About the Author(s)


Vindana Chibabhai Email symbol
Division of Clinical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Department of Microbiology, National Health Laboratory Service, Johannesburg, South Africa

Adrie Bekker symbol
Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Marianne Black symbol
Division of Clinical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Department of Microbiology, Lancet Laboratories, Johannesburg, South Africa

Despina Demopoulos symbol
Department of Paediatrics, Donald Gordon Medical Centre, Johannesburg, South Africa

Angela Dramowski symbol
Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Nicolette M. du Plessis symbol
Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

Veshni Pillay-Fuentes Lorente symbol
Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Trusha Nana symbol
Division of Clinical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Department of Microbiology, Lancet Laboratories, Johannesburg, South Africa

Helena Rabie symbol
Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Gary Reubenson symbol
Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Reenu Thomas symbol
Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Department of Paediatrics and Child Health, Christ Hani Baragwanath Academic Hospital, Johannesburg, South Africa

Citation


Chibabhai V, Bekker A, Black M, et al. Appropriate use of colistin in neonates, infants and children: Interim guidance. S Afr J Infect Dis. 2023;38(1), a555. https://doi.org/10.4102/sajid.v38i1.555

Note: Additional supporting information may be found in the online version of this article as Online Appendix 1.

Guideline

Appropriate use of colistin in neonates, infants and children: Interim guidance

Vindana Chibabhai, Adrie Bekker, Marianne Black, Despina Demopoulos, Angela Dramowski, Nicolette M. du Plessis, Veshni Pillay-Fuentes Lorente, Trusha Nana, Helena Rabie, Gary Reubenson, Reenu Thomas

Received: 19 July 2023; Accepted: 24 Oct. 2023; Published: 19 Dec. 2023

Copyright: © 2023. The Author(s). Licensee: AOSIS.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Keywords: paediatrics; neonatology; microbiology; infectious diseases; colistin; polymyxin; carbapenem; extensively drug resistant; multidrug resistant; Gram-negative.

Introduction

This document provides interim recommendations for appropriate colistin use (polymyxin E) to treat bacterial infections in neonates, infants, and children.

Colistin, a polymyxin antibiotic, was first used clinically in the 1950s. Colistin is commercially available in two forms – colistin sulphate (oral or topical powder) and colistimethate sodium (CMS) (parenteral formulation).1 Colistin acts upon the Gram-negative bacterial outer cell membrane by disrupting magnesium and calcium ions. The disturbance increases cell permeability, resulting in leakage of cell contents, and ultimately cell death.1,2 Colistin resistance can be intrinsic or acquired. Gram-negative bacteria with intrinsic resistance to colistin include Serratia marcescens, Proteus spp., Morganella spp., Providencia stuartii, and Burkholderia cepacia complex.3 Acquired resistance can be chromosomal or plasmid-mediated.

In South Africa, colistin is commonly available as vials containing 1-million international unit (IU) of CMS powdered for reconstitution. Colistimethate sodium is a prodrug, which is converted in the plasma to active colistin. Each 1-m-unit of CMS vial contains approximately 34 mg colistin base activity (CBA), or 80 mg CMS. Package insert should always be consulted for quantitative vial composition.

Antimicrobial resistance (AMR) is a global public health and One-Health problem, and is considered to the next great global challenge.4 By 2050, an estimated 10m deaths per year will be attributable to AMR.5 More recently, infections with AMR pathogens caused around 1.2m deaths globally and was associated with 4.95m deaths globally in 2019.6

The most concerning pathogens are those listed by the World Health Organization (WHO) as priority pathogens. Among these, those categorised as critical pathogens are all Gram-negative bacteria. The latter include extended spectrum β-lactamase producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii.7 Research and development (R&D) of new antimicrobial agents for these pathogens is critical.

Although all age groups are at risk of AMR infections, children under the age of 5 are particularly vulnerable, with 1 in 5 deaths attributable to AMR occurring in this age group. Children living in sub-Saharan Africa are particularly affected by AMR pathogens compounded by a lack of access to effective antimicrobials.6

The emergence of extensively drug resistant (XDR) pathogens (an isolate that is non-susceptible to at least one agent in all but two or fewer antimicrobial categories) has resulted in renewed use of colistin.1,8 Several guidelines address optimal use of colistin in adults, but these do not adequately address using colistin in neonates and children.2,9 This document aims to provide practical guidance to clinicians for appropriate use of colistin in neonates, infants, and children. Table 1 presents a summary of the recommendations.

TABLE 1: A summary of recommendations.

Methods

A panel of clinical microbiologists, paediatric infectious diseases specialists, neonatologists and clinical pharmacologists was convened, representing the National Health Laboratory Service (NHLS), the South African Paediatric Association (SAPA), the United South African Neonatal Association (USANA), the Federation of Infectious Diseases Societies of Southern Africa (FIDSSA), and the South African Society of Paediatric Infectious Diseases (SASPID) to develop consensus guidance and interim recommendations for colistin use in neonates, infants, and children.

Through teleconference meetings, important concepts related to colistin use in neonates, infants and children were discussed. These topics were then assigned to panel members. Follow up meetings were held where existing evidence of colistin use in neonates, infants, and children was presented. The literature review consisted of studies published before end December 2021. Only studies published in English were included.

Thereafter, the panel generated and agreed upon a list of questions, which the guidance document aimed to answer. Panel members were divided into groups to address each clinical question. Each panel member reviewed and evaluated the literature and proposed recommendations with a brief summary of evidence.

The draft recommendations were then reviewed by the full panel. Divergences among panellists’ views were resolved through internal discussion. The finalised draft was reviewed by the USANA, the SAPA and the FIDSSA for endorsement.

Because of the scarcity of published literature in this patient population, grading of evidence, although difficult, was included.

Strength of recommendations:

  • Strong: high level of confidence that there are strong benefits from this recommendation.
  • Moderate: relative confidence for this recommendation.
  • Weak: little confidence in the beneficial effects of this recommendation.

Quality of evidence:

  • High: includes randomised controlled trials, systematic reviews, and meta-analyses.
  • Moderate: non-randomised trials, cohort studies, case-control studies or diagnostic accuracy studies.
  • Low: evidence based on clinical experience or expert opinion.

Definitions

Definitions of severe sepsis and septic shock are included here, but the reader is recommended to refer to the Surviving Sepsis Guidelines for detailed definitions.10

Invasive infections: although this is not a comprehensive list, examples include bacteraemia, meningitis, necrotising enterocolitis (NEC)/intra-abdominal infection, bacteraemic pneumonia, bone and joint infections.

Non-severe infections: include urinary tract infection (UTI), superficial skin or soft tissue infection.

Severe sepsis:

  • ≥ 2 age-based systemic inflammatory response syndrome (SIRS) criteria
  • Confirmed or suspected invasive infection
  • Cardiovascular dysfunction, acute respiratory distress syndrome (ARDS), or ≥ 2 non-cardiovascular organ system dysfunctions.10

Septic shock: the subset of severe sepsis patients with cardiovascular dysfunction, which includes hypotension, treatment with a vasoactive medication, or impaired perfusion.10

Critically ill: a patient with a severe airway, breathing or circulatory problem, or acute deterioration of conscious state.11

Recommendations

What are clinical and microbiological indications for colistin use?
Directed/targeted colistin therapy

Colistin is not active against any Gram-positive or anaerobic bacteria. It is primarily used for invasive infections caused by XDR infections, particularly Acinetobacter spp., Pseudomonas spp., Stenotrophomonas spp., Klebsiella spp., and other Enterobacterales. These are typically hospital-acquired infections.

It is also not active against some Gram-negative bacteria for example S. marcescens, Proteus spp., Morganella spp., P. stuartii and B. cepacia complex.

