Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece
Department of Medicine, 'Henry Dunant' Hospital, Athens, Greece
Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
Abstract
Background
The increasing problem of multidrug-resistant Gram-negative bacteria causing severe infections and the shortage of new antibiotics to combat them has led to the re-evaluation of polymyxins. These antibiotics were discovered from different species of
Methods
We reviewed old and recent evidence regarding polymyxin-induced toxicity by searching Pubmed (from 1950 until May 2005).
Results
It was reported in the old literature that the use of polymyxins was associated with considerable toxicity, mainly nephrotoxicity and neurotoxicity, including neuromuscular blockade. However, recent studies showed that the incidence of nephrotoxicity is less common and severe compared to the old studies. In addition, neurotoxic effects of polymyxins are usually mild and resolve after prompt discontinuation of the antibiotics. Furthermore, cases of neuromuscular blockade and apnea have not been reported in the recent literature.
Conclusion
New evidence shows that polymyxins have less toxicity than previously reported. The avoidance of concurrent administration of nephrotoxic and/or neurotoxic drugs, careful dosing, as well as more meticulous management of fluid and electrolyte abnormalities and use of critical care services may be some of the reasons for the discrepancy between data reported in the old and recent literature.
Introduction
Polymyxins were discovered in 1947 from different species of
This class of antibiotics consists of five chemically different compounds, polymyxin A, B, C, D, and E (colistin). Only polymyxins B and E have been used in clinical practice. Colistin consists of a cyclic heptapeptide and a tripeptide side-chain acylated at the amino terminus by a fatty acid. The amino acid components in the molecule of colistin are D-leucine, L-threonine, and L-α-γ-diaminobutyric acid. Polymyxin B has the same structure as colistin but contains D-phenylalanine instead of D-leucine
Commercially, colistin appears as colistin sulfate, which is used orally for bowel decontamination and topically as a powder for skin infections, and as colistimethate sodium, which is used parenterally and by inhalation. Colistimethate sodium has been found to be less toxic and to have fewer undesirable side effects than colistin, but is also less potent. Polymyxin B is available for clinical use as polymyxin B sulfate and is used parenterally, topically (ophthalmic and otic instillation), intrathecally, by inhalation, and as an irrigation solution
Several attempts to generate less toxic derivatives were made
Methods
Data for this review were obtained through literature searches of publications included in PubMed from 1950 until May 2005, references cited in relevant articles, and the world-wide web. The main search terms used in searches of literature databases were 'colistin', 'polymyxin E', 'polymyxin B', 'adverse effects', 'nephrotoxicity', 'colomycin', 'colimycin', 'neurotoxicity' and 'toxicity'. Only English language papers were reviewed.
Results and discussion
In Tables
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
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.
Recent studies (from 1995 to 2005) reporting data on polymyxin-induced toxicity in patients without cystic fibrosis
Year [ref]
Setting
Medication used
Number. of patients
Demographics
Dosage of colistin/duration
Definition of nephrotoxicity
Nephrotoxicity
Neurotoxicity
Other toxicities
1
1995 [57]
Department of dermatology
Colistin sulfate (ointment/topically)
1
45 year old
50,000 IU for 10 days
Edematous eczema
2
1998 [58]
Department of dermatology
Colistimethate sodium (ophthalmic solution)
1
4 year old male with bilateral ocular prosthesis
After 3 weeks he developed itchy erythematous eruptions on both periorbital areas
3
1999 [72]
Neurosurgical wards
Colistimethate sodium (intraventricular)
2
16 year old male and 34 year old female
Case 1: 5 mg (62,500 IU) q12h for 19 days Case 2: 5 mg (62,500 IU) q12h for 5 days then 10 mg (125,000 IU) q12h for 12 days
No adverse reactions
4
1999 [8]
ICU (52%), transplant unit (13%), surgical and medical wards (35%)
