Bacteriostatic antibiotics, a term generally used to describe antibiotics which function via inhibition of bacterial protein synthesis, have a large variety of indications in medicine according to their mechanisms of action. Due to merely inhibiting further growth of bacteria, bacteriostatic antibiotics require a functioning host immune system to fully clear overgrowth. Due to this effect, however, observational studies have shown that there is a lower incidence of toxic shock and more tolerable side effect profiles. The following classes and specific antibiotics are generally considered bacteriostatic: tetracyclines, macrolides, clindamycin, trimethoprim/sulfamethoxazole, linezolid, and chloramphenicol. However, chloramphenicol has fallen out of favor in recent years.
The indications for tetracycline antibiotics are extremely broad. As one of the oldest classes of antibiotics, tetracyclines have been shown to have good activity against gram-positive, gram-negative, atypical, and spirochete bacteria. While older tetracyclines (tetracycline, doxycycline) have significant resistance developed in more common pathogens, they retain good activity against atypical pathogens. Newer agents within this class (tigecycline), however, are seeing increasing use in the treatment of multiresistant pathogens due to low rates of resistance. Additionally, due to their wide spectrum of activity and predictable and comparatively tolerable toxicity profile, these agents are popular in the outpatient setting.
The indications for macrolide antibiotics are dependent upon the specific macrolide antibiotic in question. There are three primary antibiotics within this class: erythromycin, clarithromycin, and azithromycin. Erythromycin has poor activity against gram-negative and anaerobic organisms. However, it is extremely effective against atypical pathogens and has some activity against Neisseria. Clarithromycin has a similar spectrum of activity to erythromycin, with additional activity against some staph and strep species. Azithromycin generally has less activity against most common gram-positive and negative pathogens, but it demonstrates higher efficacy against atypical agents.
Clindamycin is an antibiotic that has gained many indications. In a 1996 review of the literature concerning the drug, indications for it include the following uses: skin and soft tissue infections (including diabetic foot), osteomyelitis and septic arthritis, recurrent streptococcal pharyngitis, anaerobic lung infections, and as an alternative for intra-abdominal and pelvic infections. However, it has poor activity in the bloodstream and is not a recommended therapy in septic patients or those with most gram-negative infections.
Trimethoprim/sulfamethoxazole previously saw use as the primary outpatient antibiotic for a wide variety of infections. However, due to the emergence of widespread resistance, it has lost its utility for empiric coverage of infection in the outpatient setting. Currently, trimethoprim/sulfamethoxazole indications include for the treatment of uncomplicated cystitis in patients without recent antibiotic use, hospitalization, or recurrent UTI in the past year; as well as empiric treatment of non-bloody infectious diarrhea. Due to high resistance in strep and staph species, it is no longer the recommended agent in respiratory or skin/soft tissue infection.
Additionally, trimethoprim/sulfamethoxazole is one of the agents of choice for the prevention of HIV/AIDS-associated infections, specifically pneumocystis pneumonia. Its recommendations include its use as a prophylactic agent in patients with CD4 count less than 200/microliter.
Linezolid, first gaining widespread use in the 2000s, has broad activity against most gram-positive organisms. Due in large part to its expense, as well as efforts to protect it against developing resistance at large, its primary use is for the treatment of multi-drug resistant gram-positive infections. It has poor activity against gram-negative and anaerobic bacteria, and clinicians should not use it in these settings. Additionally, due to its limited spectrum of activity, it should not be used as an empiric antibiotic.
Bacteriostatic antibiotics most commonly function via the inhibition of bacterial protein synthesis pathways.
As a class, the primary mechanism of action of tetracycline antibiotics is the reversible inhibition of the 30S bacterial ribosomal subunit. 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. Specifically, they bind and inhibit the translocation of amino acids out of the ribosomes, halting protein synthesis. Clindamycin additionally affects the 50S bacterial subunit; however, it inhibits the subunit at a different site than macrolides.
Trimethoprim/sulfamethoxazole has been a successful antibiotic formulation because each of its constituents, trimethoprim, and sulfamethoxazole, prevents effective processing of folic acid and its derivatives in bacteria. The thinking is that the synergistic effect of the combination significantly increases its efficacy as compared to either agent alone. Although there is a mounting body of research suggesting that this may be untrue, the combined formulation still predominates due to a lower prevalence of resistance to the combination in the community.
