Table 1

Old studies (from 1962 to 1977) reporting data on polymyxin-induced toxicity in patients without cystic fibrosis

Year [ref]
 Setting
 Medication used
 Number of patients
 Demographics
 Dosage of colistin/duration
 Nephrotoxicity
 Neurotoxicity
 Other toxicities
1
 1962 [26]
 Medical wards
 Colistimethate sodium (IV)
 48
Adults: 150 mg q12 h Children: 5 to 10 mg/kg/day. Duration: at least 10 days
 12 pts had transient mild elevation of BUN (average increase 14 mg/dl) and returned to normal. 5 pts had prolonged elevation of BUN (average increase 50 mg/dl) and returned to normal
 13/48 pts paresthesias; 3/48 pts ataxia
 3/48 pts pruritus. No drug fever, hepatic or bone marrow toxicity
2
 1963 [19]
 Medical wards
 Colistimethate sodium (IM)
 1
 64 year old male
 6.5 mg/kg/day (150 mg q8 h) for 12 days (he received concurrently kanamycin IM for 2 days and after colistin therapy chloramphenicol)
 BUN increased from normal baseline values to 44 mg/dl (drug was stopped). The BUN continued to rise and then began to return to normal. Postmortem examination of the kidney revealed findings compatible with drug induced nephrotoxicity
Possible hepatotoxicity
3
 1963 [66]
 Medical and surgical wards
 Colistimethate sodium (IM and topically)
 62
Topically: 1% or 2% solution q4h or q12h. Duration (range): 2 to 7 d Intramuscularly (range): 150 to 300 mg/day. Duration (range): 1.5 to 19 d
 Topically: no side effects
 Topically: no side effects Intramuscularly: 15/55 pts reported one or more of the following: lethargy, dizziness, nausea, confusion, slurred speech, numbness, paresthesias, pruritus, pain at the injection
 Topically: no side effects
4
 1963 [20]
 Medical wards
 Colistimethate sodium (IM)
 11
Dosagea: 1.5 MIU q12h for a week and continued for a further week if the pt was improving (2 pts received 2 MIU q8h for 5 days and then 3 MIU q8h)
 No renal toxicity
 2 pts trigeminal paresthesia
 1 pt developed follicular rash of the face




14
Dosage (range): 1 MIU q12h to 1.5 MIU q8 h for 7 or more days


5
 1964 [28]
 Medical wards
 Colistimethate sodium (IV)
 8
 Age (range): 25 to 69 years
 Dosage: 2 to 2.5 mg/kg q12 h. Duration (range): 8 to 14 days.
 4/8 pts fall in creatinine clearance (range: 16.5 to 38 ml/min) and increase in serum creatinine (range: 0.2 to 2 mg/dl)
 No neurotoxicity
 No pruritus
6
 1964 [21]
 Children's hospital
 Colistimethate sodium (IM)
 36 new-borns
 Age (range): 6 hours to 12 days
 Dosage (range): 2.5 to 5 mg/kg/day in 2 to 4 doses. Total dose (range): 10 to 240 mg (1 new-born (3.3 kg) received 160 mg of colistin (overdosage) in 7 days)
 16 pts had renal epithelial tubular cells on urinalyses; 14 pts had urinary protein excretion
 No neurotoxicity
7
 1964 [22]
 Medical wards
 Colistimethate sodium (IM)
 1
 50 year old male
 Dosage: 300 mg/day for 5 days, then 200 mg/day for 4 days
 Urinary retention, rise in blood urea nitrogen
 Difficulty in breathing, dysphagia, generalized weakness, hallucinations, apnea requiring intubation
8
 1965 [50]
 Medical wards
 Colistimethate sodium (IM)
 1
 66 year old female with azotemia
 Dosage: 150 mg q 12 h for 8 days. Cumulative dose: 2,550 mg
7th day of colistin: circumoral paresthesias; 8th day: vomiting, difficulty in breathing, moving, speaking, and became apneic; 10th day: grand mal seizures followed by transient right facial and arm weakness
9
 1965 [24]
 Medical wards
 Colistimethate sodium (IM)
 17 (19 courses)
 Age (range): 33 to 90 years
 Total cumulative dose (range): 0.56 gr to 2.4 gr
8 pts dizziness – vertigo (1 pt discontinued), 5 pts oral paresthesias
 3 pts pain at site of injection, 3 pts nausea/vomiting, 2 pts pruritus/rash
10
 1965 [23]
 Medical wards
 Colistimethate sodium (IM)
 1
75 mg q12 h
Episodes of ptosis, muscular weakness of the face and of the extremities
11
 1965 [25]
 Medical wards (renal department)
 Colistimethate sodium (IM)
 25
 12 males, 13 females. Age (range): 14 to 66 years. All with impaired renal function
 Dosage (range): 2 MIU to 4.4 MIU/day. Duration (average): 8.5 days
 9/25 pts had an increase in plasma creatinine levels