In general, colistin should be initiated based on confirmed or presumptive identification of an invasive XDR Gram-negative infection where no other suitable agent is available. Where possible, treatment with colistin should be in consultation with neonatologist and/or infectious diseases subspecialist. Presumptive identification refers to scenarios where the precise identification and antimicrobial susceptibility profile of an invasive isolate is underway and the patient is in a unit where carbapenem-resistant Gram-negative pathogens are prevalent.

Colistin should not be used for non-invasive or superficial infections or to treat colonisation. Clinical signs and symptoms accompanied by identification of an XDR Gram-negative pathogen from a normally sterile site (e.g. blood, cerebrospinal fluid, synovial fluid, serosal fluid) is sufficient justification for colistin treatment. Conversely, identification of such a pathogen from other, not normally sterile sites (e.g. tracheal aspirate, sputum, skin swab, stool) generally should not prompt colistin treatment unless there is compelling clinical, radiological or laboratory evidence suggesting invasive disease – such cases should be discussed with a clinical microbiologist, neonatologist and/or infectious diseases subspecialist before colistin is initiated.

Empiric colistin therapy

See the following recommendations regarding empiric use of colistin

What is the recommended method for testing and reporting colistin minimum inhibitory concentration results?
Recommendation

Broth microdilution is the only reliable method for determining colistin MICs according to European Committee on Antimicrobial Susceptibility Testing (EUCAST).12,13 The Clinical and Laboratory Standards Institute (CLSI) includes broth disk elution and agar dilution on their list of approved methods. This requires specialised equipment and expertise, and laboratories unable to perform MICs using this method, should refer isolates to laboratories with capacity to perform such testing. Disk diffusion and gradient diffusion methods should not be performed, as these are unreliable methods for colistin MIC determination. Broth microdilution is the only approved method for polymyxin B.

When the colistin MIC is ≥ 2 mg/L (for the Enterobacterales and A. baumannii), or ≥ 4 mg/L for P. aeruginosa, an alternative agent should be considered, as bactericidal levels are unlikely to be achieved for organisms with MICs in excess of these cut-offs. Consultation with a clinical microbiologist or infectious diseases specialist is advised to assist with appropriate interpretation of colistin MICs dependent on which antimicrobial susceptibility testing committee guideline (EUCAST or CLSI) is followed by the local laboratory.

A summary of evidence

The CLSI and EUCAST are the two organisations that provide susceptibility breakpoints for colistin.

Challenges in the setting of breakpoints for colistin include: (1) difficulties in providing a reproducible MIC below 2 mg/L because of challenges in the test system; (2) in vivo levels of 2 mg/L required for bactericidal action, which is very difficult to obtain in patients with normal renal function; (3) MIC distribution data indicates that 2 mg/L is the most reliable cut-off point to separate wild type isolates from those with resistance mechanisms for the Enterobacterales and A. baumannii, but higher (4 μg/L) for P. aeruginosa.14

The current (2022) CLSI guidelines have set colistin breakpoints for Enterobacterales, P. aeruginosa, and Acinetobacter spp at ≤ 2 mg/L (intermediately susceptible) and ≥ 4 mg/L (resistant), with no susceptible category (Table 2).12 The CLSI definition of the intermediate category implies uncertainty related to susceptibility testing, clinical outcome, dosing, and administration.

TABLE 2: Colistin breakpoints in mg/L as per Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing.

In contrast, EUCAST has maintained the susceptibility category, for A. baumannii and the Enterobacterales at ≤ 2 mg/L, and resistant if > 2 mg /L. Pseudomonas aeruginosa has slightly higher breakpoints (susceptible if ≤ 4 mg/L and resistant if > 4 mg/L) (Table 2).13

European Committee on Antimicrobial Susceptibility Testing introduced brackets for the colistin breakpoint. This is to warn against using colistin without additional therapeutic measures. Breakpoints in brackets represent the epidemiological cut-off value (ECOFF), which distinguishes isolates with and without acquired resistance mechanisms.13

What is the recommended colistin PK/PD target for efficacy?
Recommendation

Area under the concentration time curve (AUC)/minimum inhibitory concentration (MIC) (fAUC/MIC) is the recommended PK/PD parameter for colistin efficacy.

A summary of evidence

An AUC0–24 of 50 mg.h/L is considered acceptable to achieve adequate efficacy in the presence of isolates with a MIC of ≤ 2 mg/L.2 Efficacy data are lacking for the paediatric population but extrapolation from adult data suggests that a steady state concentration (Css) of 2 mg/L equates to an AUC0–24 of 50 mg.h/L.2 However, adult and paediatric pharmacokinetic studies have shown extensive interpatient variability in Css.15,16,17

Is an intravenous loading dose required when initiating therapy with colistin in neonates, infants and children? What loading dose and maintenance dose should be recommended in patients with normal renal function?
Recommendation

All neonates, infants and children requiring colistin should receive a colistin loading dose of 4 mg – 5 mg CBA/kg body weight (equivalent dose in million units MU is 118 000 IU/kg – 150 150 IU/kg), which should precede maintenance doses of colistin 2.5 mg CBA/kg/dose 12 hourly in children > 2 years (equivalent dose in MU is 74 000 IU/kg). We recommend the same maintenance dosing strategy in children < 2 years until further data are available.

A summary of evidence

Colistin loading doses in adult patients are recommended and well established.2 A colistin loading dose prevents exposure to sub-therapeutic concentrations for a prolonged period during initial treatment, as colistin concentrations rise slowly after administration.2

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) currently suggests no paediatric loading dose with a maintenance colistin dose of 2.5 mg to 5 mg CBA/kg per day.18,19 The reason for no loading dose is mainly because of a lack of robust PK and safety data in the paediatric population. Recent PK studies in children and neonates have however shown that the FDA- and EMA-recommended colistin doses are insufficient for optimal efficacy according to recommended Pharmacokinetics (PK), pharmacodynamics (PD) parameters.15,20,21 To our knowledge, there is only report on the pharmacokinetics of colistin in neonates.20 This was a prospective, open label study, performed in neonates (5–15 days of life) receiving colistin within a neonatal intensive care unit.20 Further elaboration on loading dose is available in the supplementary document.

In addition, paediatric colistin studies reported reversible nephrotoxicity in 3% – 10% of patients,17 but the impact of immature neonatal metabolic and renal function on the metabolism and elimination of colistin has not been assessed.

Based on evidence that the standard 5 mg CBA/kg per day colistin doses without loading doses produce suboptimal exposures,22,23 and given the emerging paediatric and neonatal PK data of colistin showing benefits of a colistin loading dose and likely subtherapeutic concentrations with the suggested maintenance dose, we recommend a colistin loading dose of 4 mg – 5 mg CBA/kg body weight, followed by 2.5 mg CBA/kg twice daily maintenance dose in neonates, children, and infants. This should be performed with close monitoring of renal function (see ‘How should adverse effects be monitored and how often’).

It is important to observe that therapeutic drug monitoring to guide colistin dosing is not available in South African at the time of publication.

What maintenance dose is recommended in patients with impaired renal function and in those receiving renal replacement therapy?
Recommendation

Data on colistin pharmacokinetics in the paediatric population with renal impairment are lacking. Conclusive recommendations on dosage and/or dose interval in patients with renal impairment cannot be established. Where alternative treatment options are available, colistin should be avoided. Where no alternative is available, individual cases should be discussed with a clinical pharmacologist, microbiologist or paediatrician to assist with dose adjustment.

A summary of evidence

Overall, fewer paediatric patients experience colistin-associated acute kidney injury than adults.22 Colistin renal dose adjustments in adults are well established but are lacking for the paediatric population.2,18 Most paediatric studies evaluating the pharmacokinetics of colistin exclude patients with renal impairment.20,23,24 A recent population pharmacokinetic study of colistin explored covariates influencing target attainment in a population with a median age of 2.6 years (interquartile range [IQR] 0.8–6.8 years). Creatinine was a significant covariate and colistin dosing adjustments are proposed in impaired renal function. However, the proposed dosage changes have not been validated.

