Similarly, studies demonstrated that using linezolid a bacteriostatic agent against MRSA was non-inferior to vancomycin a bactericidal agent against MRSA. Because clinical outcomes depend on 3 factors:. Why could this be potentially clinically irrelevant? Because clinical outcomes depend on 3 factors: The host The pathogen The drug with many internal factors coming into play as listed below -Tissue penetration -Pharmacokinetics -Drug interactions -Optimal dosing TAKE-HOME POINTS: Antibiotics can be bacteriostatic for some pathogens and bactericidal for others Clinical outcomes depend on a variety of factors and the bactericidal property of an antibiotic ultimately appears to have little clinical relevance.

References: Nemeth, J. Bacteriostatic versus bactericidal antibiotics for patients with serious bacterial infections: systematic review and meta-analysis.

Journal of antimicrobial chemotherapy. French, G. Bactericidal agents in the treatment of MRSA infections — the potential role of daptomycin. Bacteriostatic agents can achieve this by obstructing the metabolic mechanisms of the bacterial cell, in most cases targeting the protein synthesis.

While doing this does not cause outright cell death, it does effectively inhibit further growth and DNA replication of the bacterial cells. When bacteriostatic agents are utilized, the treatment will regulate the number of bacterial cells. While the bacteria will not be eliminated, their numbers will not increase.

Bacteriostatic substances produce reversible results. As indicated in a recent study by Hong and colleagues 34 , ROS do indeed have a role in those downstream processes.

In the following sections, we separately consider antibiotics of six classes, what is known, what has been postulated and what should be known about the ultimate mechanisms by which they kill bacteria. See Fig. The confidence of clinicians in aminoglycoside therapy is commonly based on the known strong bactericidal effect of these drugs.

Although a great deal is known about the proximal mechanism of action of aminoglycosides 92 , 93 , no widely accepted or supported hypothesis exists so far for the ultimate mechanism by which these drugs kill bacteria. Three not mutually exclusive hypotheses stand out. A fourth hypothesis, death by superoxides, applies to all bactericidal antibiotics and will be considered separately.

The most commonly offered explanation for the bactericidal action of this class of drugs is that the ribosome—aminoglycoside interactions, mediated by the number and basicity of amino groups in the drug, give rise to toxic mistranslated proteins, which kill by increasing the permeability of the cell membrane However, to our knowledge, these toxic proteins have not been isolated, and how they actually kill remains undemonstrated.

It is also unclear why these postulated products of mistranslation are not destroyed by the proteases that usually remove mistranslated and misfolded proteins.

and F. There is also a pharmacodynamic observation consistent with the toxic mistranslated protein hypothesis. In accord with this hypothesis, the rate of ribosome binding, and thereby the abundance of toxic proteins generated by mistranslation, should be proportional to the growth rate of the target population and the number of ribosomes, which indeed has been observed However, some observations question the uniqueness of the toxic mistranslated protein mechanism explaining the bactericidal effect of aminoglycosides.

Most importantly, gentamicin can kill E. coli and S. aureus in the stationary phase, when the number of ribosomes is minimal 35 , and is more bactericidal in E.

coli variants with a reduced number of rrn operons 3. Collectively, these observations suggest a ribosome-independent but not alternative mechanism by which aminoglycosides kill bacteria.

After aminoglycoside exposure, potassium and intracellular molecules such as nucleotides leak from the bacterial cell immediately, certainly no later than protein synthesis inhibitory effects 35 , 92 , Besides, aminoglycoside exposure increases alarmone levels, resulting in increased membrane damage McCall and F.

As stated before, a direct effect of aminoglycosides on the bacterial cell membrane is not incompatible with the need for ribosomal interaction. Binding to the ribosome triggers a massive secondary, energy-dependent uptake of aminoglycosides Fluoroquinolones bind to DNA gyrase and topoisomerase IV, leading to the formation of stable drug—enzyme—DNA complexes that block DNA replication and result in DNA double-strand breaks Recombination and excision repair is involved in the repair of quinolone-damaged DNA, but continuous induction of these systems in response to exposure to the drug triggers the SOS response 31 , Initially, the quinolone—gyrase—DNA complexes are unstable, and bacteria can recover in the absence of quinolone exposure.

