© Australian Pesticides and Veterinary Medicines Authority 2017
ISBN 978-1-925390-63-6 (electronic)
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INTRODUCTION 6
Contents
Executive Summary 4
1 INTRODUCTION 5
1.1 Neomycin 5
Chemistry 5
Mode of action 5
Mechanism of action 6
Pharmacokinetics 7
2 TARGET ANIMAL SAFETY 9
2.1 Review of the scientific literature 9
Ototoxicity 10
Nephrotoxicity 14
2.2 Adverse drug experience reports for neomycin in food-producing animals 17
AERs in Australia 17
Global AERs 18
Off-label use of neomycin 20
2.3 Animal safety studies 21
Discussion of safety studies 21
2.4 Conclusion 23
Appendix A—LIST OF PRODUCT REGISTRATIONS AND LABEL APPROVALS 26
Abbreviations 28
References 30
List of tables
Table 1: AERs reported for use of neomycin-containing products in horses in Australia (1995–2014) 17
Table 2: Global AERs reported for use of neomycin-containing products (2001–2006) 19
Table 3: Product registrations and associated label approvals included in the review 26
Executive Summary
The Australian Pesticides and Veterinary Medicines Authority (APVMA) is reconsidering the approval and registration of products containing neomycin for use in food-producing animals in Australia. The scope of the reconsideration includes target animal safety and residues and trade.
The current target animal safety assessment for the reconsideration of neomycin was undertaken by the APVMA and considered published and unpublished target animal safety data and information on neomycin. This included a literature review of information available in the public domain, as well as adverse experience reports (AERs) provided to the APVMA and animal safety studies provided by holders.
The most frequently reported AER was for injection site reactions in horses. The frequency of both Australian and global AERs was low and many appeared to be related to reactions to the procaine benzylpenicillin in one of the neomycin-containing parenteral products.
The published and unpublished information indicates that, when administered at high concentrations, for prolonged durations, and/or more than once daily, neomycin causes nephrotoxicity and/or ototoxicity. This is particularly the case for parenteral formulations. However, the risk of developing nephrotoxicity or ototoxicity from either parenteral or oral formulations increases if the individual has compromised renal function, gastrointestinal inflammation or is receiving other potentially nephrotoxic drugs concomitantly.
A close examination of the published and unpublished information for food-producing animals suggests that parenteral neomycin-containing products are generally safe to use in the target species’ when administered once daily for short durations. Furthermore, oral neomycin-containing products are generally safe to use in the target species’ when administered for short durations and intra-mammary products are safe when administered according to the current approved label directions.
As a prescription animal treatment, products containing neomycin can only be prescribed by a veterinarian and used under veterinary supervision. However, additional label warnings in relation to the application of neomycin products are recommended. This includes warnings about the possibility of nephrotoxicity and ototoxicity, and contraindications for the use of neomycin-containing products in individual animals with compromised renal function, gastrointestinal inflammation or those receiving other potentially nephrotoxic drugs. For parenteral products, the maximum duration of treatment should be clearly indicated and recommended dosage regimens should be based on extended-interval administration that allows for concentration-dependent killing and avoids extended periods of trough concentrations that lead to accumulation of neomycin. For oral products, the potential for adverse effects following prolonged treatment and clear instructions to re-establish diagnosis if no clinical improvement is seen following the recommended duration of treatment should be included on product labels. For intra-mammary products, additional label statements about the potential for local irritation are recommended.
Based on consideration of the available information and that the recommended label changes are adopted, the continued use of neomycin-containing products when applied to food-producing animals is considered safe for target animals.
INTRODUCTION 6
1 INTRODUCTION
The APVMA Chemical Review team assessed the published and unpublished animal safety data on neomycin. This included a literature review of information available in the public domain including a range of published scientific studies, adverse experience reports (AERs) provided to the APVMA and animal safety studies provided by holders of active constituent approvals, product registrations and label approvals (‘holders’). The information assessed included studies conducted on products currently registered in Australia as well as products used overseas but similar to those currently registered in Australia.
1.1 Neomycin
Chemistry
Neomycin [2-deoxy-4-O-(2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl)-5-O-[3-O-(2,6-diamino-2,6-dideoxy-β-L-idopyranosyl)-β-D-ribofuranosyl]streptamine] is an aminoglycoside antibiotic produced by Streptomyces fradiae. Aminoglycosides are characterised by comprising aminosugars attached to an aminocyclitol group via glycosidic linkages.
