Pharmacologic Management of Bacterial Biofilms

The organisms residing in biofilms are dormant and represent a therapeutic problem. Management of biofilm relies on surgical debridement and utilization of antimicrobial agents that can eliminate biofilm-associated microorganisms.

Bacterial biofilms represent a community of microorganisms within a cohesive extracellular matrix.¹ Biofilm synthesis occurs in a stepwise fashion and was first described by Stoodley and colleagues.² Organisms must attach to a biotic or abiotic surface via secretion and encasement of exopolymeric substance (EPS). A microcolony is then formed, ultimately developing into a mature biofilm and releasing biofilm cells. The establishment of a biofilm may serve a protective role by promoting survival within hostile environments. Secretion of EPS is one of the most important characteristics of a biofilm and serves many functions to enhance biofilm survival.³  EPS promotes bacterial attachment to biotic and abiotic surfaces, as well as to supplying nutrients to the microorganisms. Additionally, it also serves as a mechanical barrier to shield microorganisms from host immune responses and many antimicrobial agents.⁴ Unfortunately, the immune system is unable to eradicate the infectious etiology causing collateral damage to the surrounding tissue impairing the healing process. The organisms residing in biofilms are dormant and represent a therapeutic problem.^1,2 Biofilms are able to shield microorganisms from host immune responses and many antimicrobial agents. This state of decreased metabolic activity promotes increased antimicrobial tolerance, as the efficacy of most antimicrobial agents is dependent upon active division of microorganisms. Biofilm-associated organisms can be up to 1,000 times more resistant to the effects of antimicrobial agents.⁵ Furthermore, the composition of biofilms is almost universally polymicrobial, leading to a more virulent nature.^1,2 Transfer of antimicrobial-resistant genes to the same or different species via extrachromosomal elements may occur. Development of a resistant phenotype may be the result of limited nutrition, environmental stress, or increased organism inoculum.

Antimicrobial Treatment of Biofilm 

The infectious etiology of biofilms is quite broad, contributing to its polymicrobial nature.^1,2 Biofilms may develop on many medical devices, including central venous catheters, contact lenses, pacemakers, mechanical heart valves, prosthetic joints, peritoneal dialysis catheters, and urinary catheters.⁶ Staphylococcus aureus is the most commonly isolated pathogen, followed by coagulase-negative Staphylococci, Streptococcus spp, Enterococcus spp, and  gram-negative bacilli, including Pseudomonas aeruginosa. Obtaining an accurate identification of the infecting organism is vital to guiding antimicrobial therapy. Tissue cultures have higher rates of sensitivity and specificity compared to swab cultures.⁷ Management of biofilms relies on surgical debridement and utilization of antimicrobial agents that can eliminate biofilm-associated microorganisms. Outcomes are typically poor without surgical management.⁸ In some situations, removal of the infected device is the best option.  However, this may not be an option for all patients. Choosing the appropriate antimicrobial therapy is vital to ensure adequate penetration of the EPS while maintaining efficacy against surface-attached cells and dormant organisms. Traditional susceptibility testing may not be able to accurately predict antimicrobial efficacy against biofilms.⁶  

Antimicrobial agents that inhibit basic cell processes, including DNA, RNA, and protein synthesis, are some of the most effective agents against biofilm-associated microorganisms.⁹ Broad spectrum empirical therapy should be employed until the organism or organisms can be identified. Therapy should then be tailored based on susceptibility data (see Table^9-23 ). 

Tetracyclines, including tetracycline, minocycline, and doxycycline, inhibit protein synthesis via binding to the 30S ribosomal subunit.²⁴ Tetracyclines have activity against a wide range of gram-positive and gram-negative organisms. These drugs possess excellent oral bioavailability and high bone concentrations.²⁵ Evidence is unclear as to whether the drug is bioavailable, as it may be interacting with mineral matrix.⁸ While tetracyclines can be considered as alternative agents for biofilms, their use should be reserved for part of combination therapy. 

Clindamycin, a lincosamide, is active against many strains of S. aureus, including methicillin-resistant S. aureus (MRSA), streptococci, and anaerobes, by inhibiting protein synthesis via the 50S ribosomal subunit.²⁶ Oral absorption of clindamycin approaches 100% with adequate concentrations in almost all tissues except the cerebrospinal.^26,27 Clindamycin may also play a role in toxin production and virulence factors from Group A Streptococcus and S. aureus.¹⁰ Recent data emphasize utilizing high doses to avoid subinhibitory biofilm concentrations that could further induce biofilm formation.¹¹ 

The combination of trimethoprim/sulfamethoxazole (TMP/SMX) inhibits sequential steps in the folic acid pathway.²⁸ TMP/SMX is active against many gram-positive and gram-negative aerobic organisms. While it remains efficacious against many MRSA isolates, it has variable activity against streptococci. Most of the available data discussing the use of  TMP/SMX are in gram-negative biofilms, specifically Stenotrophomonas maltophilia and Acinetobacter baumannii.¹² However, it’s recommended to use TMP/SMX in combination with a quinolone to avoid inducing resistance.