The pharmacokinetics of colistin in paediatric patients receiving renal replacement therapy (RRT) have not been adequately evaluated. No recommendations can be made concerning colistin dosing in patients receiving RRT. In adult patients, dose adjustments are recommended depending on the type of RRT received.2 In the absence of data, colistin dosing regimens during RRT should be selected through a multidisciplinary team approach, including neonatologists, nephrologists, microbiologists, clinical pharmacologists, infectious disease specialists, and chemical pathologists.

How should colistin therapy be administered?
Recommendation

Colistin may be administered as a slow bolus injection or as a slow infusion over 30 min.

A summary of evidence

The contents of the vial can be reconstituted and administered as a slow bolus injection over 3 to 5 min or as an infusion over 30 min.18,19 The volume chosen for infusion should be determined by patient’s fluid requirements. Table 3 is a CMS conversion table.18 Refer to Online Appendix 1 for a practical, stepwise approach to administering CMS.

TABLE 3: Colistimethate sodium conversion table adopted from electronic medicines compendium.
When treating an infection with colistin, is monotherapy or combination therapy recommended?
Recommendation for carbapenemase producing enterobacterales (CPE)/carbapenem resistant enterobacterales

Combination therapy with a second active antibiotic is recommended in those patients with severe sepsis or septic shock at presentation, bloodstream infection (BSI) with a non-urinary/non-biliary source of infection or severe underlying disease. Factors for consideration when selecting the second active antibiotic (meropenem, tigecycline, aminoglycoside, other) include the site(s) of infection, the antibiotic MICs and patient renal function. High dose prolonged infusion meropenem can be used when the MIC is ≤ 8 mg/L.

For non-severe infections (e.g. uncomplicated UTI) colistin monotherapy can be considered in the absence of other appropriate treatment options.

A summary of evidence

Several factors support combination therapy: in vitro data showing synergy of antibiotic combinations, lower efficacy of colistin monotherapy compared with β-lactam monotherapy, the potential to reduce mortality in severely ill patients, lower risk of resistance development (e.g. against colistin), and shorter treatment duration. However, several facts argue against combination therapy: the possible rise in resistance rates because of an overall increase in selection pressure following greater release of antibiotics into the environment, higher rates of adverse effects (such as nephro- and ototoxicity because of colistin or aminoglycosides), increased Clostridioides difficile-associated infections, fungal infections, higher costs, and possible antagonism.25

Although data supporting combination therapy is sparse, and largely for adults with Klebsiella pneumoniae Carbapenemase (KPC) BSIs, recent meta-analyses concluded that combination therapy reduces mortality and improves clinical outcomes in patients with BSIs because of CPE.25,26

The newer β-lactam-β-lactamase inhibitor combinations are not readily accessible in many countries, resulting in limited treatment options being available for CRE infections. Available treatments include colistin, the aminoglycosides, tigecycline and PK/PD-optimised doses of meropenem. The selection of specific antibiotics must be based on the likelihood of achieving therapeutic drug levels at the site of infection (site of infection, antibiotic MIC and PK/PD parameters) without irreversible or severe adverse effects related to the drug.

Data from observational studies on combination therapy are inconsistent.2 Some observational studies showed benefit of meropenem-based combination therapy for CPE (mainly KPC) when the meropenem MIC is 8 mg/L or lower.27,28 The second agents used in these patients varied and included colistin, tigecycline and aminoglycosides. In contrast, the AIDA and OVERCOME randomised controlled trials (RCTs) did not find a significant survival benefit of colistin-meropenem combination therapy over colistin monotherapy in patients with severe CPE infections.29,30

Other studies show a benefit of combination therapy only with severe sepsis or septic shock at presentation, BSI with non-urinary/non-biliary source of infection, or severe underlying disease.31,32 A systematic review and meta-analysis comparing monotherapy to combination therapy for MDR Gram-negative infections demonstrated reduced mortality in BSIs and in infections caused by CPEs when combination therapy comprising two active antibiotics was used.25 There was no reduction in mortality when combination therapy included only one active antibiotic. Clinical cure rates with mono- and combination therapy were the same. Overall, the quality of studies included in this analysis was low. The improved outcomes observed when colistin is combined with other antibiotics may be because of suboptimal pharmacokinetic properties of colistin.

Based on the available evidence, combination therapy is recommended in patients with CPE infections who have severe sepsis or septic shock at presentation, BSIs with a non-urinary/non-biliary source of infection or severe underlying disease.

Recommendation for extensively drug resistant Acinetobacter baumannii

Combination therapy with a second active antibiotic is recommended for severe sepsis/septic shock. Factors to be considered when selecting the second active antibiotic (meropenem, tigecycline, aminoglycoside etc.) include the site and source of infection, the antibiotic MICs, and patient renal function. Consideration may be given to the use of high dose extended infusion meropenem when the meropenem MIC is ≤ 8 mg/L and an alternate second active antibiotic is not available. Rifampicin is not recommended as a second antibiotic. If a second active agent is not available, colistin monotherapy is recommended. Where other antimicrobial agents with A. baumannii coverage are available (e.g. ampicillin-sulbactam, cefiderocol), these are recommended over colistin monotherapy.

For patients with non-severe infections (e.g. uncomplicated UTI, skin and soft-tissue) colistin monotherapy can be considered in the absence of other appropriate treatment options.

A summary of evidence

The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of ABR and the risk of severe side effects.25

The AIDA RCT compared colistin monotherapy to colistin-meropenem combination therapy in 406 patients, for severe infections (largely pneumonia and bacteraemia caused by A. baumannii), they however, did not find a difference in clinical outcomes.29 A planned sub-analysis of the subset of infections caused by organisms with meropenem MICs ≤ 16 mg/L was not possible because of low numbers. The OVERCOME RCT, which also compared colistin to colistin-meropenem combination therapy for carbapenem-resistant Gram negative pneumonia and BSI found no survival benefit with combination therapy.30 The XDR A. baumannii isolates prevalent currently have high carbapenem MICs (> 8 mg/L) (unpublished data) and the findings of the cited studies do not support the routine use of colistin-carbapenem combination therapy.

Similarly, despite in vitro studies demonstrating synergy when colistin is combined with rifampicin for A. baumannii, current clinical data do not support the use of colistin-rifampicin combination therapy.33,34

The XDR A. baumannii isolates prevalent in the South African public health sector currently have high carbapenem MICs (> 8 mg/L). The lowest concentration of meropenem and imipenem inhibiting 50% and 90% (MIC50 and MIC90 of 2019 paediatric bloodstream A. baumannii isolates for Gauteng, KwaZulu-Natal, Free State, and Western Cape provinces are > 8 mg/L (unpublished data courtesy of Prof Olga Perovic, Antimicrobial Resistance Laboratory, National Institute for Communicable Diseases [NICD]).

The evidence supporting combination therapy for A. baumannii is of low quality. However, the pharmacokinetic properties of colistin result in suboptimal drug levels at some infection sites when administered intravenously. This, together with its narrow therapeutic window, can result in limited clinical efficacy for many infections.2 In addition, delays in appropriate therapy (because of the MDR phenotype) may result in high bacterial burdens. Hence, combination therapy with a second active antibiotic is recommended in those patients with severe sepsis/septic shock. If a second active agent is not available, colistin monotherapy is recommended. For patients with non-severe infections (e.g. uncomplicated UTI) colistin monotherapy can be considered in the absence of other appropriate treatment options.

Recommendation for extensively drug resistant Pseudomonas aeruginosa

Combination therapy with a second active antibiotic is recommended for severe sepsis or septic shock at presentation, BSI with a non-urinary/non-biliary source of infection or severe underlying disease.

For patients with non-severe infections (e.g. uncomplicated UTI), colistin monotherapy can be considered in the absence of other appropriate treatment options.