There may be several forms of a single aminoglycoside. For example, neomycin is a complex of three separate compounds: neomycin A (neamine; inactive); neomycin B (framycetin); and neomycin C. The commercially available, registered active constituent neomycin consists almost entirely of the sulfate salt of neomycin B (over 90%), with some neomycin C and only traces of neomycin A (otherwise known as fradiomycin; less than 1%) (EMA 2002; Plumb 2002; Renshaw et al. 2003; Boothe 2012).
Mode of action
Aminoglycosides are bactericidal antibiotics, which are active predominantly against aerobic Gram-negative bacteria in a concentration-dependent manner, with a significant post-antibiotic effect. They have little or no action against anaerobic bacteria, as they require oxygen to cross the cell membrane, as described below (Reeves 2011; Boothe 2012). Neomycin is active against strains of Gram-negative bacteria (excluding Pseudomonas spp.), such as E. coli, Salmonella and Klebsiella spp. and many strains of Staphylococcus aureus (Sweetman 2002), although treatment of staphylococci should be in conjunction with synergistic antibiotics, such as β-lactams (EMA 2002; Plumb 2002; Renshaw et al. 2003; Boothe 2012).
INTRODUCTION 6
Mechanism of action
Aminoglycosides exert their antibacterial activity by interfering with protein synthesis at the membrane-associated bacterial ribosome (Riviere & Spoo 2001). This is achieved by irreversibly binding to one or more receptor proteins on the 30S subunit of the bacterial ribosome and subsequently interfering with the mRNA translation process, ultimately resulting in the production of a non-functional protein (EMA 2002; Reeves 2011). In order for neomycin to reach the ribosomal binding site of Gram-negative bacteria, it must cross the bacterial cell wall and then the cell membrane. Initially, neomycin diffuses across the cell wall by competitive displacement of bridging divalent cations (such as Mg2+ or Ca2+) and subsequent disruption of cross-links between adjacent lipopolysaccharides. This damages the cell wall and increases permeability, which allows the aminoglycoside to enter the periplasmic space in a passive and non-energy-dependent process. From there, it is actively transported across the cytoplasmic membrane via an oxygen- and energy-dependent interaction that is dependent on electron transport. The bacterial cytoplasm is negatively charged with respect to the periplasm and external environment; thus, neomycin is transported across the cytoplasmic membrane by the membrane potential, where it is then able to interact with the ribosome and cause misreading of the mRNA. This further affects cell permeability, which allows more neomycin into the cell and leads to more cell disruption and eventually, cell death (Reeves 2011; Boothe 2012). The efficacy of aminoglycosides is substantially reduced in an anaerobic environment, because the appropriate oxygen-dependent transport mechanisms described above are lacking (Riviere & Spoo 2001; EMA 2002; Huth et al. 2011).
While most antimicrobials that interfere with ribosomal protein synthesis are exclusively bacteriostatic[1], aminoglycosides are bactericidal[2] at higher concentrations.
When aminoglycosides are used in combination with β-lactam compounds (such as benzylpenicillin or cephalosporins) synergism is achieved, as the cell-wall damage produced by the β-lactam compounds allows easier access for the aminoglycosides to the bacterial cell membrane (Boothe 2012). Consequently, neomycin is often administered in conjunction with β-lactam compounds, most commonly procaine benzylpenicillin.
Concentration-dependent killing
Aminoglycosides exhibit concentration-dependent bacterial killing, where the peak aminoglycoside concentration (CMAX) is more important in determining the efficacy of bacterial killing than time above the minimum inhibitory concentration (MIC) (Freeman et al. 1997). Thus, it is more important to achieve optimal peak concentrations than to maintain drug concentrations slightly above the MIC for extended periods of time. While optimum ratios between the peak concentration and MIC have not yet been determined, the literature suggests that peak concentration:MIC ratios of 8:1 to 10:1 are necessary for optimal bactericidal activity while avoiding bacterial regrowth (Freeman et al. 1997; Boothe 2012).
INTRODUCTION 8
Post-antibiotic effect
Aminoglycosides also exhibit a post-antibiotic effect (PAE), where bactericidal action persists after serum concentrations of neomycin drop below the MIC (Riviere & Spoo 2001; Reeves 2011). The exact mechanism of PAE has not yet been determined. The PAE of aminoglycosides is dependent on the:
· bacterial strain and its MIC
· duration of exposure of bacteria to the aminoglycoside
· inherent potency of the aminoglycoside
· concentration of the aminoglycoside (the higher the concentration, the longer the duration of the PAE).