However, if exposure is maintained, the complexes become stable, the SOS response continues and when a threshold is crossed, the death process becomes irreversible, even in the absence of the drug 34 , The activity of ciprofloxacin decreases when bacteria reduce their growth rates This effect might contribute to explaining the biphasic dose response of most quinolones, producing a single concentration of maximum kill.

The optimal bactericidal concentration probably depends on the SOS response, the formation of superoxides and DNA breaks. Concentrations higher than the optimal bactericidal concentration provoke an immediate SOS-independent inhibition of respiration and growth, with decreased ROS production and less death Conversely, at the optimal bactericidal concentration, SOS-derived apoptosis-like death occurs.

This pathway depends on RecA and LexA, resulting in cell death associated with membrane depolarization and ROS-induced DNA fragmentation In summary, ultimate death by quinolones occurs by the disintegration of DNA mediated by ROS The target of rifampin and, in general, rifamycins is the product of the rpoB gene, the DNA-dependent RNA polymerase.

The drug strongly binds to the β-subunit of the core enzyme, thereby inhibiting initiation of transcription; that is, preventing effective protein synthesis On first consideration, it may seem that inhibition of protein synthesis is not sufficient to provide rapid killing.

However, in practice, rifamycins are considered to have an early bactericidal effect, not only in S. aureus Fig. coli , but even in slowly growing bacteria such as Mycobacterium tuberculosis.

In addition, the killing effect of rifampin is concentration dependent 10 , High rifampin concentrations can even kill bacteria with some types of resistance mutations in the rpoB gene By targeting RNA polymerases, rifamycins affect both translation and transcription, which together ensure the coordination of transcriptional activity to the translational needs under various growth rates , An interesting question is whether the inhibition of transcription might produce lethal effects independently from blocking protein synthesis.

A classic transcription inhibitor is the toxin MazF, a component of the stress-induced MazF—MazE toxin—antitoxin machinery. In the absence of the antitoxin MazE, MazF inhibits protein synthesis by cleaving mRNA, resulting in later death What are the causes of death?

A similar mechanism of death can be suggested for rifampin, which also selectively affects the transcription of different genes It is possible that rifampin, similarly to ribosome-binding antibiotics, reshapes the cellular proteome rather than just blocking global protein synthesis , , but both effects might be synergistic for killing, particularly in species with a low number of rrn operons 3.

Rifamycins do not stimulate the production of hydroxyl radical production, which could contribute to cell death β-Lactams target penicillin-binding proteins involved in the biogenesis of peptidoglycan There is a clear correlation between bacterial growth rate, needs of peptidoglycan biogenesis and cell lysis induced by β-lactams Lysis requires functional assembly of the divisome, the cell division machinery , suggesting that lysis specifically occurs when the cell is ready for division Why is the loss of cell wall integrity and lysis the result of reduced peptidoglycan biogenesis?

The traditional answer is induction of peptidoglycan autolysins or simply that these lysins continue their activity without compensation by biogenesis see earlier. The possibility of biophysical shearing of different layers, owing to disbalance between cell wall and membrane growth , , and resulting in cell lysis, cannot be discarded and is worth further and deeper consideration.

Finally, there is evidence that β-lactam antibiotics are bactericidal through DNA damage by ROS 34 , Vancomycin is a lipophilic cationic antibiotic that inhibits synthesis of the bacterial cell wall by binding to the dipeptide terminus d -Ala- d -Ala of peptidoglycan pentapeptide precursors, preventing subsequent transpeptidation and transglycosylation and thus peptidoglycan crosslinking Similarly, this effect explains why vancomycin-exposed cells are much more sensitive to ultrasound aureus , the bactericidal effect of vancomycin is generally weaker than that of most β-lactams Consistently, time—kill curves show that varying the concentration of vancomycin has no effect on the rate or extent of bacterial killing , probably owing to vancomycin clogging in the cell wall.

Superoxide anions might also be involved in the bactericidal activity of vancomycin in Enterococcus spp. and Staphylococcus spp. Sulfonamides and trimethoprim are bacteriostatic, but the combination is synergistic, and has a strongly bactericidal effect The two drugs inhibit two sequential steps in tetrahydrofolate synthesis required for nucleotide synthesis , but this cannot explain the bactericidal synergism.