Vancomycin binds to the peptidoglycan side chains in the cell wall, ultimately preventing cross-linking during cell wall synthesis, leading to cell death.²⁹ It’s still considered to be the drug of choice against MRSA despite its slow, bactericidal activity. Previous data suggest vancomycin diffuses into S. epidermidis and MRSA biofilms at adequate concentrations, causing cell damage.^13,14 The addition of rifampin produces much more bactericidal activity against planktonic bacteria in vitro. Therefore, combination therapy should be utilized with vancomycin to decrease therapy resistance and provide optimal efficacy.

Daptomycin is a cyclic lipopeptide with bactericidal activity against most gram-positive organisms, including MRSA and vancomycin-resistant enterococcus (VRE).³⁰ Daptomycin inserts its lipophilic tail into bacterial cell membranes, resulting in depolarization and potassium efflux and impaired protein synthesis. The result is rapid cell death. Unfortunately, daptomycin is poorly efficacious against bacteria in a dormant phase.³¹ The cell membrane disruption is likely to be much slower and more difficult to achieve due to cell membrane structure modification.  Even at higher concentrations, biofilm clearance was unobtainable.³² More data are needed on optimizing daptomycin against biofilms.

Ceftaroline is a broad-spectrum cephalosporin with antimicrobial activity similar to other β-lactams and cephalosporins.³³ It has bactericidal activity against most gram-positive organisms, including methicillin-sensitive S. aureus (MSSA), MRSA, and vancomycin-intermediate and resistant S. aureus, as well as most Enterobacteriaceae. Emerging data support the use of ceftaroline monotherapy or in combination with either vancomycin or daptomycin against MSSA and MRSA biofilms, highlighting its bactericidal activity.^15,16

Linezolid, an oxazolidinone, has activity against most gram-positive organisms, including MRSA and VRE.³⁴ It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. Added benefits of linezolid aside from its broad spectrum of activity include its wide tissue distribution and penetration, as well as its excellent oral bioavailability. Linezolid has also been shown to suppress S. aureus toxin production.¹⁷ Recent in vitro and in vivo evidence supports the use of linezolid against biofilms.⁹ Prolonged use may result in bone marrow suppression.³⁵

Rifampin inhibits DNA-dependent RNA-polymerase to inhibit RNA elongation.³⁶ Rifampin can eliminate biofilm-associated gram-positive microorganisms (both MSSA and MRSA); however, resistance develops quickly if used as a single agent.¹⁸ Adding a second agent decreases the likelihood of emerging resistance. Rifampin has broad penetration into tissues. Clinicians should be aware of the extensive list of drug-drug interactions associated with rifampin before starting this medication.

Fluoroquinolones target bacterial topoisomerases inhibiting DNA synthesis, leading to bacterial cell death.³⁷  These drugs possess good oral bioavailability and penetrate many tissues and fluids. Evidence suggests fluoroquinolones are active against biofilm-associated gram-negative bacilli.^19,20 Speculations exist as to whether fluoroquinolones decrease adhesion and biofilm formation.²¹ Fluoroquinolones should not be used to treat staphylococcal-associated biofilms due to the risk of inducing resistance.²² More data is needed to determine whether fluoroquinolones can be given monotherapy or if combination therapy produces a synergistic effect.²¹β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, inhibit bacterial cell wall synthesis.³⁸ These drugs maintain activity against susceptible biofilm-associated gram-positive organisms. The utility against biofilm-associated gram-negative bacilli remains uncertain.²³ Many β-lactam antibiotics may induce β-lactamase production in gram-negative bacilli biofilms. Until more evidence is available, β-lactams should be used in combination therapy against gram-negative biofilms. Most antimicrobial agents are unable to kill biofilm-associated bacteria despite activity against the same organism in the planktonic phase.  Antimicrobial agents that inhibit basic cell processes are considered to be the most effective agents against biofilm-associated microorganisms. Optimal treatment should combine surgical management with efficacious antimicrobial treatment.

Daniel B. Chastain is clinical assistant professor at the University of Georgia College of Pharmacy, Albany, and the infectious diseases pharmacy specialist at Phoebe Putney Memorial Hospital, Albany.

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