Nebulised N-Acetylcysteine (NAC)

Mucus typically consists of water (97%) and mucins (3%), such as MUC5AC and MUC5B, in addition to antimicrobial, immunomodulatory and protective molecules. Mucus prevents dehydration on the airway surface and aids in clearance of inhaled particles and inflammatory mediators [2]. Many chronic lung diseases are characterized by the hypersecretion of mucus which arises from hypertrophy and hyperplasia of the goblet and submucosal glands. This is usually accompanied by inadequate mucus clearance which further hinders the air passages. In these conditions, the administration of mucoactive agents is often indicated as adjuvant therapy.

NAC is also widely used by respiratory physicians as an oral mucolytic agent. The presence of the free sulfhydryl group enables it to cleave disulphide bonds in mucin (in addition to degrading fibrin, DNA and mucin polymers or F-actin) and reduce viscosity, thus causing mucus breakdown and enhancing mucocilliary clearance. It has both direct and indirect antioxidant activity, leading to oxygen radical scavenging, reduced inflammation and reduced mucus secretion. NAC is commonly used as an oral mucolytic in chronic respiratory disease, and is increasingly being considered as an adjunct in reducing frequency of COPD exacerbations due to the antioxidant activity.

It can be administered orally (300–1200 mg daily), nebulised (5 ml 10% solution six-hourly) or intravenously. Adverse side effects include nausea and vomiting, anaphylactoid reactions in 3% (urticarial rash, bronchoconstriction and hypotension) and confusion and electrolyte disturbance due to high osmolality.

Following failed conventional mucolysis therapy, nebulised N-acetylcysteine acted as a life-saving mucolytic, and prevented imminent cardiorespiratory arrest. Use of oral N-acetylcysteine as a mucolytic has been long established within respiratory medicine in managing chronic airway disease, but is rarely utilised in critically ill or mechanically ventilated patients due to the lack of comparative studies in literature. A Cochrane Database Systematic Review at 2013 concluded that they found no evidence to recommend the use of either nebulized or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis.

Methods of administration of nebulised N-Acetylcysteine (NAC) in literature:

Study	Method	Conclusion / Remark(s)
Gray et al. 2011: Injectable Drugs Guide.	1. Withdraw the required dose (and optional: dilute with NaCl 0.9% if required). 2. Give via a nebuliser using air (NOT oxygen).	• The adult dose is 3-5 mL acetylcysteine 20% injection, • Nebulised 3-4 times daily using air (avoid concentrated oxygen as it causes degradation of NAC). • Acetylcysteine may cause bronchospasm. This can be avoided either by: i.  Giving a lower dose – diluting 1 mL acetylcysteine 20% in 5 mL NaCl 0.9% and giving 3-4 mL, or; ii.  Pre-administering a nebulised bronchodilator
Brodier et al 2019	10 ml 2% N-acetylcysteine (NAC) was flushed via the bronchoscopic port	Nebulised NAC is an option when encountering airway obstruction due to refractory mucus plugging in critically ill patients.
Gallon AM 1996	4 ml nebulised NAC (for 10 mins; the nebulisers were driven by compressed air because oxygen inactivates acetylcysteine) + Deep breathing exercise + Assisted coughing Repeat after 4 hrs. Twice daily X 2 days	Following thoracotomy, nebulised acetylcysteine reduces sputum viscosity, making expectoration easier and improving oxygenation.
Masoompour et al. 2015	2 ml of NAC 20% with 8 ml normal saline ; 3 times a day for 1 day.	N-acetylcysteine via nebulization through endotracheal tubes in mechanically ventilated patients was not effective more than normal saline nebulization in reducing the density of mucous plugs

In Hospital Keningau:

Availability of N-Acetylcysteine (NAC) in Hospital Keningau : 5 g / 25 ml Inj  (20%)

KPK Application Form & Patient Off-label Treatment Consent Form are needed.

