical ventilation .
the initial empiric antimicrobial therapy included imipenem - cilastatin four times daily and ciprofloxacin 400 mg twice daily , both given intravenously .
the blood , urine and sputum cultures showed an extended - spectrum beta - lactamase ( esbl)-producing escherichia coli .
the isolates were resistant to ciprofloxacin , but susceptible to imipenem and gentamicin ( table 1 ) .
the clinical conditions of the patient improved and gentamicin and imipen - em - cilastatin were discontinued after a total of 10 days and 14 days respectively .
ten days after the antibiotic therapy was discontinued , i.e. on the 24 day in the intensive care unit , the patient had fever up to 38.6c , hypotension and peripheral blood leukocytosis ( white blood cell count 1810/l , 80% neutrophils ) .
chest x - ray showed left lung consolidation with a large pleural effusion ( figure 1a ) .
a pigtail catheter was inserted taking strict aseptic precautions to drain the effusion ( figure 1b ) . the fluid analysis revealed protein at 52.0 g / l , lactate dehydrogenase at 1477
iu / l , ph at 7.0 and white blood cells at 8450 , 96% of which were neutrophils .
a diagnosis of ventilator - associated pneumonia and pleurisy was made and colistin methanesulfonate was started with a loading dose of 9 million units followed 24 hours later by 3 million units three times daily in combination with imipenem - cilastatin 500 mg four times daily .
the patient developed a pneumothorax because of the pigtail catheter which was therefore replaced with an intercostal chest drain ( figure 1c ) .
the pleural fluid taken via the pigtail drain showed the growth of esbl - producing e. coli and carbapenem - resistant acinetobacter baumannii . on day 28 ,
the patient was still febrile and continued to require high dose vasopressor infusions to maintain his blood pressure .
the lack of clinical improvement prompted us to add intra - pleural colistin methanesulfonate at a dose of 0.5 million units in 50 ml of a 0.9% sodium chloride solution .
the medication was administered at 12-hour intervals via the intercostal drain . in between the drain
a remarkable improvement in the patient s condition was noted with a drop of the peripheral white blood cell count to 8.810/l ( normal range : 4 - 1110/l ) , reduced need for ventilation and successful discontinuation of the vasopressor support .
it showed the growth of proteus mirabilis ( table 1 ) , but neither a. baumannii nor e. coli were isolated , indicating a successful microbiological clearance of both microorganisms .
the minimum inhibitory concentrations of imipenem and meropenem for the isolated proteus mirabilis strain were 4 mg / l and 1 mg / l respectively , thus suggesting a switch from imipenem - cilastatin to meropenem 1 g three times daily intravenously .
the intra - pleural and intravenous colistin methanesulfonate therapies were discontinued after a total of 10 days and 14 days , respectively , while meropenem was continued for a total of 7 days .
culture of pleural fluid obtained on day 37 was again negative for a. baumannii and e. coli ( table 1 ) .
the intercostal drain was removed on day 42 and a follow - up chest x - ray showed the resolution of the previously identified signs of infection and effusion ( figure 1d ) . despite
the patient remained clinically stable with no further episodes of sepsis , our attempts to wean him off mechanical ventilation were unsuccessful .
he developed an acute myocardial ischemia and passed away after a total stay of 67 days in the intensive care unit .
to the best of our knowledge , this is the first report of successful intra - pleural colistin methanesulfonate therapy , in combination with intravenous antibiotics , for a pleural infection caused by multidrug - resistant gram - negative bacteria .
indeed , the patient had clinical , radiological and microbiological evidence of ventilator - associated pneumonia and pleural infection caused by multi - drug resistant strains of e. coli and a. baumannii .
he remained critically ill with refractory hypotension , fever and leukocytosis despite 4 days of appropriately dosed intravenous imipenem - cilastatin and colistin methanesulfonate therapy .