12
 1966 [46]
 Medical wards
 Colistimethate sodium (IM)
 1
 47 year old female
 100 mg q8h
Perioral paresthesia, numbness in the hands, weakness, ataxia, lightheadedness, shortness of breath, apnea
 Nausea, itching of the face, hands, and arms (no visible rash)
13
 1966 [67]
 Medical wards
 Colistimethate sodium (IM)
 21
 All had urinary tract abnormalities or had undergone prostatectomy
 Dosage: 120 mg (1.5 MIU) q8h for 7 days
 No constant effect on creatinine clearance was observed

14
 1966 [43]
 Medical wards
 Colistimethate sodium (IM)
 4 who developed acute renal failure
 Age (range): 41 to 75 years. All with pre-existing renal disease
 Dosage: 5 to 6.3 mg/kg/day. Duration (range): 3 to 12 days
 Acute tubular failure (3 pts acute tubular necrosis, 1 pt recovered)
 Retrosternal discomfort 1 pt
15
 1966 [48]
 Medical wards
 Colistimethate sodium (IM)
 1
 48 year old female
 75 mg q12h (she also received chloramphenicol 500 mg q6h po)
Diplopia and bilateral eye ptosis, weakness of neck flexion, difficulty in raising her arms
16
 1966 [51]
 Department of anaesthesiology
 Colistimethate sodium (IM)
 1
 49 year old female with nephrolithiasis
 75 mg q12 h (she also received chloramphenicol 500 mg q4h po and sulfisoxazole 1 g q4h po)
Post-operative apnea
17
 1967 [27]
 Medical and surgical wards
 Colistimethate sodium (IV)
 23
 Males, moderately to severely ill
 Dosage (range): 1.1 to 5 mg/kg/day q12h for 6 to 7 days (in 2 cases the treatment was discontinued after 2 and 3 days)
 6/23 pts renal impairment; 7/23 pts albuminuria
 1 pt circumoral paresthesia
 5/23 pts mild itching
18
 1968 [44]
 Medical wards
 Colistimethate sodium (IV)
 7
 Age (range): 28 to 48 years. 4 females, 3 males; all had terminal and irreversible renal failure
 2 to 3 mg/kg (1 dose)
2 pts mild dizziness and instability
19
 1968 [56]
 Medical wards
 Colistin sulfate (PO)
 93 (48 cases E. coli and 45 cases Shigella spp.)
E. coli : 100,000 IU/kg/day in adults and 150,000 IU/kg/day in children for 7 days Shigella: 200,000 IU/kg/day in adults and 300,000 IU/kg/day in children for 8 to 10 days
 No toxic symptoms
 No toxic symptoms
 1 pt generalized rash, 1 pt vomiting
20
 1968 [49]
 Medical wards (respiratory care unit)
 Colistimethate sodium (IM) and Polymyxin B (IM or IV)
 11
 Age (range): 36 to 74 years. 4 females, 7 males; all had acute or chronic renal disease
 Dosage of colistimethate sodium (range): 100 to 400 mg/day. Duration (range): 1 to 29 doses or 1 to 15 days. Dosage of polymyxin B: 50 mg (1 dose) IM (1 pt) and 100 mg (1 dose) IV (1 pt)
All pts at their admission had apnea that recovered in all cases. Paresthesias 2 pts, diplopia 3 pts, difficulty in swallowing 3 pts, ptosis 2 pts, generalized weakness 3 pts, blurring of vision 1 pt, slurred speech 1 pt, lethargy 1 pt, coma 1 pt
21
 1969 [42]
 Medical wards
 Colistimethate sodium (IV)
 1
 14 year old male with acute leukemia
 Dosage: 5 mg/kg/day for 5 days, then increased to 7 mg/kg/day on day 6, 10 mg/kg/day on day 7, and 17 mg/kg/day on day 9. Duration: 14 days
 Acute tubular necrosis

