Bacteriostatic Antibiotics

Mechanism of Action

Bacteriostatic antimicrobials most commonly function via the inhibition of bacterial protein synthesis pathways.

As a class, the primary mechanism of action of tetracycline antimicrobials is the reversible inhibition of the 30S bacterial ribosomal subunit.[5][6][16] This inhibition causes the arrest of bacterial protein production, which inhibits bacterial defenses and allows for host immune cells to eliminate the offending bacteria.

Macrolides function via inhibition of the larger subunit of bacterial ribosomes, the 50S subunit.[8][9] Specifically, they bind and inhibit the translocation of amino acids out of the ribosomes, halting protein synthesis.[8][9] Clindamycin additionally affects the 50S bacterial subunit; however, it inhibits the subunit at a different site than macrolides.[9]

Trimethoprim/sulfamethoxazole has been a successful antimicrobial combination formulation because each of its constituents, trimethoprim, and sulfamethoxazole, prevents effective processing of folic acid and its derivatives in bacteria.[12] The thinking is that the synergistic effect of the combination significantly increases its efficacy compared to either agent alone.[12] Although a mounting body of research suggests that this may be untrue, the combined formulation still predominates due to a lower prevalence of resistance to the combination in the community.[12]

Linezolid has a unique mechanism of action compared to other antimicrobials. It binds to the P site of the 50 S ribosome, which prevents the formation of bacterial ribosomal fMet-tRNA complex and thus preventing bacterial protein synthesis.[15][10] As a result of this, it has no cross-resistance with other classes of antimicrobials.[10][15]

Administration

Tetracycline antimicrobials are administrable either orally or intravenously.[5][6][7] Other preparations of tetracyclines are not common due to concerns for hypersensitivity reactions around the administration site. Most tetracyclines have poor oral bioavailability: generally less than 50%. However, doxycycline has shown to have enteral absorption exceeding 90% of the oral dose.[7] The preferred intravenous preparation of tetracycline antimicrobial is doxycycline and should be given into the central venous system to reduce the risk of infusion site hypersensitivity.[5][6][7]

While erythromycin administration is possible via the IV route, the most common formulation of macrolide antimicrobials is in oral dosage forms.[17][8][9] This is due to these agents causing significant pain and discomfort around the infusion site parenterally. Additionally, intravenous macrolides have correlations with thrombophlebitis.[17][18]

Clindamycin is nearly completely absorbed orally. However, it has a relatively short half-life, requiring dosing every 6 hours.[9] It can be given intravenously to both children and adults if there is a contraindication to oral medication use.[9] Finally, clindamycin has topical preparations, most commonly used for the treatment of pelvic or vaginal infections.[9][11]

Trimethoprim/sulfamethoxazole has available formulations on the market in both oral and intravenous forms; however, due to its indications, it is nearly universally encountered in its oral formulation.[12] Additionally, it has excellent absorption via the enteric system and gets excreted in its active form in the urine.[12] Trimethoprim, however, is more widely distributed throughout the body and is more readily excreted into the urine, causing variable concentrations of each component over time throughout the body.[12]

Linezolid has nearly 100% absorption orally and may be given orally or intravenously, depending on the clinical setting.[14] Additionally, the drug may be taken with or without food and has a half-life allowing for twice-daily dosing. It also appears to have widespread penetration into tissue throughout the body and can be used for infections of multiple different sites.[13][10][15]

Adverse Effects

Similar to their indications, the adverse effects of bacteriostatic antimicrobials are dependent upon the drug in question.

Due to their excellent bioavailability in most tissues throughout the body, tetracyclines can easily be deposited into vascularized bones and tissues; this becomes problematic in fetuses and children less than eight years old, where tetracycline antibiotics can deposit and cause a characteristic brown discoloration of bones, which is permanent throughout life. This adverse effect is not inherently toxic and is a relative contraindication. Additionally, this effect is directly dose-dependent.[6][7]

Macrolide antimicrobials are significant inhibitors of CYP3A4 and have several interactions via these pathways. Specifically, they increase serum concentrations of carbamazepine, corticosteroids, cyclosporin, digoxin, theophylline, valproic acid, and warfarin.[8][9] Azithromycin, however, appears to have less activity on CYP3A4 and has weaker drug interactions.[8][9]

Clindamycin commonly correlates with local hypersensitivity and skin reactions, which can be severe enough to cause toxic epidermal necrolysis or Stevens-Johnson syndrome.[9] Additionally, both oral and intravenous preparations of clindamycin deplete the bacterial reserve of the gut and strongly correlate with rates of C. difficile colitis (up to 20 to 30%) and high rates of diarrhea without underlying infection.[9]