the addition of intra - pleural colistin methanesulfonate was associated with a prompt clinical and microbiological response .
intra - pleural antimicrobial therapy is not generally recommended in the treatment of bacterial pleural infections .
however , favorable results were reported from small comparative studies when intra - pleural antimicrobial therapy was added to an adequate pleural drainage and systemic antimicrobial therapy .
many articles published in the literature described a poor colistin penetration in the pleural space , but none indicated a reference to corroborate this statement .
we searched the english language literature using pubmed , medline plus and google scholar and were not able to identify any primary studies upon which these statements could be based .
colistin was originally introduced in the clinical practice in the 1950 s and hence was not submitted to the modern requirements for rigorous pre - licensing assessments . as a result , there are considerable gaps in the understanding of its clinical efficacy in various types of infections . its clinical use has increased over the last two decades in parallel with the development and the spread of infections caused by carbapenem - resistant gram - negative bacteria .
it has become evident that the results of earlier colistin pharmacokinetic studies , which relied upon biological assays , are unreliable .
modern pharmacokinetic studies have demonstrated that previously recommended parenteral regimens lead to sub - therapeutic serum colistin levels , especially in critically - ill patients . the colistin methanesulfonate regimen received by our patient is consistent with the current evidence and recommendations .
the intra - pleural colistin methanesulfonate dose used for our patient was extrapolated from pharmacokinetic studies and case series with intra - thecal and intra - ventricular use of colistin methanesulfonate . notwithstanding the potentially significant differences between cerebrospinal and pleural spaces in terms of drug penetration ,
distribution and excretion , we felt that in the presence of an intercostal drain , a twice daily administration might result in a better average exposure over time , thereby optimizing bacterial killing .
interestingly , the summary of product characteristics for at least one commercially available colistin methanesulfonate preparation , colimicina ( ucb pharma , pianezza , italy ) , includes recommendation for intra - pleural and intra - peritoneal treatments with a dose of 0.5 - 1.0 million units per day mixed in 20 - 50 ml of ordinary saline .
these routes of administration are not recommended in the product summary characteristics of the locally available brand of colistin methanesulfonate ( colomycin , forest laboratories , bextley , united kingdom ) . despite the successful outcome in our case report
, it is important to emphasize that the safety of the intra - pleural colistin therapy remains still to be established .
respiratory depression has previously been reported in association with the intra - pleural administration of neomycin and bacitracin therapy .
therefore , this adverse event should be taken into consideration for this route of administration .
moreover , it is not known whether this topical treatment could result in the development of bacterial resistance to colistin , as was the case with the inhalational colistin therapy in patients with cystic fibrosis .
finally , even though the patient improved during the intravenous treatment and the pleural draining , we believe that the addition of the topical intra - pleural medication had a key role in the clinical and microbiological improvement , as it emerged in connection with its introduction .
the use of the intra - pleural colistin therapy should be considered in carefully selected patients with pleural infections caused by multi - resistant gram - negative bacteria .
however appropriately designed trials and further studies are needed to better clarify the efficacy , the safety , and the pharmacokinetics of this route of colistin administration .
infections caused by carbapenem - resistant , gram - negative bacteria are an increasing clinical challenge , since the antimicrobial treatment options are often limited to colistin methanesulfonate . 
 no data are available regarding the pharmacokinetics of colistin in pleural fluid . 
 we report the case of a 92-year old man with ventilator - associated pneumonia and pleurisy caused by acinetobacter baumannii and escherichia coli , which were both multidrug - resistant . after an unsuccessful treatment with intravenous colistin methanesulfonate and imipen - em - cilastatin , the addition of intra - pleural colistin methanesulfonate to the intravenous treatment led to a prompt clinical , radiological and microbiological resolution . 
 this is the first report of a successful use of intra - pleural colistin in the literature . 
 the intra - pleural colistin therapy should be considered in selected cases of pleurisy caused by multi - resistant gram - negative bacteria .