Antimicrobial resistance (AMR) is now recognised as a major public health crisis as essential antimicrobial drugs including antibiotics, antifungals, antivirals, antimalarials and anthelmintics become less effective therapeutic options. Biocides, which are chemicals used as sanitizers and disinfectants, consist of specific formulations containing one or more active ingredients that nonspecifically and fatally target microbial species. Antimicrobial resistance is one of the greatest dangers to public health of the 21st century, threatening the treatment and prevention of infectious diseases globally. Disinfection, the elimination of microbial species via the application of biocidal chemicals, is essential to control infectious diseases and safeguard animal and human health. In an era of antimicrobial resistance and emerging disease, the effective application of biocidal control measures is vital to protect public health.
Staphylococcus aureus (MRSA)
Candida auris
2
2
Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter
Pseudomonas
Acinetobacter
Staphylococcus
E. coli
Klebsiella
Proteus
Pseudomonas
qacE
qacA/B
Pseudomonas
qacA/B
S. aureus
qac
qacA/B
norA/b
smr
Enterococcus
Staphylococcus
Bacillus
Pseudomonas
Vibrio
Acinetobacter
Proteus
Neisseria
Staphylococcus
S. aureus
S. pneumonia
S. aureus
E. faecium
P. aeruginosa
S. aureus
Burkholderia cepacia
Achromobacter spp
qacEΔ1
E. coli
P. aeruginosa
Staphylococcus
A. baumannii
P. aeruginosa
K. pneumonia
2
2
A. baumannii
K. pneumoniae
P. aeruginosa
Table 1.
Enzyme Type | Representative Enzymes | Known Substrates | Inhibitor Profile | Clinically Associated Pathogens | Biocidal Resistance |
---|
Serine β-lactamases | Penicillinase | PC1/blaZ | Penicillins | CA and TZ | MRSA | qacA/B (acquired), norA and lmrS (intrinsic) genes encoding MFS pumps. MecA (MATE superfamily) and sepA multidrug efflux pump genes. SMR pumps encoded by smr (also known as qacC/D and Ebr), qacG, qacH and qacEΔ1 (acquired) [35][36][37][35,36,37] |
Broad- spectrum (TEM, SHV-type) |
TEM-1, -2 and -13, SHV-1 and -11 | Penicillins and 1st-generation cephalosporins [38] |
2
2
Candida
Candida auris
Candida
C. auris
2
2
Candida
C. auris
C. albicans
Aspergillus
Aspergillus
2
2
Medically Important Pathogen | Associated Disease | Antimicrobial Resistance | Biocidal Resistance |
---|
Fungal | Candida albicans | Candidemia, mucosal candidiasis, cutaneous infections | Mutations in ERG11 and Upc2p, and overexpression of Cdr1, Cdr2 and Mdr1 confer azole resistance Polyene resistance is linked to changes in ERG3 and ERG6 Mutations in CaFKS1 confer resistance to echinocandins [58] |
Fungal biocide resistance is not yet completely understood, being related to multiple defence mechanisms, including mutations, inducible efflux, exclusion or reduced access of antiseptic or disinfectant (chlorhexidine), enzymatic inactivation (formaldehyde) and phenotypic modulation (alcohol) [59][74][59,74] Virulence factors such as biofilm-forming capabilities and melanin further contribute to protection against biocides in fungi |
||
Cryptococcus neoformans | Cryptococcal meningitis, pulmonary cryptococcosis, cutaneous infections | Mutations in ERG11, overexpression of ERG11 due to chromosome 1 duplication and upregulation of AFR1 gene (encodes ABC transporter) confer resistance to azoles [75] Mutation in ERG2 resulting in its inactivation, confers resistance to amphotericin b [76 | CA, TZ and SB | Enterobacteriaceae (E. coli, K. pneumonia, Proteus sp.) non fermenters (i.e., Pseudomonas aeruginosa., Acinetobacter baumannii) and Neisseria gonorrhoeae | ] | Acquired efflux resistance to QACs and chlorhexidine encoded by qacEΔ1, qacE, qacG, qacH and emrE (SMR), qacA (MFS) and cep A genes common in many Enterobacteriaceae [39][40][39,40] and non-fermenters [41][42][41,42] Multidrug efflux MATE pumps (chromosomally encoded) conferring resistance to biocides and antimicrobials, examples include YdhE of E. coli, PmpM of P. aeruginosa, and AbeM of A. baumannii [43] Upregulation of chromosomally encoded RND pumps conferring cross-resistance to biocides, antimicrobials and other agents (dyes, metals), examples include AcrAB-TolC, AcrEF-TolC in E. coli and other Enterobacteriaceae [39] MtrD in N. gonorrhoeae [44] MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexJK pumps in Pseudomonas [45] AdeABC, AdeFGH, AdeIJK and AbeD efflux systems in A. baumannii [46] |
