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Consequences of bio film resistance: superbugs

The investigation of antimicrobial resistance often overlooked persister cells as a cause for biofilm recalcitrance, especially because these cells are capable to survive sustained periods of antibiotic exposure and to change their phenotype to a growing state in the absence of the environmental stress. Therefore, the clinical relevance is that persister cells can be associated with chronic or recurrent infections as well as the fact that they can be considered a reservoir for antibiotic-resistant mutants due to their antimicrobial tolerance (Humphreys and McBain, 2014).

The study of biofilm cells that are associated with indwelling medical devices has demonstrated that the resistance problem is real, as provided in the examples listed in Table 4.3. These examples state that the microorganisms that are isolated from biofilms in medical devices or that were grown in conditions similar to reality were less susceptible to the antimicrobials.

The increased concern of the medical community to certain bacteria had contributed to the development of the superbug concept. Superbugs are bacteria that are susceptible to very few antimicrobials, that have a particular pathogenicity, or that can be easily transmissible and consequently cause outbreaks in healthcare facilities (Jones and Howe, 2014). The major clinically relevant superbugs are S. aureus, enterococci, Enterobacteriaceae, P. aeruginosa, and A. baumannii (Niveditha et al., 2012). Their resistance was observed in several cases listed in Table 4.3.

S. aureus infections are mainly related to soft tissue infections, however, it can also be responsible for certain invasive infections, with the mortality range 20-30% (Corey, 2009; Dancer, 2008). S. aureus is inherently susceptible to a variety of antimicrobials,

Table 4.3 Antimicrobial resistance observed in microorganisms associated with medical device biofilms

Medical device

Species

Observed resistance

References

Catheter

Mycobacterium avium

Bacteria grown in catheter as a biofilm were

significantly more resistant to clarithromycin than the planktonic counterpart.

Falkinham (2007)

Candida albicans

In vitro Candida formation in the presence of human serum is accompanied by alterations in the expression of several drug resistance genes.

Samaranayake et al. (2015)

Urinary catheter

Escherichia coli, Klebiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter lwoffi, coagulase-negative staphylococci, and Enterococcus spp.

Biofilm producers had higher resistance than

planktonic bacteria to ampicillin (83.3% vs. 60%), cephotaxime (73.3% vs. 35%), norfloxacin (80% vs. 60%), and nalidixic acid (93.3% vs. 70%).

Subramanian et al. (2012)

Enterococci

Significant relationship between the production of biofilm and the resistance to amoxicillin, co-trimoxazole, ciprofloxacin, gentamycin, cefotaxime, and cefuroxime.

Akhter et al. (2014)

Intravenous and peritoneal catheters

Staphylococcus lugdunensis

One strain was multiresistant and two carried the ermC gene.

Generally the strains were antimicrobial susceptible, but they carry virulence factors such as fbl, ica, atlL, vwbl, and slush.

These strains were also high-rate biofilm producers.

Giormezis et al. (2015)

Continued

Table 4.3 Continued

Medical device

Species

Observed resistance

References

Endotracheal tubes

P. aeruginosa, S. aureus, P. mirabilis, K. pneumoniae, Enterobacter, and E. faecalis

Biofilm isolates were less susceptible to tobramycin, cefotaxime, and cefuroxime than tracheal isolates.

Adair et al. (1999)

P. aeruginosa

Tobramycin and polymyxin E bactericidal activity, alone or in combination, was observed before biofilm attachment to endotracheal tubes. However, no activity was observed since biofilm formation.

Tarquinio et al. (2014)

A. baumannii and P. aeruginosa

The treatment failure and relapse episodes were related to A. baumannii and P. aeruginosa, even when appropriate treatment was applied.

Gil-Perotin et al. (2012)

Prosthetic joint

E. faecalis and E. faecium

Mature biofilms had higher tolerance to antibiotics such as rifampicin-containing combinations than new biofilms.

Holmberg and

Rasmussen (2016)

S. aureus

Cefazolin is not able to control the infection and the new implant is promptly colonized.

