colistin belongs to the polymyxin class of antibiotics which is a group of cationic polypeptides .
however , the popularity rapidly faded in 1970s because of significant renal and neurological toxicity and was replaced with less toxic antibiotics with a comparable or broader antibacterial spectrum such as aminoglycosides . with the recent emergence of multi drug - resistant ( mdr ) gram - negative organisms , in particular pseudomonas aeruginosa , acinetobacter baumannii , and klebsiella pneumonia , colistin has been reconsidered as a potential therapeutic agent for the past 10 - 15 years .
this has not only increased the clinical usage of this ancient drug , but has also increased the prevalence of all the toxicities related to colistin .
neurotoxicity is the second most common toxicity after nephrotoxicity following colistin therapy . among the various manifestations of its neurotoxicity ,
several cases of respiratory failure due to colistin were reported in the previous era . however ,
a 31-year - old white female with history of spina bifida , paraplegia , hydrocephalus status post ventriculo - peritoneal shunt , osteomyelitis of the left hip status post left leg amputation , and chronic sacral decubitus ulcer presented with foul smelling discharge from her sacral wound for 2 weeks .
the culture from the wound grew two biotypes of pseudomonas aeruginosa : one was resistant to all antibiotics except for colistin while the other was resistant to all antibiotics except for colistin and imipenem .
in addition , methicillin - resistant staphylococcus aureus ( mrsa ) grew from the intraoperative bone culture .
she was started on colistimethate sodium ( cms ) 200 mg intravenously every 12 hours for her mdr p. aeruginosa .
she was then discharged to a sub - acute rehabilitation center on cms and vancomycin .
after three days , she was noted to have sudden respiratory distress in the sub - acute rehabilitation center for which emergency medical service ( ems ) was called . on arrival
she was immediately started on bag - valve mask ventilation ( bvm ) and was taken to the emergency room ( er ) . in the
er , she was noted to have oxygen saturation at 80s on bvm and was emergently intubated . shortly after resuscitation ,
her arterial blood gas analysis revealed ph of 7.45 , paco2 of 25 , and pao2 of 280 mmhg ( on fio2 of 100% ) .
her labs were significant for leukocytosis with white cell count of 20,000/mm and an acutely elevated creatinine of 2.2 mg / dl ( baseline creatinine was 0.9 mg / dl at the time of discharge ) with metabolic acidosis with bicarbonate of 18 mmol / l secondary to her renal failure . on further inquiry , there was no exposure to any narcotics or muscle relaxants that might have contributed to her respiratory depression .
she was in a supervised unit prior to the presentation , which deterred the possibility of any toxic exposure to the patient .
two sets of blood cultures were negative while the wound culture revealed the same biotypes of mdr p. aeruginosa .
neurological workup was unrevealing and ventilation / perfusion scan ( v / q scan ) for pulmonary embolism was low probability .
colistin was stopped as it was thought to be the cause of renal failure and respiratory failure and the patient was started on imipenem .
her respiratory and neurological status remained stable during hospitalization and tolerated imipenem and vancomycin for her osteomyelitis and chronic decubitus ulcer infection .
our patient developed acute respiratory failure requiring intubation and mechanical ventilation 6 days after initiation of colistin .
respiratory muscle paralysis , as depicted , is one of the manifestations of the neurotoxic effect of colistin .
we applied the naranjo adverse drug reaction probability scale to our case , which indicated a probable relationship .
the case is limited with the unavailability of arterial blood gas prior to the event as she was emergently intubated on presentation .
also , since colistin is reserved for severely ill patients with multiple co - morbidities , it may be difficult to establish direct causal relationship for acute respiratory failure and colistin .
colistin was most likely to be the culprit of her respiratory failure from the timing of apnea as well as rapid recovery after stopping colistin .
acute renal failure leading to presumed high concentration of serum colistin may be another contributory factor for her respiratory failure .
she had a chronic deep vein thrombus which is unlikely to cause acute respiratory failure since low probability for pulmonary embolism by v / q scan and she recovered within 24 hours without any intervention .
reported cases of respiratory paralysis associated with polymyxin / colistin use since 1960 to present colistin is also called polymyxin e and is a part of polymyxin family which is a group of polypeptide antibiotics .
it exerts its bactericidal effect by displacing the divalent cations magnesium and calcium , which stabilize anionic lipopolysaccharide molecules in the outer membrane of gram - negative bacteria .
however , they were gradually abandoned in most parts of the world because of nephrotoxicity and neurotoxicity .
the emergence of mdr gram negative bacteria led to the revival of polymyxins in more recent era as a valuable therapeutic option . in the last decade , intravenous polymyxins , particularly in the form of cms ,
have been used to treat serious p. aeruginosa and a. baumannii infections of various types , including pneumonia , bacteremia , and urinary tract infections .