A summary of evidence

There is little data available limiting a robust recommendation. In the small number of carbapenem-resistant P. aeruginosa cases included in the AIDA and OVERCOME RCTs, no survival benefit was demonstrated for colistin–carbapenem combination therapy over colistin monotherapy.29,30 Available data are mainly small retrospective studies that used a variety of active and non-active second antibiotic agents, and it is not possible to make conclusions about the value of colistin-combination therapy.

It is suggested that combination therapy is used in those patients with severe sepsis/septic shock and colistin monotherapy is used for non-severe infections.

When is empiric treatment with colistin indicated?
Recommendation

In authors’ view, empiric colistin therapy can be considered in critically ill patients in centres where invasive infections caused by carbapenem-resistant Gram-negative pathogens are prevalent. However, empiric colistin should be stopped as soon as possible e.g. alternative antibiotic active against isolate, clinical improvement, exclusion of invasive infection, non-infectious cause for illness identified.

For most patients, empiric colistin use is strongly discouraged. It is recommended that empiric use of colistin be approved through the hospital AMS committee on a case-by-cas e basis.

When empiric colistin treatment is being considered, it should only be initiated following consultation with a clinical microbiologist, neonatologist or infectious diseases specialist as there are frequently better alternatives available. Strict guidelines must be in place to guide the empiric use of colistin to prevent overuse of this last resort antibiotic and risk of colistin resistance (see AMS recommendations).

It is controversial as to whether colistin should ever be prescribed empirically that is without confirmed or presumptive infection with a carbapenem-resistant Gram-negative pathogen.

The possible harms related to delayed initiation of potentially life-saving treatment must be weighed up against the benefits of preserving activity for this ‘last-line’ agent against highly-resistant bacteria. Table 4 outlines a step-by-step guide for prescribing colistin empirically.

TABLE 4: Step-by-step guide for empiric colistin use.
A summary of evidence

Infections with XDR Gram-negative organisms are associated with increased mortality. One possible explanation for the increased mortality seen is the likely delay in starting treatment with an appropriate empiric antimicrobial, as none of these organisms would be susceptible to the standard empiric treatment regimens used. Inappropriate empiric antibiotic therapy and delays in starting appropriate antimicrobial therapy are associated with increased mortality.35,36,37 A recent study looking at starting empiric colistin/imipenem in patients with severe sepsis showed a significant reduction in vasopressor requirement and faster improvement in inflammatory markers when treatment was appropriate.38 The choice of empiric antimicrobial therapy should be based on the local epidemiology of isolated pathogens as well as culture–site specific local antibiograms (e.g., blood culture specific antibiograms). Empiric use of colistin in units with a high burden of XDR Gram-negative bacteria (> 15% XDR) may be considered, but could lead to the overuse of this last resort antibiotic and increase the risk of colistin resistance. Therefore, strict guidelines must be in place to guide the empiric use of colistin for suspected invasive infection with XDR Gram-negative bacteria. Access to facility level data in the South African public sector is available on the NICD dashboard.39

Should inhaled colistin be used to treat hospital-acquired pneumonia/ventilator-associated pneumonia?
Recommendation

Inhaled colistin in ventilator-associated pneumonia (VAP) because of colistin-only susceptible Gram-negative bacteria in critically ill children is not routinely recommended.

However, inhaled colistin, in addition to systemic colistin, may be considered in VAP because of colistin-only susceptible Gram-negative bacteria for treatment failure by systemic colistin alone and with the availability of small particle nebulisers.

Although inhaled colistin may be a beneficial adjunct to IV colistin by leading to shorter time to bacterial eradication, significant differences in the clinical and microbiological outcomes of children with VAP have not been demonstrated.

When considering adding inhaled colistin to systemic colistin, prior consultation with a paediatric infectious disease specialist/microbiologist is recommended.

Practical considerations
  • Ensure optimal dosing of systemic colistin before adding inhaled colistin.
  • The ideal nebuliser should be able to deliver colistin particles of < 3 μm diameter.
  • Administer immediately after dissolving in 4 mL sterile isotonic saline solution over 15 min at a dose of 4 mg CBA/kg 12 hourly (120 000 IU/kg 12 hourly).
  • Monitor for respiratory side effects, for example, bronchospasm.
A summary of evidence

The hydrophilic structure of colistin limits its penetration into lung parenchyma.41 Nebulised colistin potentially achieves higher concentrations in the airways with less systemic toxicity, compared with intravenous (IV) colistin.42,43 To reach the lung parenchyma, the particle size, expressed as mass median aerodynamic diameter (MMAD), should be about 3 μm.44 Most nebulisers are designed to effectively deliver drug to the airways, not the lung parenchyma, and create aerosols of 5 μm MMAD.44 Nebulisers able to provide sufficiently small particles (< 3 μm) to reach the lung parenchyma include jet, ultrasonic, and vibrating-mesh nebulisers.45 In addition, the absorption rate will depend on many factors including the location of deposition (central versus peripheral) as well as the volume and mechanical properties of airway secretions.43

Although inhaled colistin is widely used for cystic fibrosis (CF), the pharmacodynamics might be different in a patient without chronic lung disease.46,47 The bacteria in patients with CF are mainly found in the mucus rather than on the epithelial surface.43

The evidence for inhaled colistin in adults with VAP because of multidrug resistant (MDR) Gram-negative organisms is of low quality.48 Expert opinion from professional societies, such as the Infectious Disease Society of America (IDSA) and the European Society for Clinical Microbiology (ESCMID) are conflicting.49 The evidence for inhaled colistin in the paediatric population is limited to small retrospective studies, with no respiratory complications reported: most infants received inhaled colistin in addition to active systemic antibiotics.50,51 Monotherapy with inhaled colistin (without systemically administered antibiotics) was successful in 17 neonates.52,53 A matched case control study found that infants treated with nebulised colistin plus systemic colistin, had better outcomes than infants treated with systemic colistin alone.54 The addition of inhaled colistin to IV colistin led to a shorter time to bacterial eradication in critically ill children with VAP because of colistin-only susceptible GNB. However, it did not lead to a significant difference in the clinical and microbiological outcomes of VAP.55

A PK/PD study suggested that a dose of 4 mg CBA/kg (120 000 IU/kg) attained high colistin levels in tracheal aspirate from neonates for 12 h.56

Adverse effects associated with inhaled colistin are bronchospasm and nephrotoxicity. High concentrations may cause damage to the airways. Nebulised steroids and β-2-agonists can be used to prevent and treat bronchospasm.44

Should intraventricular/intrathecal colistin be used to treat meningitis?
Recommendation

The use of intraventricular/intrathecal colistin in combination with IV colistin can be considered in patients with suitable indwelling devices and clinical/microbiological indications for colistin therapy (See above recommendations for indications). In addition, for patients without a suitable indwelling device but persistent CNS infection despite maximum recommended IV colistin dosing, neurosurgery and microbiology/infectious diseases consultation is recommended prior to initiating intraventricular/intrathecal colistin. Proposed dosing of intrathecal/intraventricular colistin is detailed in Table 5.

TABLE 5: Suggested/proposed colistin intrathecal/intraventricular dose.
Summary of evidence

Colistin does not cross the blood-CSF barrier well.57 Intrathecal (through the lumbar thecal sac) or intraventricular (lateral ventricle) dosing of colistin bypasses this barrier and can achieves much higher CSF colistin levels than with IV dosing.

Intrathecal and intraventricular colistin administration has not been well studied.58 Available low quality evidence suggests possible limited benefit and no concerns of long-term/irreversible harm.57,58.59,60,61,62 We therefore, recommend consideration in patients with suitable indwelling devices, such as lumbar or external ventricular catheters/drains. For patients without a suitable indwelling device but persistent CNS infection despite maximum recommended IV colistin dosing, neurosurgery and microbiology/infectious diseases consultation is strongly recommended prior to initiating intraventricular/intrathecal colistin.