Colistimethate sodium (IV)
59 (60 cases)
Mean age: 42.1 years. Mean (± SD) APACHE II: 13.1 (± 7.0)
Mean duration: 12.6 d (2 to 34 d). Mean daily dose: 152.8 mg (approximately 2 MIU) (60–300 mg)
22 pts (37%; 11/41 with normal baseline renal function had worsening during treatment (mean increase in serum creatinine 0.9 ± 0.6 mg/dl) and 11/19 with abnormal baseline renal function had worsening during treatment (mean increase in serum creatinine 1.5 ± 1.4 mg/dl)). Nephrotoxicity did not cause discontinuation
No neuromuscular disorders
5
2000 [73]
Medical wards
Colistimethate sodium (aerosol)
3
67 year old male, 45 year old male, 59 year old male
150 mg (2 MIU) q12h for 13 days, 100 mg (approximately 1.5 MIU) q12h for 14 days, 150 mg (2 MIU) q12h for 11 days
No nephrotoxicity
No hematological toxicity
6
2002 [74]
Neurosurgical wards
Colistimethate sodium (IV)
1
14 year old male
1 MIU q6h for 30 days
No adverse reactions
7
2003 [10]
Abdominal organ transplantation ICU
Colistimethate sodium (IV)
23 (20 had received organ transplantation, 3 abdominal surgery)
Mean age: 52 years
Mean duration: 17 days (7 to 36 days)
Renal failure was defined by a requirement either for intermittent hemodialysis or for continuous venous hemofiltration
1/2 pts developed renal failure requiring artificial kidney support (the other 21 pts were already receiving artificial kidney support)
1 pt diffuse muscular weakness (resolved after discontinuation)
8
2003 [11]
ICU
Colistimethate sodium (IV)
24 with sepsis, 26 courses of colistin
Mean age: 44.3 years. Mean APACHE II: 20.6
Mean duration: 13.5 days (4 to 24 days). Dosage: 3 MIU q8h
Renal failure was defined as an increase in serum creatinine >1 mg/dl during treatment
3 pts (14.3%). Only 1 pt required continuous venovenous hemodiafiltration
No clinically apparent neuromuscular transmission blockade
9
2003 [36]
Tertiary care hospital
Polymyxin B (parenterally)
60 receiving polymyxin B
Mean age: 61 years
Mean duration: 13.5 days (1 to 56 days). Mean daily dose: 1.1 MIU
Renal failure was defined as doubling of serum creatinine value of ≥ 2.0 mg/dl
7/50 pts (14%)
10
2003 [74]
ICU
Colistimethate sodium (IV)
35 (21 received colistin (CO group) and 14 imipenem (IM group))
Mean age: CO group 56.9 years, IM group 64.5 years. Mean APACHE II: CO group 19.6, IM group 20.5
CO group: mean duration 14,7 days (10 to 21 days). Dosage: 2.5 to 5 mg/kg/day
In patients with normal renal function (creatinine <1.2), renal failure was defined as creatinine value >2 mg/dl, as a reduction of creatinine clearance of 50% relative to antibiotic initiation, or need for renal replacement therapy. In patients with normal renal function, renal failure was defined as increase of 50% of the baseline creatinine level, as a reduction of creatinine clearance of 50% relative to antibiotic initiation, or need for renal replacement therapy
5/21 pts (24%; CO group), 6/14 pts (42%; IM group)
11
2004 [75]
ICU
Colistimethate sodium (IV)
1
41 year old male
2 MIU/day continuous infusion
No adverse reactions
12
2004 [76]
ICU
Colistimethate sodium (IV)
1
48 year old male
9 MIU/day (2.5 mg/kg/day) for 15 days
No adverse reactions
13
2004 [37]
Tertiary care hospital, ICU (92%)
Polymyxin B (IV)
25 (29 courses: 21 IV, 6 aerosol, 2 combination)
Mean age: 55 years. Mean APACHE II: 21
Loading dose on day 1 with 2.5 to 3 mg/kg IV polymyxin B. Aerosolized: approximately 2.5 mg/kg/day (approximately 1.75 MIU). Mean duration: 19 d (2 to 57 d)
Nephrotoxicity was defined as the doubling of serum creatinine during therapy
3/29 courses (10%)
2/29 courses (7%) onset of seizures and neuromuscular weakness possibly related to polymyxin B
14
2005 [12]
ICU
Colistimethate sodium (IV)
43
Mean age: 56.5 years. APACHE II: 25.8 ± 3.7
3 MIU q8h
Acute renal failure was defined as a rise of ≥ 2 mg/dl in serum creatinine level in patients with previously normal renal function. In patients with a history of renal insufficiency, acute on chronic renal failure was defined as at least doubling of the baseline serum creatinine level (defined as the creatinine level at the initiation of colistin treatment)
8/43 pts (18.6%; 3/35 pts with normal renal function (8.6%) and 5/8 pts with chronic renal failure (62.5%))
