Synergy
Synergy is often defined as when the effect of two or more agents is greater than the sum of the individual agents and often used to overcome resistance. Typically, it is suggested to give the Beta-lactam first and then give the other antibiotic fairly soon after. This has been shown to decrease mortality. Beta-lactams can bind to the PBP enzymes and allow the other antibiotic to penetrate better, plus are normally more effective than the second drug.
Many combinations have in vitro synergy, with complementary mechanisms of action:
- Carbapenems and polymycins
- Polymyxin monotherapy often discouraged due to regrowth of bacteria within 24 hours in in vitro studies
- β-lactams + aminoglycosides
- Aminoglycosides generally not used as monotherapy in severe infections, like endocarditis
- β-lactams + daptomycin
- May be used for persistent staphylococcal infections or those with reduced susceptibility to daptomycin
- Exploits “seesaw” effect
- As daptomycin MIC increases, β-lactam MICs decrease due to cell wall thickening and increased usage of PBPs
- “Seesaw” effect also observed with vancomycin and β-lactams
- Dual β-lactam synergy has been demonstrated in some cases
- Ampicillin + ceftriaxone
- Ceftazidime-avibactam + aztreonam
- Potentially active against metallo-β-lactamase producers
- Aztreonam stable against MBLs, avibactam provides protection against co-expressed βlactamases (e.g., ESBLs, KPC, AmpC)
- Ertapenem and meropenem or doripenem
- Ertapenem acts as a “suicide substrate,” is hydrolyzed by carbapenemases
- Second carbapenem is allowed to access active site
- In this case, ertapenem should be administered first
- Ceftriaxone + ampicillin
- Increasingly used for ampicillin-susceptible enterococcal endocarditis
- Use of these agents overwhelms PBPs, leading to bactericidal activity
- Similar clinical outcomes to ampicillin + gentamicin with significantly lower risk of adverse events
There is some evidence that the Beta-lactam needs to come before other drugs when used in combination (or for synergy). There could be many reasons for this: modifying the cell wall could allow for easier entry of the other drug for example, but it’s likely that beta-lactams are just usually more effective and more likely to be susceptible, so hitting with the better drug first allows quicker recovery. See Joe Amoah et al., “Administration of a β-Lactam Prior to Vancomycin as the First Dose of Antibiotic Therapy Improves Survival in Patients with Bloodstream Infections,” Clinical Infectious Diseases, no. ciab865 (October 4, 2021).
Some “Fun” Virulence Factors
Bactiria have a few mechanisms of evading host defenses. These may also make treating them harder. They typically fiit into 3 groups:
- Adherence Factors: Many pathogenic bacteria colonize mucosal sites by using pili (fimbriae) to adhere to cells. Neisseria gonorrhoeae, Neisseria meningitidis, Escherichia coli, and Pseudomonas aeruginosa all have pili.
- Invasion Factors: These surface components that allow the bacterium to invade host cells can be encoded on plasmids, but more often are on the chromosome.
- Endotoxins: The lipopolysaccharide endotoxins on Gram-negative bacteria cause fever, changes in blood pressure, inflammation, lethal shock, and many other toxic events. E. coli, Salmonella, Shigella, Vibrio cholerae, and Neisseria meningitidis are some bacteria that produce endotoxins.
- Capsules: Many bacteria are surrounded by capsules that protect them from opsonization and phagocytosis. Acapsule is found most commonly among gram-negative bacteria: Escherichia coli (in some strains) Neisseria meningitidis. Klebsiella pneumoniae.
- Exotoxins: Exotoxins include several types of protein toxins and enzymes produced and/or secreted from pathogenic bacteria. Major categories include cytotoxins, neurotoxins, and enterotoxins.The various forms of Clostridia are prime examples of bacteria that produce exotoxins. Some Gram-negative bacteria, such as Pseudomonas aeruginosa, produce exotoxins as do most Gram-positive bacteria. Toxic shock syndrome is caused by staphylococcal or streptococcal exotoxins.
- Siderophores: Siderophores are iron-binding factors that allow some bacteria to compete with the host for iron, which is bound to hemoglobin, transferrin, and lactoferrin. They are produced in response to iron deficiency by Gram-positive and Gram-negative bacteria.
The Bacterial Community
Bacteria also have some factors that enhance bacterial community fitness.
Quorum Sensing
Quorum sensing is a mechanism employed by bacteria to communicate and coordinate their behavior based on population density. This process involves the production and detection of signaling molecules, allowing bacteria to regulate gene expression collectively. For example, some microbes won’t produce toxins until their population is high enough to evade host response. It’s like waiting for a fight until your buddies show up as backup.
Quorum Sensing Mechanisms: Bacteria use quorum sensing to regulate a wide array of physiological activities, including biofilm formation, virulence factor expression, and antibiotic resistance. Through this mechanism, bacteria can synchronize their activities to enhance their survival and pathogenicity. The coordinated action of bacteria in response to quorum-sensing signals can lead to the formation of biofilms, which are notorious for their resistance to antimicrobial agents.
Impact on Antimicrobial Resistance: Quorum sensing has been found to play a role in the development of antimicrobial resistance by facilitating the exchange of genetic material, upregulating efflux pumps, and modulating the expression of resistance genes. Additionally, the activation of quorum sensing pathways can lead to the development of tolerance to antibiotics, enabling bacterial populations to survive and thrive in the presence of antimicrobial agents.
Biofilms
Biofilms are complex structures formed by microorganisms, which can have significant implications for antimicrobial resistance and human health. These biofilms are composed of bacterial colonies or single types of cells that adhere to surfaces and are embedded in an extracellular polymeric matrix. This matrix, consisting of substances like eDNA, proteins, and polysaccharides, provides high resistance to antibiotics, making biofilm-associated infections challenging to treat.
Biofilm Formation and Resistance: Biofilms are known to increase the resistance of microorganisms to antimicrobial agents. Bacteria living in biofilms can exhibit a 10 to 1,000-fold increase in antibiotic resistance compared to similar bacteria living in a planktonic state. The extracellular polymeric substance (EPS) layer of biofilms can trap antibacterial drugs, reducing their effectiveness against the organisms present in the biofilm.