Linezolid has a unique mechanism of action compared to other antibiotics. It inhibits the P site of the 50 S ribosome, which prevents the formation of bacterial ribosomes instead of preventing protein synthesis. As a result of this, it has no cross-resistance with other classes of antibiotics.
Tetracycline antibiotics are administrable either orally or intravenously. 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 been shown to have enteral absorption >90% of the oral dose. The preferred intravenous preparation of tetracycline antibiotics is doxycycline and should be given into the central venous system to reduce the risk of infusion site hypersensitivity.
While erythromycin administration is possible via the IV route, the most common formulation of macrolide antibiotics is in oral forms. This is due to these agents causing significant pain and discomfort around the infusion site parenterally. Additionally, intravenous macrolides have correlations with thrombophlebitis.
Clindamycin is nearly completely absorbed orally. However, it has a relatively short half-life, requiring re-dosing every 6 hours. It can be given to both children and adults intravenously if there is a contraindication to oral medication use. Finally, clindamycin has topical preparations, most commonly used for the treatment of pelvic or vaginal infections.
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. Additionally, it has excellent absorption via the enteric system and gets excreted in its active form in the urine. Trimethoprim, however, is more widely distributed throughout the body and is more readily excreted into the urine, causing variable levels of each component over time throughout the body.
Linezolid has near 100% absorption orally and may be given either orally or intravenously, depending on the clinical setting. 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.
Similar to their indications, the adverse effects of bacteriostatic antibiotics are dependent upon the drug in question.
Due to their excellent bioavailability in most tissues throughout the body, tetracyclines can deposit into vascularized bones and tissues easily; 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.
Macrolide antibiotics 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. Azithromycin, however, appears to have less activity on CYP3A4 and has weaker drug interactions.
Clindamycin commonly correlates with local hypersensitivity and skin reactions, which can be severe enough to cause toxic epidermal necrolysis or stevens-johnson syndrome. Additionally, both oral and intravenous preparations of clindamycin deplete the bacterial reserve of the gut and are strongly associated with rates of C. difficile colitis (up to 20 to 30%) as well as high rates of diarrhea without underlying infection.
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. For most of these agents, it increases blood level, therefore increasing activity. However, it appears to inactivate oral contraceptives. Additionally, as a sulfa antibiotic, there is a significant risk of allergy within the general population. A final effect of trimethoprim/sulfamethoxazole is that it causes an approximately 10% rise in serum creatinine level without affecting renal function, which can mimic signs of nephrotoxicity.
Linezolid is generally well-tolerated in the general population. While it has traditionally shown correlations with a risk of serotonin syndrome when given in combination with other serotonergic medications, this risk is low.
The contraindications to the various bacteriostatic agents are specific to each class of drug/agent in question. Contraindications to most tetracycline antibiotics are as follows: kidney dysfunction (except doxycycline), children less than eight, pregnant patients, and active colitis. There are no absolute contraindications to macrolide antibiotics. However, clinicians should pay significant attention to drug interactions, cardiac arrhythmias, and hypersensitivity related to drug breakdown products. Clindamycin has poor penetrance into the central nervous system and is contraindicated in a nervous system infection. trimethoprim/sulfamethoxazole is contraindicated in sulfa-allergic patients.  Linezolid has no significant contraindications; however, due to antibiotic stewardship efforts, its use should be avoided except in resistant gram-positive infections.
One advantage of most bacteriostatic antibiotics, as a class, is that they usually do not require intensive monitoring as other classes of bactericidal drugs. Tetracycline antibiotics do not typically require monitoring of blood drug levels, nor do they have an easily identifiable metabolite to monitor their activity in vivo. 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. Macrolides generally do not require specific monitoring in vivo. However, if patients are taking other agents with macrolides, corresponding levels of other drugs should be monitored for alterations in their activity. Clindamycin does not require laboratory monitoring for side effects; however, clinical monitoring for symptomatic diarrhea and colitis is recommended. There is no monitoring required for trimethoprim/sulfamethoxazole therapy. There is no monitoring required for linezolid.
In general, due to the comparatively slower mechanism of action of bacteriostatic antibiotics, the toxicity profiles of bacteriostatic agents are generally lesser than their comparable bacteriocidal analogs. Tetracycline antibiotics, while generally well tolerated, have the following toxicities: irritant gastritis, photosensitivity, hepatotoxicity, nephrotoxicity (except doxycycline), and hypersensitivity reactions (may not be allergic, related to expired antibiotics). The most common toxicities of macrolide antibiotics are allergic reactions, gastrointestinal distress and promotility, cardiac arrhythmias (erythromycin, QT prolongation), and tinnitus (erythromycin). 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. The most significant toxicity reported in the literature for linezolid is myelosuppression and thrombocytopenia, with rates approaching 2.5%.