Dastgheyb et al. (2015)

Variety of indwelling medical devices

67 isolates

46 of the isolates were biofilm producers and their antibiotic resistance was higher in comparison with nonproducers.

Amoxicillin was ineffective against isolated bacteria.

Mishra et al. (2014)

such as в-lactams, glycopeptides, macrolides, tetracycline, clindamycin, and aminoglycosides. However, along the years several resistance mechanism were acquired such as production of в-lactamase to inactivate в-lactam rings or the acquisition of a gene encoding a modified penicillin-binding protein (intrinsically resistant to в-lactams) found in the case of MRSA and coagulase-negative staphylococci (Llarrull et al., 2009). The spreading of MRSA around the world is a consequence of epidemiology of S. aureus colonization, misuse of antimicrobials and antibiotics in hospitals, and lapses in basic procedures for infection control (Dancer, 2008).

Enterococci are part of the normal flora of the lower gastrointestinal tract of healthy adults. The most common species are E. faecalis and E. faecium and are also the major infection agents. 10 to 15% of native-valve of endocarditis are caused by enterococci and they can also promote bacteremia from urinary tract infections (Alberici et al., 2015; Jones and Howe, 2014). Enterococci are inherently resistant to several antimicrobial classes. They are resistant to cephalosporin and they have low sensibility to penicillin, amoxicillin, and carbapenems since they produce the low-affinity penicillin-binding proteins (Rathnayake et al., 2012).

Enterobacteriaceae are a large group of Gram-negative bacilli that are part of the commensal flora of human and animals’ gastrointestinal tract. Several species are opportunistic pathogens, and the most common urinary tract pathogen is E. coli (Alberici et al., 2015). Other species that can be included in this group are Klebsiella spp., Enterobacter cloacae, and P. mirabilis. Since enterobacteriaceae are Gram-negative, they possess an outer membrane that prevents the penetration of large molecules (vancomycin and daptomycin) and several penicillins (Ruppe et al., 2015).

P. aeruginosa is an opportunistic pathogen due to its ability to survive and grow in the presence of limited nutrients and a variety of environmental conditions as well as its inherent resistance to a wide range of antimicrobials. As described earlier, P. aeruginosa is a Gram-negative bacterium, therefore it has an outer membrane that confers inherent resistance to several antimicrobials such as в-lactams. This resistance to penicillins and cephalosporins is a combination of reduced permeability, low-affinity penicillin-binding proteins, в-lactamase production, and efflux (Smith et al., 2013). Horizontal gene transfer is important, however, the acquisition of potent в-lactamases is mediated through chromosomal mutations that modify the expression of intrinsic resistance mechanisms, such as efflux pumps (Vestergaard et al., 2016; Ruppe et al., 2015).

Another opportunistic pathogen is A. baumannii, especially in intensive care units of hospitals. A. baumannii is associated with a wide range of hospital infections and outbreaks. In fact, the most common is VAP. The mechanism of resistance of this bacterium is not yet extensively studied. Nonetheless, it is known that the outer membrane of A. baumannii is even less permeable than that of E. coli. This is a consequence of the existence of porins and the constitutive expression of efflux pumps, which contributes with resistance to antimicrobials such as в-lactam, aminoglycosides, chloramphenicol, quinolones, tetracycline, and tigecycline (Ruppe et al., 2015; Peleg et al., 2008).

Candida albicans is the most common pathogen of the Candida species. In fact, 10% of all nosocomial bloodstream infections that are associated with catheters are septicemias caused by Candida species. Other medical devices are also colonized by Candida such as urinary catheters, prosthetic heart valves, and pacemakers (Adam et al.,

2002). The main reasons for recalcitrant yeast cells are the increased drug resistance of the biofilm compared with planktonic cells and the transcriptional changes in virulence genes associated with biofilms (Samaranayake et al., 2015). Biofilms of Candida showed resistance to clinical antifungal agents such as amphotericin B and fluconazole (Ramage et al., 2001).

 
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