The synergy is more likely due to the disruption of a previously unrecognized metabolic feedback loop by trimethoprim, which results in cyclic mutual potentiation of the effects of the two drugs, leading to amplified depletion of tetrahydrofolate, an essential cofactor in the biosynthesis of thymine , Most probably, thymine starvation promotes cell killing by ROS-mediated DNA damage Surely, we would all love to have a unique, broadly supported hypothesis for how antibiotics kill bacteria; this is particularly so if we were the investigators responsible for providing that hypothesis.

This is not the case; there is no a priori reason to expect that the same antibiotics targeting different species of susceptible bacteria would reach these ultimate killing effects by the same processes under different growth conditions.

On the other, more positive, side, this Perspective suggests that antibiotics with markedly different structures, targets and effects on the structure and physiology of bacteria have proximate mechanisms of action that converge through different processes in the death of bacteria by physical or genetic destructuring, the ultimate effects Fig.

Moreover, we believe that the links between proximate and ultimate mechanisms of the bactericidal and bacteriostatic actions can be elucidated for specific antibiotics and different species of bacteria under different growth conditions.

A multifactorial perspective of bacterial killing will be needed to fully understand how the effects of the primary antibiotic action on targets can be modulated, and eventually amplified, in the context of complex interactions and changes of cell metabolism, and general cellular responses, including ROS production, SOS induction and RpoS regulatory effects.

Certainly many of these responses are sensitive to the environment, and therefore the bactericidal effect is expected to differ in various circumstances, bacterial species and lifestyles. A wide field of research is being opened. But is it worth the effort? Is this information, which is critical to the clinical applications of these drugs, not entirely sufficient?

We suggest it is not. Elucidating how and when different antibiotics prevent the replication of bacteria and kill them is not just an academic exercise. This information will be useful for developing much-needed new antibiotics. It will also be helpful for designing protocols for the administration of existing antibiotics and combinations of antibiotics that are effective clinically, and at the same time minimize the likelihood of emergence and rise of resistance to these drugs in target bacteria and commensals and disturbance of the microbiota.

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They must work together with the immune system to remove the microorganisms from the body. However, there is not always a precise distinction between them and bactericidal antibiotics; high concentrations of some bacteriostatic agents are also bactericidal, whereas low concentrations of some bactericidal agents are bacteriostatic.

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Download as PDF Printable version. In other projects. Wikimedia Commons. Agent that stops bacteria from reproducing. Chloramphenicol Clindamycin Ethambutol Lincosamides Macrolides Nitrofurantoin Novobiocin Oxazolidinone Spectinomycin Sulfonamides Tetracyclines Tigecycline Trimethoprim.

doi : PMID In Andrews J, Shetty N, Tang JW eds. Infectious Disease: Pathogenesis, Prevention and Case Studies. ISBN Agonist Endogenous agonist Irreversible agonist Partial agonist Superagonist Physiological agonist.

Antagonist Competitive antagonist Irreversible antagonist Physiological antagonist Inverse agonist Enzyme inhibitor. Drug Neurotransmitter Agonist-antagonist Pharmacophore. Mechanism of action Mode of action Binding Receptor biochemistry Desensitization pharmacology.

Selectivity Binding , Functional Pleiotropy drugs Non-specific effect of vaccines Adverse effects Toxicity Neurotoxicity. Dose—response relationship Hill equation biochemistry Schild plot Del Castillo Katz model Cheng-Prussoff Equation Methods Organ bath , Ligand binding assay , Patch-clamp.

Efficacy Intrinsic activity Potency EC50 , IC50 , ED50 , LD50 , TD50 Therapeutic index Affinity. In vitro, linezolid has bacteriostatic activity against staphylococci and enterococci but bactericidal activity against streptococci, including S. pneumoniae [ 52 , 53 ]. Similarly, antibacterial agents that are considered to be bactericidal as a broad class may only exhibit bacteriostatic activity in vitro.