22
 1969 [29]
 Medical wards (pediatrics)
 Colistimethate sodium (IM)
 1
 4 year old female with appendicitis
 Dosage: 30 mg/kg q6h (total dose received 1,050 mg during 42 h
 Acute renal failure
 Neuromyal hyperactivity, seizure-like episodes, uncoordination, disorientation, flaccid quadriplegia, respiratory arrest, apnea
23
 1970 [4]
 Medical and surgical wards
 Colistimethate sodium (IM)
 288 (317 courses)
205 courses received a total of <1 gr, 69 courses 1 to 2 gr, 43 courses > 2 gr. All courses were administered IM q12 h
 Total: 64/317 courses (renal insufficiency 63 pts, acute tubular necrosis 6 pts, hematuria 1 pt)
 Total: 23/317 courses (paresthesias 15 pts, respiratory insufficiency and apnea 6 pts, nausea and vomiting 4 pts, dizziness 3 pts, muscular weakness 2 pts, peripheral neuropathy, confusion, psychosis, convulsive seizure 1 pt each)
 Total allergic reactions: 7/317 (drug fever 3 pts, eosinophilia 2 pts, macular eruption 2 pts, urticarial eruption 1 pt)
24
 1970 [68]
 Medical wards and ICU
 Colistimethate sodium (aerosol)
 20
 Age (range): 23 to 81 years
 Group 1: 50 mg q8h for 7 days. Group 2: 100 mg q8h for 7 days
 No toxic symptoms
 1 pt experienced palpitations and a sensation of chest tightness (treatment was discontinued)
25
 1970 [3]
 Department of pediatrics
 Colistimethate sodium (IM)
 1
 Age: 10 months (male)
 15 mg q6 h (2 doses) and then 250 mg (38.5 mg/kg) (3 dose)
 Acute renal failure
 No neurotoxicity
26
 1970 [30]
 ICU, neurosurgical department
 Colistimethate sodium (IV, IM, and aerosol)
 14
 Age (range): 31 to 71 years
 Mean duration: 9.7 days. Dosage: 26 MIU/day: 10 MIU IM, 10 MIU IV, and 6 MIU aerosol
 In all pts a considerable fall in creatinine clearance and rises in blood urea and serum creatinine levels were observed. 5 pts developed acute tubular necrosis (histological confirmed). In 6 pts renal function returned to normal

27
 1970 [69]
 Department of renal disease
 Colistimethate sodium (route of administration not reported)
 1
 41 year old
 Duration: 7 days. Dose: 6.3 mg/kg/day
 Severe oliguric renal failure

28
 1970 [31]
 Department of pediatrics
 Colistimethate sodium (IM)
 1
 3 year old
 150 mg q8h (she received 3 injections)
 No renal toxicity
 No neurotoxicity
29
 1970 [32]
 Medical wards (urology department)
 Colistimethate sodium (IM)
 1
 33 year old male with a solitary kidney
 25 mg q6h for 5 days and 250 mg q6h for 1 day
 Increase in serum creatinine levels compared to baseline levels (1.1 mg/dl to 3 mg/dl) Returned to approximately normal values after 6 months
 Muscular weakness, generalized paresthesias, speech disturbances, ptosis, hypotonia, areflexia, ataxia, difficulty in breathing
30
 1971 [47]
 Department of neurology
 Colistimethate sodium (IM)
 1
 70 year old male with myasthenia gravis
 150 mg (one injection)
2 hours after the injection: muscular weakness; 30 minutes later he developed respiratory arrest
31
 1971 [70]
 Department of respiratory diseases
 Polymyxin B (aerosol)
 2
 Case 1: 51 year old female. Case 2: 57 year old male
 Case 1: 15 mg Case 2: 10 mg
Case 1: pruritus, nausea, flashing, dyspnea Case 2: acute respiratory acidosis
32
 1973 [33]
 Medical wards (Hemodialysis Centre)
 Colistimethate sodium (IM)
 2
 Case 1: 16 year old female. Case 2: 23 year old female
 Case 1: 150 mg q6h 1st day, 150 mg q4h 2nd day (20 mg/kg/day) Case 2: 180, 240, 180, 120 mg in divided doses on 1st, 2nd, 3rd, 4th day, respectively
 Both pts developed acute renal failure
 Case 1: neuromuscular blockade that resulted in quadriplegia, apnea, cardiac arrest Case 2: circumoral – acral paresthesias
33
 1974 [71]
 Medical wards
 Colistimethate sodium (IM)
 1
 66 year old male
 6 MIU/day for 60 days
 No renal toxicity
 Total ophthalmoplegia, flaccid paralysis of both upper limbs, reduced speech fluency, difficulty in finding words, apathy
34
 1977 [34]
 Department of pediatrics
 Colistimethate sodium (IM)
 1
 5 year old male
 200,000 IU/kg/day for 8 days
 Acute oliguric renal failure
 Muscular weakness, speech disturbances

a1 mg of colistimethate sodium is approximately equal to 12,500 IU. BUN, blood urea nitrogen; ICU, intensive care unit; IM, intramuscularly; IV, intravenously; MIU, million international units; po, per os; Pt(s), patient(s); ref, reference.

Falagas and Kasiakou Critical Care 2006 10:R27   doi:10.1186/cc3995

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