Case Report by Brodier et al 2019

The patient in this case report acutely deteriorated 48 h after admission becoming unresponsive and severely hypoxaemic. Intubation did not achieve ventilation, and subsequent direct bronchoscopy revealed a thick, solid, obstructing tracheal mucus plug, superior to the carina. It was resistant to aspiration despite the use of saline flushes, chest physiotherapy and bronchodilators and the bronchoscope could not pass it. 10 ml 2% N-acetylcysteine (NAC) was flushed via the bronchoscopic port, utilising ingenuitive clinical judgement in this critical situation.

This caused sufficient mucolysis to enable removal of the thick mucus cast, enabling ventilation and gas exchange. Such resistant mucus plugging is a rare cause of failed ventilation, with limited therapeutic options. Here, the unlicensed and rarely reported use of nebulised N-acetylcysteine was a life-saving mucolytic, allowing removal of the obstructing plug and re-establishing ventilation.

For this patient, mucolytic management continued with nebulised NAC, hypertonic saline flushes and bronchodilatory nebulisers.

Other Mucolytics

Expectorants increase airway water or the volume of airway secretions, thereby improving the ability to expectorate purulent secretions. Hypertonic saline is an example of an expectorant which has osmotic pressure greater than that of physiologic isotonic 0.9% NaCl. Hypertonic saline has been shown to significantly reduce the number of exacerbations in cystic fibrosis patients when compared to isotonic saline and has better mucociliary clearance.

Drug	Device	Indication	Proposed Mechanism of Action	Notes
Expectorants
Hypertonic saline 7%	Nebulizer	Cystic fibrosis, and bronchiectasis	Increases the amount of sodium and chloride in airway surface liquid, thereby increasing the osmotic gradient and rehydrating the mucus layer [5,7]	Improves lung function and quality of life in bronchiectasis [8]. Should not be given via a vibrating mesh nebulizer. Improves mucus clearance, airflow, and reduces rates of exacerbation among patients with cystic fibrosis [4,9].
Classical mucolytics
NAC (Mucomyst®)	Nebulizer	ABPA	Severs disulfide bonds that link mucin monomers to polymers, and solubilizes sputum antioxidant and anti-inflammatory	No evidence for use in any lung disease.
S-carboxymethylcysteine (carbocysteine)	Oral	COPD, and cystic fibrosis	Increases concentrations of sialomucins and reduces that of fucomucins, acts as a free radical scavenger [10], and has antioxidant and anti-inflammatory properties	Reduces measured sputum viscosity [11,12].
Dry powder mannitol (Bronchitol®)	Dry powder inhaler	Cystic fibrosis, bronchiectasis, and COPD	Increases mucus secretion	Nonabsorbable. Associated with bronchoconstriction and cough when used in children with cystic fibrosis.
Peptide mucolytics
Dornase alfa (Pulmozyme®)	Nebulizer	Cystic fibrosis	Hydrolyzes DNA polymer and reduces DNA length	Hydrolyzes DNA, improves lung function, and decreases the frequency of exacerbation [13,14].
Non-destructive mucolytics
Unfractionated heparin (UFH)	Nebulizer	COPD, and cystic fibrosis	Modifies ionic interactions and the intermolecular hydrogen bonds between mucin molecules, and untangles the charged oligosaccharide side chains of mucin	UFH reduces the elasticity and yield stress in the samples from cystic fibrosis patients [15].
Low molecular weight dextran (DCF 987)	Nebulizer	COPD	Disrupts the polyionic oligosaccharide mucin network and increases secretion hydration	Proven lung safety in animal studies [16,17].

·         ABPA = allergic bronchopulmonary aspergillosis;

·         COPD = chronic obstructive pulmonary disease;

·         NAC = N-acetylcysteine.