There has been a traditional bias against bacteriostatic antibiotics 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. This perception, however, is untrue in several settings. 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. 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 on 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 compliance 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 antibiotics while limiting drug resistance and adverse events. [Level V]
|||Pankey GA,Sabath LD, Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004 Mar 15; [PubMed PMID: 14999632]|
|||Nemeth J,Oesch G,Kuster SP, Bacteriostatic versus bactericidal antibiotics for patients with serious bacterial infections: systematic review and meta-analysis. The Journal of antimicrobial chemotherapy. 2015 Feb; [PubMed PMID: 25266070]|
|||Fridkin SK,Gaynes RP, Antimicrobial resistance in intensive care units. Clinics in chest medicine. 1999 Jun; [PubMed PMID: 10386258]|
|||McCabe WR, Antibiotics and endotoxic shock. Bulletin of the New York Academy of Medicine. 1975 Oct; [PubMed PMID: 1058731]|
|||Smilack JD, The tetracyclines. Mayo Clinic proceedings. 1999 Jul; [PubMed PMID: 10405705]|
|||Vicente D,Pérez-Trallero E, [Tetracyclines, sulfonamides, and metronidazole]. Enfermedades infecciosas y microbiologia clinica. 2010 Feb; [PubMed PMID: 20097452]|
|||Cobos-Trigueros N,Ateka O,Pitart C,Vila J, [Macrolides and ketolides]. Enfermedades infecciosas y microbiologia clinica. 2009 Aug-Sep; [PubMed PMID: 19625112]|
|||Jelić D,Antolović R, From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials. Antibiotics (Basel, Switzerland). 2016 Sep 1; [PubMed PMID: 27598215]|
|||Smieja M, Current indications for the use of clindamycin: A critical review. The Canadian journal of infectious diseases = Journal canadien des maladies infectieuses. 1998 Jan; [PubMed PMID: 22346533]|
|||Gudiol C,Cuervo G,Shaw E,Pujol M,Carratalà J, Pharmacotherapeutic options for treating Staphylococcus aureus bacteremia. Expert opinion on pharmacotherapy. 2017 Dec; [PubMed PMID: 29115883]|
|||Austin MN,Beigi RH,Meyn LA,Hillier SL, Microbiologic response to treatment of bacterial vaginosis with topical clindamycin or metronidazole. Journal of clinical microbiology. 2005 Sep; [PubMed PMID: 16145097]|
|||Masters PA,O'Bryan TA,Zurlo J,Miller DQ,Joshi N, Trimethoprim-sulfamethoxazole revisited. Archives of internal medicine. 2003 Feb 24; [PubMed PMID: 12588198]|
|||Guillard P,de La Blanchardière A,Cattoir V,Fischer MO,Verdon R,Saint-Lorant G, Antimicrobial stewardship and linezolid. International journal of clinical pharmacy. 2014 Oct; [PubMed PMID: 25135806]|
|||Metaxas EI,Falagas ME, Update on the safety of linezolid. Expert opinion on drug safety. 2009 Jul; [PubMed PMID: 19538105]|
|||Manfredi R, Update on the appropriate use of linezolid in clinical practice. Therapeutics and clinical risk management. 2006 Dec; [PubMed PMID: 18360656]|
|||Maaland MG,Papich MG,Turnidge J,Guardabassi L, Pharmacodynamics of doxycycline and tetracycline against Staphylococcus pseudintermedius: proposal of canine-specific breakpoints for doxycycline. Journal of clinical microbiology. 2013 Nov; [PubMed PMID: 23966509]|
|||Ratcliffe AT,Ismail KM, Intravenous macrolide use: a reminder of the dangers of rapid infusion rates. Journal of clinical anesthesia. 2012 Nov; [PubMed PMID: 23101782]|
|||de Dios García-Díaz J,Santolaya Perrín R,Paz Martínez Ortega M,Moreno-Vázquez M, [Phlebitis due to intravenous administration of macrolide antibiotics. A comparative study of erythromycin versus clarithromycin]. Medicina clinica. 2001 Feb 3; [PubMed PMID: 11222159]|