No paresthesias, vertigo, muscle weakness, or apnea were observed
15
2005 [77]
ICU (84%), medical (11%), surgical (5%)
Colistimethate sodium (aerosol, IV, IM, intrathecal)
80 (85 courses: 71 aerosol, 12 IV or IM, 2 intrathecal)
Mean age: 57 ± 15 years
Mean duration of aerosol: 12 ± 8 d. Mean duration of IV or IM: 11 ± 6 d. Mean duration of intrathecal: 8 d and 10 d
Nephrotoxicity was defined as a serum creatinine increase of 50% or 1 mg/dl with respect to the baseline level during treatment
12 courses of IV or IM were recorded. Mean ± SD baseline serum creatinine: 1.25 ± 0.79 mg/dl. Mean ± SD final serum creatinine: 1.20 ± 0.64 mg/dl. Mean ± SD baseline BUN: 8.95 ± 8.96 μmol/l. Mean ± SD final BUN: 8.39 ± 8.06 μmol/l
16
2005 [38]
Mainly ICU pts
Colistimethate sodium (IV)
17 (19 courses)
Median age: 51 years. Median APACHE II: 14
Mean ± SD duration: 43.4 ± 14.6 days. Mean ± SD daily dose: 4.4 MIU (352 mg) ± 2.1 MIU (168 mg)
Renal failure was defined as an increase more than 50% of the baseline creatinine level to a value higher than 1.3 mg/dl or as a decline in renal function requiring renal replacement therapy
Median baseline serum creatinine: 0.6 mg/dl. Slight increase of the median of values of creatinine at the end by 0.1 mg/dl. Median baseline BUN: 42 mg/dl. Median final BUN: 41 mg/dl. 1 pt had an increase of more than 50% of the baseline creatinine level to a value higher than 1.3 mg/dl at the end of colistin treatment
No apnea or other evidence of neuromuscular blockade. 1 pt polyneuropathy (improved after the end of colistin treatment)
No hepatobiliary toxicity
17
2005 [35]
ICU (80%), medical and surgical wards (20%)
Colistimethate sodium (IV)
50 (54 episodes)
Mean age: 59.2 years. Mean APACHE II: 16.1
Mean duration: 21.5 days. Mean daily dose: 4.5 MIU
Renal failure was defined as an increase more than 50% of the baseline creatinine level to a value higher than 1.3 mg/dl or as a decline in renal function requiring renal replacement therapy
4/50 pts (8%)
1 pt polyneuropathy (not confirmed) resolved without discontinuation
18
2005 [78]
ICU
Colistimethate sodium (aerosol)
8
Mean age: 59.6 years. Mean APACHE II: 14.6
Dosage (range): 1.5 to 6 MIU/day. Duration (mean): 10.5 days
Worsening of renal function: 1 pt
No neurotoxicity
19
2005 [79]
ICU
Colistimethate sodium (IV)
1
57 year old male
250 mg q6h for 4 days
Acute renal failure (on the 4th day of colistin therapy)
20
2005 [80]
Neurosurgical wards
Colistimethate sodium (intraventricular)
1
23 year old female
125,000 IU q12h for 3 weeks
No adverse reactions
21
2005 [81]
ICU
Colistimethate sodium (IV)
55
Mean age: 40 ± 16 years. Mean APACHE II: 21 ± 7
Duration (mean): 13 ± 5 days
Renal failure was defined as a serum creatinine value of 2 mg/dl or higher, as a reduction in creatinine clearance of 50% compared to therapy initiation, or as a decline in renal function that prompted renal replacement therapy
No adverse reactions. Mean creatinine levels before treatment: 2.3 ± 0.5 mg/dl. Mean creatinine levels after treatment: 2.5 ± 0.6 mg/dl
22
2005 [82]
ICU
Colistin (IV)
1
35 year old male
6 MIU/day for 12 days, 3 days, and 1 day
Acute renal failure occurred at the 2nd and 3rd introduction of colistin. Renal function returned to normal values within 3 and 5 days after colistin withdrawal
23
2005 [83]
ICU
Colistimethate sodium (IV)
14
Mean age: 49 years
Mean dose: 6 MIU/day. Mean duration: 12 days
1 pt experienced deterioration of renal function (serum creatinine up to 2.8 mg/dl)
24
2005 [84]
ICU, medical wards
Colistimethate sodium (aerosol)
21
Mean age: 60.6 ± 15 years. Mean APACHE II: 23.1 ± 9.1
19 pts received 2 MIU/day, 1 pt 3 MIU/day, and another pt 4 MIU/day. Median duration: 14 days
Renal failure was defined as a decrease in the estimated creatinine clearance rate of 50%, compared with the rate at the start of therapy, or a decline in renal function that necessitated renal replacement therapy
No episodes of acute renal failure
No symptoms of neurotoxicity
1 pt experienced bronchospasm that resolved on discontinuation of colistin therapy
BUN, blood urea nitrogen; ICU, intensive care unit; IM, intramuscularly; IV, intravenously; MIU, million international units; Pt(s), patient(s); ref, reference; SD, standard deviation.