References:

1. Gray et al. Injectable Drugs Guide: Acetylcysteine. Pharmaceutical Press 2011.
2. Brodier et al. Use of nebulised N-acetylcysteine as a life-saving mucolytic in intensive care: A case report. Journal of the Intensive Care Society 2019, 0(0) 1–3. Accessed at: https://journals.sagepub.com/doi/full/10.1177/1751143719870089  [12 Mac 2020]
3. Out et al 2018. Nebulised N-Acetylcysteine for Unresponsive Bronchial Obstruction in Allergic Brochopulmonary Aspergillosis: A Case Series and Review of the Literature. J. Fungi 2018, 4(4), 117. Accessed at: https://www.mdpi.com/2309-608X/4/4/117/htm   [12 Mac 2020]
4. Masoompour et al. 2015. Evaluation of the Effect of Nebulized N-Acetylcysteine on Respiratory Secretions in Mechanically Ventilated Patients: Randomized Clinical Trial. Iran J Med Sci. 2015 Jul; 40(4): 309–315. Accessed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487455/   [12 Mac 2020]
5. Gallon AM 1996. Evaluation of nebulised acetylcysteine and normal saline in the treatment of sputum retention following thoracotomy. Thorax 1996;51:429-432. Accessed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1090682/pdf/thorax00323-0097.pdf  [12 Mac 2020]
6. Tam et al. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev. 2013 Jul 12;(7):CD007168. Accessed at: https://www.ncbi.nlm.nih.gov/pubmed/23852992   [12 Mac 2020]

Further Reading:

For detailed explanation of pharmacology of N-Acetylcysteine in lung diseases, this is a good read:

Santus et al. Oxidative Stress and Respiratory System: Pharmacological and Clinical Reappraisal of N-Acetylcysteine. COPD. 2014 Dec; 11(6): 705–717.

ESBL- and AmpC-producing Enterobacteriaceae , including Carbapenem-resistant Enterobacteriaceae (CRE)

Summary of positive and negative aspects and dosing of potentially useful drugs in the treatment of infections with ESBL- and AmpC-producing Enterobacteriaceae:

Drug	Positive aspects	Negative aspects	Dosing (for adults with normal renal function) and comments
Meropenem, imipenem, doripenem	Reference drugs, usually active	Ecological impact; less experience with doripenem	Standard dosing is recommended
Ertapenem	Not active against P. aeruginosa; usually active; convenient for outpatient therapy and deescalation from other carbapenems	Ecological impact if CPE endemicity / outbreak; doubts in cases of septic shock (insufficient dosing?); anecdotal failures described with development of resistance (porin loss)	1 g/day in most situations; for septic shock or high-inoculum infections with borderline MIC isolates, use other alternatives or increase dose to 2 g/day
Amoxicillin-clavulanic acid	No inoculum effect; probably noninferior to carbapenems in UTI and biliary tract infections; not active against P. aeruginosa; convenient for oral switch	Not available for i.v. use in many countries; heterogeneous resistance rates, usually >40% among ESBL producers; AmpC producers are resistant	Intravenous, 2.2 g/8 h; oral, at least 1.250 g/8h for UTI
Ceftolozane-tazobactam	Areas with large proportions of susceptible isolates	Reserve drug for MDR P. aeruginosa infection; scarce experience so far; 10-30% resistance rates among ESBL producers, lower rates in AmpC producers	1.5 g/8h; approved for cUTI and cIAI (with metronidazole); consider 3 g/8 h for pneumonia
Ceftazidime-avibactam	Large proportion of susceptible isolates	Reserve drug for KPC- or OXA-48-producing Enterobacteriaceae	2.5 g/8 h; approved for cUTI and cIAI (with metronidazole); in Europe, also approved for HAP in case of limited options
Cefotaxime, ceftriaxone, ceftazidime, cefepime	Some ESBL-E may be susceptible; cefepime is usually active against AmpC producers	Most isolates are resistant (except to cefepime in the case of AmpC producers); inoculum effect; ecological impact; clinical data are scarce and contradictory	If used, high doses are recommended (cefotaxime, 1 g/6 h to 2 g/8 h; ceftazidime or cefepime, 2 g/8 h)
Cefoxitin, cefotetan, cefmetazole, moxalactam, flomoxef	Not active against P. aeruginosa; areas with large proportions of susceptible isolates (ESBL producers); probably useful against UTI for stable patients	AmpC producers are resistant; inoculum effect; observational studies with contradictory results; anecdotally described development of resistance during therapy	High doses; close follow-up needed
Temocillin	Active against ESBL and AmpC producers; not active against P. aeruginosa	Not available in many countries; comparative studies are lacking	Probably 2 g every 8 h
Gentamicin, tobramycin, amikacin	Active against many ESBL and AmpC producers; useful for UTI	Nephrotoxicity; less efficacious in non-UTI infections; heterogeneous resistance rates	Standard dosing; may be considered empirically as carbapenem sparing agents (in monotherapy or in combination with a lower-spectrum beta- lactam) until microbiological data are available
Tigecycline	Active against most ESBL and AmpC producers; not active against P. aeruginosa	FDA and EMA warnings for use only if other options are unavailable/unsuitable; probably not a good option for UTI or HAP	100-mg loading dose, 50 mg/12 h; may be an alternative in cIAI
Fosfomycin (i.v.)	Noninferior to piperacillin-tazobactam in cUTI (pending publication of data)	Not available in many countries; scant experience; risk of emergence of resistant subpopulations with monotherapy	4 g/6 h to 6–8 g/8 h
Ciprofloxacin, levofloxacin	Potentially useful for fully susceptible isolates; convenient for oral switch	Ecological impact; most isolates are resistant; failures for isolates with MICs of 0.5–1 mg/liter have been described	For i.v. ciprofloxacin, 400 mg/8–12 h; for oral ciprofloxacin, 500–700 mg/12 h; for levofloxacin (i.v., oral), 750 mg/24 h
Trimethoprim-sulfamethoxazole ( Bactrim / Co-trimoxazole )	Convenient for oral switch	Most isolates are resistant; scant published experience	i.v. or oral, 160/800 mg/8–12 h