At low concentrations, bactericidal drugs may merely exhibit bacteriostatic activity. Quinupristin-dalfopristin is generally considered to be bactericidal in vitro against most strains of staphylococci and streptococci but is bacteriostatic against Enterococcus faecium [ 54 , 55 ].

Although all quinolones are bactericidal, they have a single concentration at which they are most bactericidal: the paradoxical effect of decreased killing at higher concentration most likely results from dose-dependent inhibition of RNA synthesis [ 56 , 57 ]. Furthermore, the robustness of the bactericidal activity of a drug depends on bacterial load and growth phase.

These dense populations are predominantly nongrowing bacteria. Organisms present at high loads are therefore slower growing than those used for in vitro MBC measurement [ 13 ] or represent bacterial populations that are predominantly in a nongrowth phase [ 58 ].

The lack of efficacy with a high bacterial load has been demonstrated in vivo for various bactericidal antibacterials. These include vancomycin and cefotaxime in experimental endocarditis due to gram-positive bacteria [ 59 , 60 ] and penicillin but not clindamycin in experimental mouse thigh infection with Clostridium difficile and S.

pyogenes [ 61 , 62 ]. Nonmicrobiological factors affect response to therapy, including host defense mechanisms, site of infection, underlying disease [ 13 , 14 , 63 ], and an antibacterial agent's critical intrinsic pharmacokinetic and pharmacodynamic properties.

Inadequate penetration of the infection site is one of the principal factors related to failure of antibacterial therapy. The active drug needs to reach the bacteria in appropriate body fluids and tissues at concentrations necessary to kill or suppress the pathogen's growth. The ability of antibacterial agents to cross the blood-brain barrier is an important consideration for the treatment of meningitis.

Aminoglycosides do not efficiently penetrate bronchial secretions [ 64 ]; therefore, pulmonary infections require higher doses of the drug [ 65 ]. Availability of free active drug is affected by the degree of protein binding.

Higher doses than those reflected by in vitro data may be necessary clinically. To treat intracellular bacteria, efficient penetration of cells is necessary e.

By enveloping themselves in a fibrous exopolysaccharide glycocalyx, bacteria are protected from host defenses and the action of antibacterials [ 66—69 ]: clindamycin may impact bacterial eradication by direct antibacterial activity as well as by inhibiting the development of glycocalyx biofilms by S.

aureus [ 70 , 71 ] and adherence via fibronectin binding of S. aureus to host cells [ 72 ]. Bacteria within cardiac vegetations may reach very high concentrations 10 8 —10 10 organisms per gram of tissue. At such densities, rates of metabolism and cell division appear to be reduced, resulting in a reduced susceptibility to bactericidal effects of cell wall—active agents.

The bacteria are dormant, being surrounded by fibrin, platelets, and possibly calcified material [ 73 , 74 ]. Bacteria considered susceptible to various antibacterials in most situations are relatively resistant in endocarditis [ 75 ]. Clinical cure is often achieved, but prolonged administration of relatively high doses of a bactericidal cell wall—active antibacterial agent is generally required for true sterilization of the vegetation to kill any dormant bacteria when they start to produce cell walls with division.

Enterococcal endocarditis represents a particular dilemma, with pathogens often showing resistance to penicillins, aminoglycosides, and vancomycin, the agents primarily considered in the treatment of endocarditis due to gram-positive organisms [ 4 ].

As single agents, they exhibit bacteriostatic activity against susceptible enterococci in vitro [ 80 ]. The combination of penicillin or vancomycin with gentamicin or streptomycin is required for therapy. Linezolid, which is bacteriostatic in vitro against enterococcal species, has cured some cases of vancomycin-resistant E.

faecium endocarditis [ 81 , 82 ]. It is often considered that antibacterials for the treatment of meningitis need to be bactericidal not just because of the need to eradicate infection as rapidly as possible but also because of the poor immunologic competence of the CNS. However, penetration of many antibacterials into CSF is poor or variably dependent on the degree of inflammation.

Certain antibacterial agents that are generally considered to be bacteriostatic—tetracycline [ 83 ], chloramphenicol [ 84 ], linezolid [ 85 , 86 ], and trimethoprim-sulfamethoxazole [ 87 , 88 ]—penetrate CSF efficiently and have been used successfully to treat gram-positive bacterial meningitis.