Ventricular volume and CSF drainage rates must be considered when selecting a dosing regimen.63 The CSF volume in neonates is small (approximately 5 mL) compared with that in older infants (50 mL) and adults (125 mL – 150 mL).56 Doses of 4 mg CBA/day (120 000 IU/day) in adult patients yields CSF through concentrations above 2 mg/L.23,64 The IDSA suggests that for infants, adult intraventricular antimicrobial doses should be reduced by 60% or more. A retrospective review of colistin use for MDR Gram-negative infections in a Pakistan neonatal unit, briefly described the management of 15 cases of meningitis. Seven neonates received intraventricular colistin, five of whom also received IV colistin. The five neonates who received both intraventricular and IV colistin, and one of two who received only intraventricular therapy, survived. None of the eight neonates who received only IV colistin survived. The basis for the dose selection in this unit was not provided.61

Individualised dosing based on predicted ventricular volume and CSF drainage is recommended. Multidisciplinary (neurosurgery, microbiology, infectious diseases, paediatrics and clinical pharmacology) consultation is recommended for dose selection.

If administering intrathecal or intraventricular colistin, a single daily dose is recommended.

How should patients receiving colistin be monitored for adverse events and how frequently?
Recommendation: Nephrotoxicity and electrolytes
  • Close monitoring of renal function, sodium, potassium and magnesium, with dosage adjustments when necessary (See Online Appendix 1).
  • Maintain adequate hydration.
  • Limit co-administration of other nephrotoxic drugs.

Definitions of acute kidney injury are detailed in Online Appendix 1. The ICU patients requiring organ support require more frequent monitoring but if not requiring organ support, monitoring every 72 h is sufficient. Ideally, monitoring should be clinician directed. Collect a specimen for baseline renal function prior to colistin initiation, but do not delay initiating colistin loading dose while awaiting results.

A summary of evidence

Adverse effects because of colistin have been reported since the early 1960s, mostly from adult studies, with rates as high as 50%.65 Reported adverse effects included nephrotoxicity and less commonly, neurotoxicity.

Data on colistin safety in the neonatal/paediatric population is limited and mostly restricted to retrospective reviews, with recent reported rates of nephrotoxicity ranging from 0% to 24%. These rates have reduced compared with older reports, attributed to improved fluid and electrolyte management in intensive care units, as well as better monitoring of renal function and reduced concomitant use of other nephrotoxic agents. The suggested mechanism of nephrotoxicity is increased membrane permeability, causing tubulopathy, influx of electrolytes and water, leading to cell oedema and lysis.65 Definitions used for nephrotoxicity are not standardised and include an increase in serum creatinine > 50% above baseline, a decrease in urine output below 50% of baseline or < 1 mL/kg/h, or an increase in serum creatinine of > 0.5 mg/dL (44 μmol/L).66,67,68 A case series reported a 19% renal toxicity rate in neonates receiving colistin.69 Another retrospective study in 104 children reported nephrotoxicity in 10.5% of patients receiving colistin.66 These children, however, were also receiving other concomitant nephrotoxic drugs and none on colistin alone developed nephrotoxicity. Another study reported nephrotoxicity in 2 of the 18 neonates treated with colistin.67 In other retrospective studies in neonates, including preterm neonates, colistin was well tolerated, with no reported cases of renal impairment.70 Electrolyte imbalances, particularly hypomagnesemia, hyponatremia and hypokalemia, are reported in those on colistin. In a retrospective study 12 neonates on IV colistin, 2 had significant hyponatremia and hypokalemia. In this study magnesium replacement was required at least once for all patients.71 Another case-control study that compared 47 neonates who were given colistin with 59 neonates treated with other antimicrobial agents concluded that colistin use was significantly associated with hypokalemia and hypomagnesemia.72

Measures used to prevent or limit nephrotoxicity include strict monitoring of renal function with dosage adjustments when necessary, proper hydration and limiting co-administration of other nephrotoxic drugs.9

Recommendations: Neurotoxicity
  • Daily clinical monitoring for neurotoxicity is recommended.
  • Inspection for cumulative neurotoxicity by concomitant medication which also cause neurotoxic side effects by reviewing medication chart daily.
A summary of evidence

Neurotoxicity is the second most common adverse effect reported with polymyxins.73 Manifestations of neurotoxicity include dizziness, generalised weakness, muscle weakness, facial and peripheral paraesthesia, partial deafness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, neuromuscular blockade and apnoea.65 Neurotoxicity usually develops in the first 4 days of treatment.74 In a neonatal study, neurotoxicity was not an obvious problem. However, the authors observe that sedation and mechanical ventilation may have affected these findings.20 In a systematic review of polymyxin toxicity, neurotoxicity was reported more frequently in older literature than more recently, but still old, published literature (until 2005).65 Neurotoxicity was reported more frequently after a loading dose was compared in a single study, but this finding was not statistically significant.65 Concomitant administration of colistin with curariform muscle relaxants and other neurotoxic agents must be avoided because these combinations may trigger progression to neuromuscular blockade.65 Where possible, concomitant use should be avoided. Where unavoidable, close daily monitoring by physical examination is necessary and daily review of the prescriptions necessary to determine the need for concomitant use. Of note, however, detecting of neurotoxic symptoms in neonates is challenging.

What is the recommended duration of colistin therapy?
Recommendation

Treatment duration is dependent on site of infection, its severity, source control attainment, and PK/PD. Duration of treatment may differ according to indication. To prevent development of resistance to colistin, duration of therapy should be as short as possible, and guided by clinical and biomarker responses. Duration of therapy should be discussed with infectious diseases specialist/microbiologist:

  • Meningitis: Gram-negative meningitis typically treated for 21 days.
  • VAP: typically treated for 5–7 days.
  • UTI: typically, 3–5 days.
  • Bacteraemia: typically treated for 7 days. Consult microbiologist/neonatologist/infectious diseases specialist if inadequate clinical response, and considering prolongation of colistin therapy.
  • Intra-abdominal infection/NEC: 4–8 days.
A summary of evidence

The optimal duration of antibiotic therapy depends on many factors. The integration of signs of resolution, biomarkers, clinical judgement, and microbiologic eradication might help to define this optimal duration in patients with life-threatening infections caused by XDR Gram-negative bacteria. It is important to observe that prolonged therapy is not required for infections caused by MDR and XDR pathogens compared with susceptible isolates of the same species.75

Which antimicrobial stewardship tools are recommended while prescribing and administering colistin to patients?
Recommendations
  • Colistin (an antibiotic of last resort) should be reserved to treat suspected or confirmed XDR Gram-negative and/or carbapenem-resistant infections and is listed as a ‘Reserve’ antibiotic in the WHO AWaRe classification76
  • Prescription and administration of colistin for inpatients should be actively managed and tightly regulated through institutional regulation of colistin use by hospital AMS programmes and/or pharmaceutical and therapeutics committees (PTC) using one/more AMS tools.77
  • Antimicrobial stewardship tools for colistin may include requirement for prescription authorisation, Section 21 reporting, implementation of post-prescription dosing and duration review by an AMS team or specialist (microbiologist, infectious diseases specialist, infectious diseases pharmacist).9,77 An AMS ‘bundle’ to control and monitor colistin use should be implemented.78,79
  • At national level, surveillance of colistin consumption and resistance rates should be conducted by the Department of Health and monitored/reported by other stakeholders for example South African Antibiotic Stewardship Programme (SAASP), the NICD and/or the Ministerial Advisory Committee on Antimicrobial Resistance (MAC-AMR).80,81,82
  • At hospital level, surveillance systems should be established to monitor ABR rates among key pathogens causing healthcare-associated infection (Enterobacterales, Acinetobacter spp and Pseudomonas spp. etc.).
The general principles of antimicrobial stewardship, which apply to colistin use are outlined in Table 6
A summary of evidence

The previous South African colistin use guideline (2016) gave recommendations for colistin prescribing and administration in adults and children but did not include AMS for colistin use in humans. Although there is plentiful guidance on AMS implementation in hospital inpatients, few guidelines address colistin stewardship specifically.9,77,80,81,82,83 However, many generic AMS principles remain highly relevant to AMS for colistin as listed in Table 6. Table 7 outlines recommendations for monitoring colistin use according to a ‘colistin bundle’.