Generally, trimethoprim/sulfamethoxazole is well-tolerated in both immunocompetent and immunocompromised patients. However, there are some drug-drug interactions with warfarin, methotrexate, phenytoin, digoxin, and oral contraceptives.[12] For most of these agents, it increases blood concentrations, therefore increasing activity. However, it appears to inactivate oral contraceptives.[12] Additionally, as a sulfonamide-containing (sulfa) antimicrobial, there is a significant risk of allergy within the general population.[12] A final effect of trimethoprim/sulfamethoxazole is that it causes an approximately 10% rise in serum creatinine concentrations without affecting renal function, which can mimic signs of nephrotoxicity.[12]

Linezolid is generally well-tolerated in the general population.[14] While it has traditionally shown correlations with a risk of serotonin syndrome when given in combination with other serotonergic medications, this risk is low.[15][14]

Contraindications

The contraindications to the various bacteriostatic agents are specific to each class of drug/agent in question. Contraindications to most tetracycline antimicrobials are as follows: kidney dysfunction (except doxycycline), children less than eight, pregnant patients, and active colitis.[6][7] There are no absolute contraindications to macrolide antimicrobials. However, clinicians should pay significant attention to drug interactions, cardiac arrhythmias, and hypersensitivity related to drug breakdown products.[7] Clindamycin has poor penetrance into the central nervous system and is contraindicated in a nervous system infection.[9] trimethoprim/sulfamethoxazole is contraindicated in sulfa-allergic patients. [12] Linezolid has no significant contraindications; however, its use should be avoided except in resistant gram-positive infections due to antimicrobial stewardship efforts.[15][10]

Monitoring

One advantage of most bacteriostatic antimicrobials, as a class, is that they usually do not require intensive monitoring as other classes of bactericidal drugs. Tetracycline antimicrobials do not typically require monitoring of blood drug concentrations, nor do they have an easily identifiable metabolite to monitor their activity in vivo.[6][7] However, caution is necessary regarding patients' consumption of certain metallic elements (Ca, Al, Mg, etc.), specifically due to their inactivation by divalent and trivalent cations.[6][7] Macrolides generally do not require specific monitoring in vivo. However, if patients are taking other agents with macrolides, corresponding concentrations of other drugs should be monitored for alterations in their activity.[8][9] Clindamycin does not require laboratory monitoring for side effects; however, clinical monitoring for symptomatic diarrhea and colitis is recommended.[9] There is no monitoring required for trimethoprim/sulfamethoxazole therapy.[12] There is no monitoring required for linezolid.[14]

Toxicity

In general, due to the comparatively slower mechanism of action of bacteriostatic antimicrobials, the toxicity profiles of bacteriostatic agents are generally lesser than their comparable bacteriocidal analogs.[1][4] Tetracycline antimicrobials, while generally well tolerated, have the following toxicities: irritant gastritis, photosensitivity, hepatotoxicity, nephrotoxicity (except doxycycline), and hypersensitivity reactions (may not be allergic).[6][7] The most common toxicities of macrolide antimicrobials are allergic reactions, gastrointestinal distress and promotility, cardiac arrhythmias (erythromycin, QTc prolongation), and tinnitus (erythromycin).[8][9] These agents, however, are generally well tolerated. Trimethoprim/sulfamethoxazole has less than 10% gastrointestinal, dermatologic toxicities and a very rare risk of aplastic anemia. The toxicity regimen of linezolid is generally limited to low risks of gastrointestinal distress, headache, and rash.[14] The most significant toxicity reported in the literature for linezolid is myelosuppression and thrombocytopenia, with rates approaching 2.5%.[14]

Enhancing Healthcare Team Outcomes

There has been a traditional bias against bacteriostatic antimicrobials for a variety of indications, particularly in more acute settings, due to a misconception that they have clinically slower rates of activity and lose efficacy.[1][3] This perception, however, is untrue in several settings.[2][1][3] With appropriate stewardship and understanding of the risk and benefits of these agents, they can be used in a variety of clinical indications to help maintain the efficacy of many of the broad spectrum bactericidal agents commonly in use in hospitals and outpatient clinics.[2] The level of evidence for the composite studies in this article is I-II.

The use of these bacteriostatic agents requires an interprofessional team approach to patient care. The prescribing/ordering clinician will decide which antimicrobial to use; this decision should be in tandem with a board-certified infectious disease pharmacist, in conjunction with the latest antibiogram data - especially in the inpatient setting. The pharmacist should also perform a complete medication reconciliation to rule out potential drug-drug interactions. Nursing will be responsible for administering these drugs in the inpatient setting, and for outpatients, they can still counsel the patient on proper administration. Nursing can also evaluate patient adherence and should be cognizant of potential adverse reactions so they can be reported to the prescriber immediately. This interprofessional team approach will optimize the therapeutic potential for bacteriostatic antimicrobials while limiting drug resistance and adverse events. [Level 5]