TEM-30 and -31, SHV-10 | ||||||
Aspergillus niger | Penicillins | Reduced binding to CA or inhibitor resistant apart from AV | ||||
Pulmonary aspergillosis, Aspergillus bronchitis, allergic bronchopulmonary aspergillosis (ABPA) | Azole resistance related to point mutations in | Cyp51A gene, overexpression of Cyp51A gene and upregulation of efflux pumps [77] | ESBL (TEM, SHV, PER, VEB, CTX-M-type) |
TEM-3, and -10, SHV-3, CTX-M-1, -14, -15 and -44, PER-1, VEB-1 | Penicillins, 1st, 2nd- and 3rd-generation cephalosporins and monobactam | CA, TZ, SB and AV |
Viral | Human papillomavirus (HPV) (nonenveloped) |
Cervical cancer | No treatment available | Nonenveloped viruses are more resistant to biocides, showing reduced susceptibility/resistance to lipophilic agents such as Qacs [13 | TEM-50 and -158 | Reduced binding to CA or inhibitor resistant apart from AV |
] | Carbenicillinase | PESE-1, -3 and -4, CARB-1 | Penicillins and carbenicillin | CA, TZ and SB | ||
Carbapenemase (KPC, GES, SME-type) | KPC-2 and -10, IMI-1, SME-1, and -2, GES-2 and -7 | All beta lactams | Variable to CA, TZ and AV | P. aeruginosa, and K. pneumonia (and other Enterobacteriaceae) | ||
OXA-type (Broad spectrum, ESBL and Carbapenemase) |
OXA-1, OXA-9, OXA-10, OXA-2 [38] | |||||
Human immunodeficiency virus (HIV) (enveloped) |
Penicillins (oxacillin, cloxacillin) | Variable to CA, TZ and AV | Enterobacteriaceae (K. pneumonia, E. coli, Enterobacter sp.), nonfermenters and Neisseria gonorrhoeae | |||
Acquired immunodeficiency syndrome (AIDS) | Drug resistance is caused by changes in the genetic structure of HIV that affect the ability of drugs (e.g., HAART) to block the replication of the virus | [78] | Enveloped viruses are the least resistant to inactivation by biocides, where their lipid envelope is easily compromised by most disinfectants and antiseptics [ | OXA-11, OXA-14, OXA-15, | Penicillins, 3rd-generation cephalosporins, monobactams | |
13 | OXA-3, OXA-51, OXA-58, OXA-23, OXA-48 | All beta lactams/carbapenems | ||||
] | AmpC cephamycinases | AmpC (chromosomal encoded) |
All beta lactams except carbapenems | Inhibitor resistant apart from AV | Citrobacter, Serratia, Enterobacter spp., and P. aeruginosa (expression usually inducible) and Enterobacteriaceae (not as inducible) | Studies report on the presence of efflux pumps belonging to the MATE and RND families in Enterobacter, where AmpC is inducible in these species [47] qacE∆1 is commonly reported in enteric pathogens, being associated with class 1 integrons that carry multiple gene cassettes including AmpC β-lactamases [48] |
MOX, ACC, FOX, DHA, CMY, MIR-type (plasmid encoded) | Non fermenters and Enterobacteriaceae | |||||
Metallo-β-lactamases | Carbapenemases (IMP, VIM, NDM-type) | IMP-1, VIM -1 and -2, NDM-1 [38] | All beta lactams except aztreonam | EDTA or 1-10 phenanthroline, mercaptopropionic acid or sodium mercaptoacetic acid and dipicolinic acid | Pseudomonas and Acinetobacter sp. | RND efflux pumps on plasmids that carry resistance determinants such as blaNDM-1 have been reported [41][49][41,49] Association of qac genes with the presence of NDM, VIM and IMP beta lactamases reported in clinical A. baumanii [42] |
CA—clavulanate acid, TZ—Tazobactam, SB—Sulbactam, AV—Avibactam.
Candida
Cryptococcus
Aspergillus
C. albicans
C. glabrata
C. auris
Candida krusei
C. auris
Cryptococcus
Saccharomyces
Aspergillus, Neurospora
Cryptococcus
Candida
CaCDR1
CaCDR2
Candida
Trichosporon
Rhodotorula
Candida albicans
Candida
Candida
Cryptococcus
Candida
Aspergillus
Campylobacter
Listeria
Salmonella
E. coli O157
Vibrio
Clostridium
Streptococcus
E. coli
Pseudomonas
Pseudomonas
E. coli
Salmonella typhimurium
Salmonella
S. enteritidis
S. typhimurium
Salmonella
Cryptococcus
Candida
Aspergillus
Candida auris,
C. auris