TABLE 6: General antimicrobial stewardship principles for colistin use.
TABLE 7: Examples of colistin bundle elements.

South African Health Products Regulatory Authority form completion and application for colistin

Summary

Colistin is not registered by the South African Health Products Regulatory Authority (SAHPRA). For its access a Section 21 application form must be submitted to SAHPRA. The form allows access to unregistered medicines under Section 21 of the Medicines and Related Substances Act, 1965 (Act 101 of 1965) which states:

[T]he Authority may in writing authorize any person to sell during a specified period to any specified person or institution a specified quantity of any particular medicine, medical device or IVD which is not registered.85

The form comprises six subsections: particulars of the applicant, particulars of the person, institution or company importing the unregistered medicine, particulars of the patient, particulars of the unregistered medicine for which a Section 21 application is being made, informed consent form and a progress report. This should be duly completed by the medical personnel responsible for the patient’s management and handed to the relevant pharmacist. This application is then submitted to SAHPRA by the pharmacy departments. (More information concerning the Section 21 application process can be found at https://www.sahpra.org.za/document/2-52-section-21-access-to-unregistered-medicines/).

Acknowledgements

The authors would like to acknowledge Professor Olga Perovic for providing MIC data from the Centre for Healthcare-Associated Infections, Antimicrobial Resistance and Mycoses (CHARM) at the NICD ‘Team Australia’ consisting of Jason Roberts, Nicolette Graham, Roger Nation, Amanda Gwee, Cornelia Landersdorfer, Toni Lai for their efforts in trying to help address the question of renal adjustment of colistin dose.

Competing interests

The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

Authors’ contributions

V.C., A.B., M.B., D.D., A.D., N.M.d.P., V.P.-F.L., T.N., H.R., G.R. and R.T. authors contributed to various sections of the guideline by conducting literature reviews, writing of these sections of the manuscript and review of the completed manuscript. V.C., A.B., M.B., D.D., A.D., N.M.d.P., V.P.-F.L., T.N., H.R., G.R. and R.T. authors were involved in discussion of, and agreement on the recommendations included in the manuscript. V.C. conceived the presented idea.

Funding information

This guideline received no specific grant funding from any funding agency in the public commercial or not-for profit sectors

Data availability

No raw data are available for this guidance document.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors, and the publisher.