·         CPE: carbapenemase-producing Enterobacteriaceae

·         cUTI: complicated urinary tract infection

·         cIAI: complicated intrabadominal infection

Recommended dosing for the most frequently used drugs against carbapenem-resistant Enterobacteriaceae (CRE) for patients with normal renal function:

Drug	Usual/standard dose(s)	Dosing for CRE and comments
Meropenem	1 g/8 h	2 g/8 h by EI (isolates with MICs of 2–8 mg/liter; for isolates with higher MICs, it is probably not efficacious)
Ertapenem	1 g/24 h	Consider 2 g/day for double-carbapenem regimens
Colistin (a)	From the EMA, loading dose, 6–9 MU, and then 9 MU/day in 2–3 doses; from the FDA, 2.5–5 mg of colistin base activity/kg/day	EMA dose is recommended for severe CRE infections; the need for a loading dose and high continuation dose in patients without severe infection/shock is controversial
Polymyxin B (b)	From the FDA, 1.5–2.5 mg/kg/day in 2 doses	For mild infections and isolates with MICs of ≤1 mg/liter, the FDA dose is probably appropriate; for severe infections and isolates with MICs of up to 4 mg/liter, a loading dose of 2–2.5 mg/kg followed by 3 mg/kg/day in 2 doses is recommended (controversially)
Tigecycline	100-mg loading dose and then 50 mg/12 h	For HAP, cUTI, BSI, or shock, consider a 200-mg loading dose and then 100 mg/12 h
Gentamicin, tobramycin	5–7 mg/kg/day	For HAP or shock without other options, higher doses (10–15 mg/kg) might be considered, but the risk of toxicity is high; TDM is recommended
Amikacin	15–20 mg/kg/day	For HAP or shock without other options, higher doses (25–30 mg/kg) might be considered, but the risk of toxicity is high; TDM is recommended
Fosfomycin	4 g/6 h to 8 g/8 h	Use in combination; high sodium concn
Temocillin	2 g/8–12 h	KPC producers are occasionally susceptible; continuous infusion improves PK-PD target attainment
Aztreonam	1–2 g/8 h	MBL producers are susceptible if they are not ESBL or AmpC producers
Ceftazidime	1–2 g/8 h	OXA-48 producers are susceptible if they are not ESBL or AmpC producers
Ceftazidime-avibactam	2.5 g/8 h	KPC and OXA-48 producers are frequently susceptible
Meropenem-vaborbactam	2/2 g/8 h	KPC producers are frequently susceptible
Please refer to the text for explanations and references. EI, extended infusion; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; HAP, hospital-acquired pneumonia; cUTI, complicated urinary tract infection; BSI, bloodstream infection; MU, million units; TDM, therapeutic drug monitoring; MBL, metallo-β-lactamase. a = One million units of colistimethate sodium = 80 mg colistimethate sodium = 34 mg of colistin base activity. b = One million units of polymyxin B = 100 mg of colistin base activity.