Nephrotoxicity
Incidence
Although most of the studies or case reports published until 1983 did not include the definitions of nephrotoxicity, early reported experience with the use of polymyxins, mainly of colistin, revealed a high incidence of nephrotoxicity. The majority of the studies in the older literature referred to intramuscular administration of colistimethate sodium
During the past seven years, colistimethate sodium has been re-introduced to clinical practice for the treatment of multidrug-resistant bacterial infections, mainly in the intensive care unit setting
Mechanisms
It has been suggested that the toxicity of polymyxins may be partly due to their D-amino acid content and fatty acid component. The proposed mechanism by which polymyxin B induces nephrotoxic events is by increasing membrane permeability, resulting in an increased influx of cations, anions, and water, leading to cell swelling and lysis
Clinical manifestations
Renal insufficiency, manifested by an increase in serum creatinine levels and decrease in creatinine clearance, represents a major adverse effect of the use of polymyxins. Occurrence of haematuria, proteinuria, cylindruria, or oliguria may also be associated with the administration of polymyxins. In addition, acute tubular necrosis can also develop
Risk factors
Nephrotoxicity resulting from the use of colistimethate sodium appears to be less compared with that associated with polymyxin B. It is unclear whether there are independent factors that predispose patients to the development of nephrotoxic events. Children seem to experience less polymyxin-induced toxicity, probably in part because prescription of polymyxins, and generally all medications, is based on individual body weight in this patient population
Treatment
When primary signs of renal dysfunction are present, early discontinuation of polymyxins is necessary. Quick diuresis by intravenously administered mannitol has also been proposed to enhance renal clearance of the drug and thus to reduce serum drug levels
Neurotoxicity
Incidence
The incidence of neurotoxicity related to the use of polymyxins reported in the old literature was considerably less compared to nephrotoxicity. Specifically, the most frequently experienced neurological adverse effects were paresthesias that occurred in approximately 27% and 7.3% of patients receiving intravenous and intramuscular colistimethate sodium, respectively
Mechanisms
The interaction of polymyxins with neurons, which have a high lipid content, has been associated with the occurrence of several neurotoxic events. In addition, the probability of development of neurotoxicity has been directly associated with the concentration of the active form of polymyxins in the blood
Clinical manifestations
The reported neurological toxicity is associated with dizziness, generalized or not muscle weakness, facial and peripheral paresthesia, partial deafness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and neuromuscular blockade. The last of these usually produces a myasthenia-like clinical syndrome, as well as respiratory failure or apnea due to respiratory muscle paralysis
Risk factors
Risk factors that may potentially trigger the development of neurotoxicity include hypoxia and the co-administration of polymyxins with muscle-relaxants, narcotics, sedatives, anesthetic drugs, or corticosteroids
Treatment
Mild neurological manifestations of polymyxins usually subside after prompt cessation of the drugs. In the presence of neuromuscular blockade, immediate discontinuation of polymyxins and other neurotoxic agents is also the first-line approach. Further management consists of mechanical respiratory support if apnea has been developed. The intravenous administration of calcium and cholinesterase inhibitors, such as neostigmine and edrophonium, has led to conflicting results
Other adverse events
Incidence
In studies published in the old literature, the reported incidence of allergic reactions related to colistimethate sodium use was approximately 2%
Mechanisms
Several milder adverse reactions, including pruritus, dermatitis, and drug fever, probably represent the result of the irritative effects of the active forms of polymyxins
Clinical manifestations
Pruritus, contact dermatitis, macular rash or urticaria, ototoxicity, drug fever, and gastrointestinal disturbances may develop, although rarely, during treatment with polymyxins
An old case report suggested that the administration of colistimethate sodium intramuscularly in a patient with Gram-negative rod bacteremia was possibly associated with hepatotoxicity because an observed rise in serum glutamic oxaloacetic transaminase levels returned to normal after the drug was discontinued; in addition, post-mortem histological examination of the liver revealed non-specific changes (focal vacuolization of hepatic cells in the centrilobular fields with areas of focal necrosis), which were interpreted as drug-induced toxicity
Risk factors
Patients with known allergy to bacitracin are also at higher risk of developing hypersensitivity reactions with the use of polymyxins, as cross-reaction between bacitracin and polymyxins exists
Treatment
In most instances, withdrawal of polymyxins in combination with appropriate supportive treatment is adequate for the treatment of such adverse effects.