References

  1. Falagas ME, Kasiakou SK. Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 2005;40(9):1333–1341. https://doi.org/10.1086/429323
  2. Tsuji BT, Pogue JM, Zavascki AP, et al. International consensus guidelines for the optimal use of the polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10–39. https://doi.org/10.1002/phar.2209
  3. Leclercq R, Cantón R, Brown DFJ, et al. EUCAST expert rules in antimicrobial susceptibility testing. Clin Microbiol Infect. 2013;19(2):141–160. https://doi.org/10.1111/j.1469-0691.2011.03703.x
  4. World Economic Forum. Antibiotic resistance is the next great global challenge – We must act now [homepage on the Internet]. [cited 2018 Aug 14]. Available from: https://www.weforum.org/agenda/2016/09/antimicrobial-resistance-is-the-next-global-commons-issue/
  5. Publications | AMR Review [homepage on the Internet]. [cited 2020 Dec 04]. Available from: https://amr-review.org/Publications.html
  6. Murray CJ, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet. 2022;399(10325):629–655.
  7. World Health Organization (WHO). WHO | Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug resistant bacterial infections, including tuberculosis [homepage on the Internet]. [cited 2021 Jan 19]. Available from: http://www.who.int/medicines/areas/rational_use/prioritization-of-pathogens/en/
  8. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268–281. https://doi.org/10.1111/j.1469-0691.2011.03570.x
  9. Labuschagne Q, Schellack N, Gous A, et al. COLISTIN: Adult and paediatric guideline for South Africa, 2016. S Afr J Infect Dis. 2016;31(1):3–7. https://doi.org/10.4102/sajid.v31i1.95
  10. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc. 2020;21(2):e52–e106.
  11. Paediatric emergency triage, assessment and treatment: Care of critically-ill children [homepage on the Internet]. [cited 2023 Jan 12]. Available from: https://www.who.int/publications-detail-redirect/9789241510219
  12. Clinical & Laboratory Standards Institute. M100Ed32 | Performance standards for antimicrobial susceptibility testing. 32nd ed [homepage on the Internet]. [cited 2022 Feb 02]. Available from: https://clsi.org/standards/products/microbiology/documents/m100-preorder/
  13. EUCAST: Clinical breakpoints and dosing of antibiotics [homepage on the Internet]. [cited 2022 Feb 02]. Available from: https://www.eucast.org/clinical_breakpoints/
  14. Satlin MJ, Lewis JS II, Weinstein MP, et al. Clinical and laboratory standards institute and European Committee on Antimicrobial Susceptibility Testing Position Statements on Polymyxin B and colistin clinical breakpoints. Clin Infect Dis. 2020;71(9):e523–e529. https://doi.org/10.1093/cid/ciaa121
  15. Ooi MH, Ngu SJ, Chor YK, Li J, Landersdorfer CB, Nation RL. Population pharmacokinetics of intravenous colistin in pediatric patients: Implications for the selection of dosage regimens. Clin Infect Dis. 2019;69(11):1962–1968. https://doi.org/10.1093/cid/ciz067
  16. Roberts JA, Hafiz Abdul Aziz M, Lipman J, et al. Challenges and potential solutions-individualised antibiotic dosing at the bedside for critically ill patients: A structured review On behalf of The International Society of Anti-Infective Pharmacology (ISAP) and the PK/PD Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Lancet Infect Dis. 2014;14(6):498–509. https://doi.org/10.1016/S1473-3099(14)70036-2
  17. Antachopoulos C, Iosifidis E. Colistin use in neonates and children with infections Due toof carbapenem-resistant bacteria. Pediatr Infect Dis J. 2017;36(9):905–907. https://doi.org/10.1097/INF.0000000000001655
  18. Pharmaceuticals B. Colistimethate sodium 1 million IU powder for solution for injection [homepage on the Internet]. 2018, pp. 1–10. [cited 2023 Jan 26].Available from: https://wwwmedicinesorguk/emc/product/5648
  19. Monarch Pharmaceuticals Inc. Coly-Mycin® M Parenteral, Pharmaceutical company, Texas; 2006.
  20. Nakwan N, Usaha S, Chokephaibulkit K, Villani P, Regazzi M, Imberti R. Pharmacokinetics of colistin following a single dose of intravenous colistimethate sodium in critically ill neonates. Pediatr Infect Dis J. 2016;35(11):1211–1214. https://doi.org/10.1097/INF.0000000000001263
  21. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009;53(8):3430–3436. https://doi.org/10.1128/AAC.01361-08
  22. Antachopoulos C, Geladari A, Landersdorfer CB, et al. Population pharmacokinetics and outcomes of critically ill pediatric patients treated with intravenous colistin at higher than recommended doses. Antimicrob Agents Chemother. 2021;65(6):e00002–21. https://doi.org/10.1128/AAC.00002-21
  23. Wacharachaisurapol N, Phasomsap C, Sukkummee W, et al. Greater optimisation of pharmacokinetic/pharmacodynamic parameters through a loading dose of intravenous colistin in paediatric patients. Int J Antimicrob Agents. 2020;55(6):105940. https://doi.org/10.1016/j.ijantimicag.2020.105940
  24. Mesini A, Loy A, Gattorno M, et al. Colistin area under the time–concentration in children treated with intravenous loading dose and maintenance therapy. Clin Infect Dis. 2018;66(5):808–809. https://doi.org/10.1093/cid/cix757
  25. Schmid A, Wolfensberger A, Nemeth J, Schreiber PW, Sax H, Kuster SP. Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic review and meta-Analysis. Sci Rep. 2019;9(1):15290. https://doi.org/10.1038/s41598-019-51711-x
  26. Nørgaard SM, Jensen CS, Aalestrup J, Vandenbroucke-Grauls CMJE, De Boer MGJ, Pedersen AB. Choice of therapeutic interventions and outcomes for the treatment of infections caused by multidrug-resistant gram-negative pathogens: A systematic review. Antimicrob Resist Infect Control. 2019;8(1):170. https://doi.org/10.1186/s13756-019-0624-1
  27. Daikos GL, Tsaousi S, Tzouvelekis LS, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: Lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322–1328. https://doi.org/10.1128/AAC.02166-13
  28. Tumbarello M, Trecarichi EM, De Rosa FG, et al. Infections caused by KPC-producing Klebsiella pneumoniae: Differences in therapy and mortality in a multicentre study. J Antimicrob Chemother. 2015;70(7):2133–2143. https://doi.org/10.1093/jac/dkv200
  29. Paul M, Daikos GL, Durante-Mangoni E, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: An open-label, randomised controlled trial. Lancet Infect Dis. 2018;18(4):391–400. https://doi.org/10.1016/S1473-3099(18)30099-9
  30. Kaye K. Trial for the treatment of extensively drug-resistant gram-negative Bacilli (OVERCOME) [homepage on the Internet]. [cited 2022 Feb 03]. Available from: https://clinicaltrials.gov/ct2/show/NCT01597973
  31. Falcone M, Russo A, Iacovelli A, et al. Predictors of outcome in ICU patients with septic shock caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae. Clin Microbiol Infect. 2016;22(5):444–450. https://doi.org/10.1016/j.cmi.2016.01.016
  32. Gutiérrez-Gutiérrez B, Salamanca E, De Cueto M, et al. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): A retrospective cohort study. Lancet Infect Dis. 2017;17(7):726–734. https://doi.org/10.1016/S1473-3099(17)30522-4
  33. Scudeller L, Righi E, Chiamenti M, et al. Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli. Int J Antimicrob Agents. 2021;57(5):106344. https://doi.org/10.1016/j.ijantimicag.2021.106344
  34. Aydemir H, Akduman D, Piskin N, et al. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect. 2013;141(6):1214–1222. https://doi.org/10.1017/S095026881200194X
  35. Cook A, Hsia Y, Russell N, et al. Association of empiric antibiotic regimen discordance with 30-day mortality in neonatal and pediatric bloodstream infection – A global retrospective cohort study. Pediatr Infect Dis J. 2021;40(2):137–143. https://doi.org/10.1097/INF.0000000000002910
  36. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: Results from a guideline-based performance improvement program*. Crit Care Med. 2014;42(8):1749–1755. https://doi.org/10.1097/CCM.0000000000000330
  37. Liang SY, Kumar A. Empiric antimicrobial therapy in severe sepsis and septic shock: Optimizing pathogen clearance. Curr Infect Dis Rep. 2015;17(7):493. https://doi.org/10.1007/s11908-015-0493-6
  38. Trifi A, Abdellatif S, Abdennebi C, et al. Appropriateness of empiric antimicrobial therapy with imipenem/colistin in severe septic patients: Observational cohort study. Ann Clin Microbiol Antimicrob. 2018;17:39. https://doi.org/10.1186/s12941-018-0292-7
  39. DSB00003 – AMR surveillance reporting landing page [homepage on the Internet]. MicroStrategy. [cited 2023 Jan 12]. Available from: https://mstrweb.nicd.ac.za/MicroStrategy/asp/Main.aspx?Server=NICDSANDMSTRI01&Project=Surveillance&Port=0&evt=2048001&src=Main.aspx.2048001&documentID=E654D30643F2E930CCF5A192C0E4512C&currentViewMedia=1&visMode=0
  40. Goldstein B, Giroir B, Randolph A, International consensus conference on pediatric sepsis. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc. 2005;6(1):2–8. https://doi.org/10.1097/01.PCC.0000149131.72248.E6
  41. Imberti R, Cusato M, Villani P, et al. Steady-state pharmacokinetics and BAL concentration of colistin in critically Ill patients after IV colistin methanesulfonate administration. Chest. 2010;138(6):1333–1339. https://doi.org/10.1378/chest.10-0463
  42. Athanassa ZE, Markantonis SL, Fousteri MZF, et al. Pharmacokinetics of inhaled colistimethate sodium (CMS) in mechanically ventilated critically ill patients. Intensive Care Med. 2012;38(11):1779–1786. https://doi.org/10.1007/s00134-012-2628-7
  43. Ratjen F, Rietschel E, Kasel D, et al. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother. 2006;57(2):306–311. https://doi.org/10.1093/jac/dki461
  44. Kollef MH, Hamilton CW, Montgomery AB. Aerosolized antibiotics: Do they add to the treatment of pneumonia? Curr Opin Infect Dis. 2013;26(6):538–544. https://doi.org/10.1097/QCO.0000000000000004