Longer intervals between dosing (eg once-daily dosing) that provide a drug-free period in which bacteria are not exposed to the drug appear to preserve bactericidal activity of aminoglycosides and reduce the risk of antimicrobial resistance, as well as toxicity (Freeman et al. 1997). Studies in animal models have shown that the degree of cochlear damage induced by aminoglycosides is more dependent on the total daily dose than the frequency with which it is administered. It has been hypothesized that extended-interval dosing may result in less saturation of cochlear cells and accumulation of aminoglycosides than more frequent administration (Freeman et al. 1997).
Pharmacokinetics
Absorption
As for other aminoglycosides, neomycin is a polycation (positively charged) and is highly polar, with the result that it is poorly absorbed (usually less than 10%) from the healthy gastrointestinal tract. However, substantial disruption of the intestinal mucosa (eg from enteritis) may increase permeability (Boothe 2012). In individual animals with impaired renal function, drug concentrations during the trough period may accumulate and result in nephrotoxicity (Boothe 2012).
Neomycin is absorbed rapidly and nearly completely following intramuscular administration, with peak serum concentrations achieved within 30 to 90 minutes. Intrauterine and intra-mammary administration of aminoglycosides also result in effective therapeutic local concentrations, but significant tissue residues have been observed (Reeves 2011).
INTRODUCTION 8
Distribution
Aminoglycosides do not bind well to plasma proteins, they are poorly lipid-soluble and do not easily enter cells or penetrate cellular barriers. As they are polar at physiologic pH, distribution of aminoglycosides to extracellular fluids is limited and tissue penetration is generally minimal, with the exceptions of the renal tubules and inner ear endolymph, where accumulation is common (Boothe 2012).
Metabolism and excretion
Orally administered aminoglycosides are eliminated unchanged in the faeces in healthy animals. Following parenteral administration, neomycin is excreted unchanged primarily by renal glomerular filtration, with 80–90% of administered neomycin excreted in the urine (within 24 hours following intramuscular administration) (Riviere & Spoo 2001; Huth et al. 2011; Reeves 2011; Boothe 2012).
Glomerular filtration rates vary between species and are usually less in neonates, which are generally more sensitive to aminoglycosides (Boothe 2012). Furthermore, excretion varies as a result of changes to glomerular filtration rates in association with both cardiovascular and renal function, age, etc, and the half-life varies in response to the volume of extracellular fluid.
Aminoglycosides have relatively short plasma half-lives of approximately 1 hour in carnivores and 2 to 3 hours in herbivores and the elimination kinetics generally follow a three-compartment model (Boothe 2012):
· first ‘deep’ phase: binding of drug in renal tubular cell
· β-phase: approximately 90% of the drug is excreted unchanged from the kidneys
· second ‘deep’ (or γ phase): remaining drug excreted over protracted period (gradual release from renal intracellular binding sites; terminal elimination half-life 20–200 hours)
TARGET ANIMAL SAFETY 22
2 TARGET ANIMAL SAFETY
The purpose of this target animal safety assessment was to summarise the published and unpublished information concerning the safety of neomycin in food-producing animals and to present an assessment of the potential risks associated with its use. Where the literature on food-producing animals was lacking, studies conducted in companion or laboratory animals and humans were also included.
The parenteral use of neomycin in human medicine is no longer recommended because of toxicity concerns. As a result, there is very little recent toxicity information available on to the use of neomycin in humans and the majority of the literature relating to the safety of aminoglycosides has been conducted using gentamycin. However, neomycin has a similar mechanism of action to gentamycin, so the information on aminoglycoside toxicity in general will be included in this assessment and any research that was generated using neomycin will be specifically highlighted as such.
Unless indicated otherwise, the cited information has been sourced from peer-reviewed, scientific publications or from other information available in the public domain and not from examination of the original unpublished reports.
2.1 Review of the scientific literature
As well as being potent antimicrobials, aminoglycosides are also capable of causing toxic side effects in the kidney and inner ear. Thus, their use is usually reserved for more serious infections. In food-producing animals, systemic use of some aminoglycosides (including neomycin) is often restricted because of widespread resistance and persistence of residues in kidney tissues, such that they are usually used therapeutically rather than metaphylactically or prophylactically, or as growth promotants (Reeves 2011).