Multidrug-resistant A. baumannii and P. aeruginosa

For multidrug-resistant A. baumannii and P. aeruginosa, the polymyxins (ie, colistin and polymyxin B) are usually the cornerstones for therapy. Combination therapy is also advised when polymyxins are used to treat multidrug-resistant A. baumannii and P. aeruginosa.

Most multidrug-resistant A. baumannii and P. aeruginosa retain susceptibility for the polymyxins. Aminoglycosides may be useful, particularly for urinary tract infections, assuming susceptibility is retained for one of these antibiotics. Otherwise, there are a limited number agents with potential activity. Carbapenem-resistant A. baumannii and P. aeruginosa are typically resistant to all beta-lactams and fluoroquinolones. The intrinsic resistance of these organisms further limits antibiotic options. Although sulbactam has been used to treat some infections due to A. baumannii, most multidrug-resistant isolates of A. baumannii have reduced susceptibility to this agent.

Acinetobacter Infection

In the setting of resistance to first line agents, therapeutic options are generally limited to polymyxins (colistin [polymyxin E] and polymyxin B), minocycline, and tigecycline. We generally use polymyxins, for which there is the most clinical experience in treating extensively drug-resistant Acinetobacter. Furthermore, tigecycline may not reach adequate levels in the serum, urinary tract, or CNS to successfully treat infections in these compartments. Susceptibility testing for these agents should be performed as well prior to their use given the possibility of resistance.

We generally favor using a second agent, such as a carbapenem, minocycline, tigecycline, or rifampin, in addition to polymyxins for serious infections (eg, bacteremia, pneumonia, critical illness) with resistant isolates. There are no definitive clinical data that demonstrate improved outcomes with combination versus monotherapy, and some randomized trials have suggested that certain combinations (colistin and rifampin or colistin and meropenem) resulted in comparable clinical outcomes as monotherapy with colistin. Nevertheless, infections with multidrug-resistant Acinetobacter are associated with high mortality rates, and we are concerned that the use of a single agent is not adequate, particularly since resistance can develop during therapy, leaving no therapeutic alternatives.

Inhaled colistin may be beneficial in select patients, although not all studies suggest a benefit. We favor use of inhaled colistin among patients with severe pneumonia due to Acinetobacter that is resistant to beta-lactams and carbapenems (ie, sensitive to colistin only), since intravenous colistin yields low lung concentration.

Pseudomonas aeruginosa infection

A polymyxin (colistin or polymyxin B) is the only therapeutic option for some strains of multidrug-resistant P. aeruginosa. Thus colistin is being increasingly used despite its well-known propensity for causing nephrotoxicity and ototoxicity

References:

1. ·         Rodríguez-Baño et al. Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae. Clinical Microbiology Reviews Feb 2018, 31 (2) e00079-17
2. ·         UptoDate: Overview of carbapenemase-producing gram-negative bacilli
3. ·         UptoDate: Acinetobacter infection: Treatment and prevention
4. ·         UptoDate: Principles of antimicrobial therapy of Pseudomonas aeruginosa infections

All information accessed on 24 Feb 2020