the major manifestations of colistin induced neurotoxicity include dizziness , weakness , facial and peripheral paresthesias , vertigo , visual disturbances , confusion , ataxia , and neuromuscular blockade .
koch - weser et al . , reported the incidence of the neurotoxic manifestations to be about 7% , paresthesias being the most common .
the proposed mechanism is a non - competitive myoneuronal presynaptic blockade of acetylcholine release , in contrast to the competitive blockade by most other antibiotics like neomycin , kanamycin , and streptomycin .
a total of 32 cases of colistin / polymyxin - induced respiratory failure were found in the literature .
recent studies have depicted the toxicities associated with colistin use to be less frequent than previously described .
the most important risk factor known to be associated with respiratory failure with polymyxin use is the renal disease , which was present in 24 out of 29 patients reported .
patients with preexisting renal insufficiency had a greater likelihood of developing nephrotoxicity during colistin therapy , compared to patients with normal baseline renal function .
concomitant drug therapies also play a major role in potentiating the effect of neuromuscular blockade , which was noted in 11 out of 29 patients .
this includes use of other neurotoxic drugs ( anesthetics , aminoglycosides , and paralytics ) , corticosteroids , narcotics and/or muscle relaxants .
most of the cases had other neuromuscular symptoms like circumoral tingling , paresthesias , and restlessness prior to the development of respiratory failure .
the duration of apnea lasted from few hours up to several days , maximum noted to be 11 days and 20 out of 29 patients recovered , indicating reversibility of the blockade .
the number of doses prior to the respiratory failure seems to be variable and range from a single dose to 45 doses [ table 1 ] .
the management of patient with respiratory failure induced by colistin involves discontinuation of the drug and respiratory support .
intermittent monitoring of unassisted tidal volumes and forced vital capacity using a bedside spirometer will help determine recovery . monitoring arterial blood gas
more importantly , one should be alert for the possibility of respiratory paralysis in any patients receiving this antibiotic and particularly in those patients with renal abnormality and with concomitant neurotoxic drug use . careful observation , regular neurological monitoring , and early appreciation of the symptoms of neuromuscular toxicity especially of dyspnea and restlessness may prevent respiratory arrest .
neostigmine is not indicated in polymyxin or colistin - induced neurotoxicity and may be contraindicated as seen in earlier experiments that the blocking action of polymyxin b was shown to be neostigmine resistant .
animal studies have noted the ability of polymyxin b to discharge histamine from tissue mast cells , which lead to deposition of chelated calcium along the nerve sheaths , leading to toxicity .
higginbotham also reported use of heparin prevents death from respiratory arrest in mice receiving colistin .
the use of antihistamines and heparin in polymyxin induced respiratory failure has not been studied in human subjects .
as the use of colistin increased in recent years for treatment of life - threatening mdr infections , there are more reports of associated toxicities .
clinicians should be aware of colistin - related adverse reactions , especially nephrotoxicity and neurotoxicity .
since the formulation of the drug itself has changed , it has necessitated new data with the new formulation .
regular monitoring of renal function as well as development of a tool to monitor neurological toxicity is essential to prevent and manage the toxicities associated with colistin use .
 the emergence of multi - drug - resistant gram negative bacillary infections has regained popularity of ancient drugs such as polymyxins . 
 we report a case of acute respiratory failure induced by use of intravenous colistimethate , which is one of the forms of polymyxin . 
 the patient is a 31 year old female with paraplegia due to spina bifida who underwent excisional debridement of large lumbosacral decubitus ulcer with osteomyelitis infected with pan - resistant pseudomonas aeruginosa and mrsa . 
 six days after initiation of intravenous colistimethate and vancomycin , she developed acute respiratory failure requiring mechanical ventilation . 
 pan - culture was negative including a chest radiograph . 
 v / q scan showed low probability for pulmonary embolism . 
 echocardiogram showed normal right ventricle with no strain or pulmonary hypertension . 
 colistimethate was discontinued . within 24 hours , she was extubated . in the early years after introduction of polymyxin 
 , there were several reports of acute respiratory paralysis . 
 the mechanism is thought to be noncompetitive myoneuronal presynaptic blockade of acetylcholine release . 
 though a direct causal relationship for respiratory failure is often difficult to establish in current era with multiple co morbidities , the timeframe of apnea , acuity of onset as well as rapid recovery in our case clearly point out the causal relationship . 
 in addition , our patient also developed acute renal failure , presumably due to colistimethate induced nephrotoxicity , a possible contributing factor for her acute respiratory failure . in summary 
 , colistimethate can induce acute neurotoxicity including respiratory muscular weakness and acute respiratory failure . 
 clinicians should consider its toxicity in the differential diagnosis of acute respiratory failure especially in critically ill patients . 
INTRODUCTION
CASE REPORT
DISCUSSION
CONCLUSION