Adverse events related to aerosolised colistin
Treatment with aerosolized colistin may be complicated by sore throat, cough, bronchoconstriction, and chest tightness. The nature of bronchoconstriction that develops during nebulization of polymyxins has been proposed to be associated with several mechanisms. Among them are direct chemical stimulation, the liberation of histamine, allergy in the airway, irritation from chemicals or from the foam that is produced during nebulization, and hyperosmolarity in the airway
Prevention of adverse events
Early and correct adjustment of the dose of polymyxins in the presence of impaired renal function, frequent urinalyses and serum urea or creatinine measurements, close daily monitoring of urinary output and of neurological status, and the avoidance of concurrent administration of other agents with known nephrotoxicity or neurotoxicity may help prevent the development of adverse effects. Bronchoconstriction usually responds to treatment with bronchodilators; thus, pre-treatment of patients receiving inhaled colistimethate sodium with these medications could prevent the occurrence of this adverse event
Recommendations regarding the dosage of polymyxins differ between various manufacturers. Colistin manufactured in the United States contains colistimethate sodium equivalent to 150 mg colistin base activity in each vial. The recommended dosage is 2.5 to 5 mg/kg per day, divided into 2 to 4 equal doses in adult patients with normal kidney function
The recommended dosage for intravenous polymyxin B sulphate is 1.5 mg to 2.5 mg/kg/day (15,000 IU to 25,000 IU/kg/day), divided into 2 equal doses for adults and children older than 2 years with normal renal function; 1 mg of polymyxin B is equal to 10,000 IU. Infants with normal renal function may receive up to 4 mg/kg/day (40,000 IU/kg/day) in cases of life-threatening infections
Overdoses
Overdoses with polymyxins, mainly with colistimethate sodium, have been reported several times in the old literature. Although, one case of a three year old child who received intramuscularly 450 mg (approximately 5.5 million IU) of colistimethate sodium reported no adverse effects, the majority of cases with polymyxin overdose resulted in acute renal failure and various manifestations of neurotoxicity, including neuromuscular blockade and apnea
Drug interactions
The concurrent use of polymyxins with curariform muscle relaxants and other neurotoxic drugs such as ether, tubocurarine, succinylcholine, gallamine, decamethonium, and sodium citrate must be avoided, since these agents may trigger the development of neuromuscular blockade
Conclusion
The data from the recent literature suggest that the incidence of toxicity resulting from the use of polymyxins is less frequent and severe compared to what has been previously reported. Possible explanations for the observed discrepancy include the fact that the available formulation of colistimethate sodium for intramuscular administration was used intravenously in the old studies until a new formulation was prepared. In addition, the intramuscular formulation also contained dibucaine hydrochloride, which could potentiate the neurotoxic effect of colistimethate sodium. It should be highlighted that the dosages of polymyxins used in most of the studies published in the old literature were considerably higher compared to the recommended dosages administered nowadays. In fact, several reported cases of polymyxin-induced toxicity were associated with overdose. Thus, this may account for the observed difference in the incidence of polymyxin-induced toxicity noted between the old and recently published studies. A major limitation in the interpretation of polymyxin-induced nephrotoxicity and neurotoxicity in the intensive care unit setting, however, is the frequent existence of multiple organ failure, septic shock, and mechanical ventilation support. These conditions may considerably influence the assessment of polymyxin-induced toxicity. Dosage adjustment of polymyxins in the presence of impaired renal function and prompt discontinuation of polymyxins after development of early signs of their toxicity were not always performed in a timely fashion. Furthermore, the already reported experience regarding the toxicity of polymyxins in the old literature has led to more correct use of these antibiotics by physicians nowadays. In addition, the avoidance of co-administration of potential nephrotoxic and/or neurotoxic agents with polymyxins, as well as the development of critical care supplies, may also explain the observed differences. In the coming years further research is needed to assess the safety profile of polymyxins, clarify several aspects of their toxicity, and investigate the benefits of different dosing regimens, including the administration of these antibiotics in fewer daily doses.
Key messages
• Polymyxins are valuable antibiotics for use in patients in the intensive care setting.
• Polymyxins have been recently re-introduced in clinical practice for the treatment of patients with multidrug-resistant Gram-negative bacterial infections.
• Nephrotoxicity and neurotoxicity represent the major adverse effects of polymyxins.
• Data from the recent literature suggest that the use of polymyxins is associated with lower and less severe toxicity compared to that reported in the old literature.
• Caution is needed when polymyxins are administered, particularly in patients with renal dysfunction.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MEF conceived the study idea. Both authors contributed to the reviewing of the articles and writing of the manuscript. Both authors approved the final manuscript. MEF had full access to all the data in the study and takes responsibility for the integrity of the review of the data.