  45. Solé-Lleonart C, Rouby JJ, Blot S, et al. Nebulization of antiinfective agents in invasively mechanically ventilated adults: A systematic review and meta-analysis. Anesthesiology. 2017;126(5):890–908. https://doi.org/10.1097/ALN.0000000000001570
  46. Castellani C, Duff AJA, Bell SC, et al. ECFS best practice guidelines: The 2018 revision. J Cyst Fibros. 2018;17(2):153–178. https://doi.org/10.1016/j.jcf.2018.02.006
  47. Zampoli M, Verstraete J, Frauendorf M, et al. Cystic fibrosis in South Africa: Spectrum of disease and determinants of outcome. ERJ Open Res [Internet]. 2021;7(3):00856–2020. https://doi.org/10.1183/23120541.00856-2020
  48. Vardakas KZ, Mavroudis AD, Georgiou M, Falagas ME. Intravenous plus inhaled versus intravenous colistin monotherapy for lower respiratory tract infections: A systematic review and meta-analysis. J Infect. 2018;76(4):321–327. https://doi.org/10.1016/j.jinf.2018.02.002
  49. Rello J, Solé-Lleonart C, Rouby JJ, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: A position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2017;23(9):629–639. https://doi.org/10.1016/j.cmi.2017.04.011
  50. Nakwan N, Wannaro J, Thongmak T, et al. Safety in treatment of ventilator-associated pneumonia due to extensive drug-resistant Acinetobacter baumannii with aerosolized colistin in neonates: A preliminary report. Pediatr Pulmonol. 2011;46(1):60–66. https://doi.org/10.1002/ppul.21324
  51. Celik IH, Oguz SS, Demirel G, Erdeve O, Dilmen U. Outcome of ventilator-associated pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa treated with aerosolized colistin in neonates: A retrospective chart review. Eur J Pediatr. 2012;171(2):311–316. https://doi.org/10.1007/s00431-011-1537-z
  52. Kang CH, Tsai CM, Wu TH, et al. Colistin inhalation monotherapy for ventilator-associated pneumonia of Acinetobacter baumannii in prematurity. Pediatr Pulmonol. 2014;49(4):381–388. https://doi.org/10.1002/ppul.22750
  53. Choudhry S, Ahmad E, Batool A, Raja N. Use of colistin for the treatment of multi drug resistant isolates in neonates. JPMA J Pak Med Assoc. 2017;67(8):1157–1160.
  54. Hussain K, Salat MS, Ambreen G, et al. Intravenous vs intravenous plus aerosolized colistin for treatment of ventilator-associated pneumonia – A matched case-control study in neonates. Expert Opin Drug Saf. 2020;19(12):1641–1649. https://doi.org/10.1080/14740338.2020.1819980
  55. Polat M, Kara SS, Tapısız A, Tezer H, Kalkan G, Dolgun A. Treatment of ventilator-associated pneumonia using intravenous colistin alone or in combination with inhaled colistin in critically ill children. Paediatr Drugs. 2015;17(4):323–330. https://doi.org/10.1007/s40272-015-0133-5
  56. Nakwan N, Chokephaibulkit K, Imberti R. The use of colistin for the treatment of multidrug-resistant gram-negative infections in neonates and infants: A review of the literature. Pediatr Infect Dis J. 2019;38(11):1107–1112. https://doi.org/10.1097/INF.0000000000002448
  57. Nau R, Blei C, Eiffert H. Intrathecal antibacterial and antifungal therapies. Clin Microbiol Rev. 2020;33(3):e00190-19. https://doi.org/10.1128/CMR.00190-19
  58. Karvouniaris M, Brotis AG, Tsiamalou P, Fountas KN. The role of intraventricular antibiotics in the treatment of nosocomial ventriculitis/meningitis from gram-negative pathogens: A systematic review and meta-analysis. World Neurosurg. 2018;120:e637–e650. https://doi.org/10.1016/j.wneu.2018.08.138
  59. Imberti R, Iotti GA, Regazzi M. Intraventricular or intrathecal colistin for the treatment of central nervous system infections caused by multidrug-resistant Gram-negative bacteria. Expert Rev Anti Infect Ther. 2014;12(4):471–478. https://doi.org/10.1586/14787210.2014.896740
  60. De Bonis P, Lofrese G, Scoppettuolo G, et al. Intraventricular versus intravenous colistin for the treatment of extensively drug resistant Acinetobacter baumannii meningitis. Eur J Neurol. 2016;23(1):68–75. https://doi.org/10.1111/ene.12789
  61. Ambreen G, Salat MS, Hussain K, et al. Efficacy of colistin in multidrug-resistant neonatal sepsis: Experience from a tertiary care center in Karachi, Pakistan. Arch Dis Child. 2020;105(9):830–836. https://doi.org/10.1136/archdischild-2019-318067
  62. Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal use of polymyxins in patients with Gram-negative meningitis: A systematic review of the available evidence. Int J Antimicrob Agents. 2007;29(1):9–25. https://doi.org/10.1016/j.ijantimicag.2006.08.024
  63. Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America’s Clinical Practice guidelines for healthcare-associated ventriculitis and meningitis*. Clin Infect Dis. 2017;64(6):e34–e65. https://doi.org/10.1093/cid/ciw861
  64. Imberti R, Cusato M, Accetta G, et al. Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate. Antimicrob Agents Chemother. 2012;56(8):4416–4421. https://doi.org/10.1128/AAC.00231-12
  65. Falagas ME, Kasiakou SK. Toxicity of polymyxins: A systematic review of the evidence from old and recent studies. Crit Care. 2006;10(1):R27. https://doi.org/10.1186/cc3995
  66. Sahbudak Bal Z, Kamit Can F, Yazici P, et al. The evaluation of safety and efficacy of colistin use in pediatric intensive care unit: Results from two reference hospitals and review of literature. J Infect Chemother. 2018;24(5):370–375. https://doi.org/10.1016/j.jiac.2017.12.017
  67. Jajoo M, Kumar V, Jain M, Kumari S, Manchanda V. Intravenous colistin administration in neonates. Pediatr Infect Dis J. 2011;30(3):218–221. https://doi.org/10.1097/INF.0b013e3182064bfe
  68. Çağan E, Kıray Baş E, Asker HS. Use of colistin in a neonatal intensive care unit: A Cohort study of 65 patients. Med Sci Monit Int Med J Exp Clin Res. 2017;23:548–554. https://doi.org/10.12659/MSM.898213
  69. Alan S, Yildiz D, Erdeve O, et al. Efficacy and safety of intravenous colistin in preterm infants with nosocomial sepsis caused by Acinetobacter baumannii. Am J Perinatol. 2014;31(12):1079–1086. https://doi.org/10.1055/s-0034-1371361
  70. Jasani B, Kannan S, Nanavati R, Gogtay NJ, Thatte U. An audit of colistin use in neonatal sepsis from a tertiary care centre of a resource-limited country. Indian J Med Res. 2016;144(3):433–439. https://doi.org/10.4103/0971-5916.198682
  71. Serafettin Tekgunduz K, Kara M, Caner I, Demirelli Y. Safety and efficacy of intravenous colistin in neonates with culture proven sepsis. Iran J Pediatr. 2015;25(4):e453. https://doi.org/10.5812/ijp.453
  72. İpek MS, Aktar F, Okur N, Celik M, Ozbek E. Colistin use in critically ill neonates: A case–control study. Pediatr Neonatol. 2017;58(6):490–496. https://doi.org/10.1016/j.pedneo.2016.10.002
  73. Kelesidis T, Falagas ME. The safety of polymyxin antibiotics. Expert Opin Drug Saf. 2015;14(11):1687–1701. https://doi.org/10.1517/14740338.2015.1088520
  74. Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton AE. Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med. 1970;72(6):857–868. https://doi.org/10.7326/0003-4819-72-6-857
  75. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, Van Duin D, Clancy CJ. Infectious Diseases Society of America 2022 guidance on the treatment of extended-spectrum β-lactamase producing enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis Off Publ Infect Dis Soc Am. 2022;75(2):187–212. https://doi.org/10.1093/cid/ciac268
  76. World Health Organization (WHO). WHO | WHO releases the 2019 AWaRe classification antibiotics [homepage on the Internet]. [cited 2021 Jun 2]. Available from: http://www.who.int/medicines/news/2019/WHO_releases2019AWaRe_classification_antibiotics/en/
  77. Levy Hara G, Kanj SS, Pagani L, et al. Ten key points for the appropriate use of antibiotics in hospitalised patients: A consensus from the Antimicrobial Stewardship and Resistance Working Groups of the International Society of Chemotherapy. Int J Antimicrob Agents. 2016;48(3):239–246. https://doi.org/10.1016/j.ijantimicag.2016.06.015
  78. Messina AP, Brink AJ, Richards GA, Van Vuuren S. Opportunities to optimise colistin stewardship in hospitalised patients in South Africa: Results of a multisite utilisation audit. S Afr Med J Suid-Afr Tydskr Vir Geneeskd. 2017;108(1):28–32. https://doi.org/10.7196/SAMJ.2017.v108i1.12561
  79. Majavie L, Johnston D, Messina A. A retrospective review of colistin utilisation at a tertiary care academic hospital in South Africa. S Afr J Infect Dis. 2021;36(1):205. https://doi.org/10.4102/sajid.v36i1.205
  80. South African antimicrobial resistance national strategy framework: A one health approach 2017 – 2024 | Department of Health Knowledge Hub [homepage on the Internet]. [cited 2020 Dec 03]. Available from: https://www.knowledgehub.org.za/elibrary/south-african-antimicrobial-resistance-national-strategy-framework-one-health-approach
  81. Implementation plan for the antimicrobial resistance strategy framework in South Africa (2014 – 2019) | Department of Health Knowledge Hub [homepage on the Internet]. [cited 2022 Mar 28]. Available from: https://www.knowledgehub.org.za/elibrary/implementation-plan-antimicrobial-resistance-strategy-framework-south-africa-2014-2019
  82. Mendelson M, Brink A, Gouws J, et al. The One Health stewardship of colistin as an antibiotic of last resort for human health in South Africa. Lancet Infect Dis. 2018;18(9):e288–e294. https://doi.org/10.1016/S1473-3099(18)30119-1
  83. Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2017;2:CD003543. https://doi.org/10.1002/14651858.CD003543.pub4
  84. The WHO AWaRe (Access, Watch, Reserve) antibiotic book – Infographics [homepage on the Internet]. [cited 2023 Oct 17]. Available from: https://www.who.int/publications-detail-redirect/WHO-MHP-HPS-EML-2022.02
  85. SAHPRA. 2. 52 Section 21 access to unregistered medicines. Vol. 1965. 2020, pp. 1–15, SAHPRA; Pretoria.


Crossref Citations

No related citations found.