However, in animal experiments, ampicillin has been more effective than chloramphenicol in S. pneumoniae meningitis [ 89 ], and clinical outcome has been poor in pediatric patients with penicillin-resistant S.

pneumoniae meningitis treated with chloramphenicol [ 90 ]. Rare cases of vancomycin-resistant E. faecium meningitis have been successfully treated with linezolid [ 85 , 86 ]. Because drug penetration may be poor in osteomyelitis because of decreased vascular supply, it might seem logical to choose a bactericidal agent for therapy; however, clindamycin, a bacteriostatic agent, achieves high concentrations in bone and is considered an appropriate agent for the treatment of gram-positive bacterial osteomyelitis [ 91 , 92 ].

Successful outcome of osteomyelitis is determined by adequate surgical debridement and choice of an antimicrobial agent to which the organism is susceptible, rather than that agent's bactericidal properties. The use of bactericidal antibacterial therapy has been suggested to treat bacterial infections in severely neutropenic patients [ 93 , 94 ].

Supporting evidence appears to rely more on presumed syngergistic activity of combination therapy, usually a β-lactam plus an aminoglycoside.

Gram-positive bacteria have now become an important difficult-to-treat cause of infection in neutropenic patients [ 93 , 95 , 96 ]. Bacteriostatic agents have not been adequately studied in these patients. Table 1 lists bactericidal and alternative bacteriostatic antibacterial classes used for serious gram-positive bacterial infections.

Bactericidal versus bacteriostatic antibacterial classes for serious gram-positive bacterial infections.

Some data indicate that potentially adverse clinical consequences may result from the rapid lytic action of bactericidal antibacterial agents [ 97 , 98 ]. Endotoxin surge is well documented after antibacterial therapy in the CSF of infants with gram-negative bacterial meningitis [ 99 , ].

In meningitis due to S. pneumoniae , rapid death of microorganisms results in the production of increased cell wall fragments and intracellular pneumolysin, which intensify the WBC response and prostaglandin release, resulting in increased cerebral edema and the high mortality rate for pneumococcal meningitis [ 90 , ].

Even chloramphenicol is lytic to S. pneumoniae , so no matter what agent is used, a marked inflammatory reaction may occur as a result of bacterial lysis. Exotoxins of staphylococci and streptococci may produce toxic shock syndrome.

Although these bacteria are usually susceptible to clindamycin, its bacteriostatic action had for some time been considered a disadvantage, and bactericidal antibacterial agents were preferred.

However, clindamycin has been shown to completely inhibit toxic shock syndrome toxin-1 production by S. aureus in both growth- and stationary-phase cultures [ ]. At high bacterial loads, clindamycin is also more effective than penicillin in reducing mortality of experimental thigh infection with either Clostridium perfringens [ 62 ] or S.

pyogenes [ 61 ]. Clindamycin is now considered a major component of therapy for staphylococcal and streptococcal toxic shock syndrome [ ]. Bacteriostatic agents inhibit protein synthesis in resting slow-growing bacteria not affected by bactericidal β-lactams.

The presumption of the superiority of in vitro bactericidal over bacteriostatic action in the treatment of gram-positive bacterial infections is intuitive rather than based on rigorous scientific research.

Most authors agree that the possible superiority of bactericidal activity over bacteriostatic antibacterials is of little clinical relevance in the treatment of the great majority of gram-positive bacterial infections.

The one proven indication for bactericidal activity is in enterococcal endocarditis. Meningitis is usually treated with bactericidal agents, but bacteriostatic agents, such as chloramphenicol and linezolid, have been used effectively. The editorial help of Peter Todd, Marion Stafford, and Pat C. Pankey is greatly appreciated.

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Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Factors Affecting Clinical Outcome of Antibacterial Therapy.

Clinical Situations in Which Bactericidal Action is Considered Necessary. Disadvantages of Bactericidal Action. Advantages of Bacteriostatic Action. Journal Article.

Clinical Relevance of Bacteriostatic versus Bactericidal Mechanisms of Action in the Treatment of Gram-Positive Bacterial Infections.

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Abstract The distinction between bactericidal and bacteriostatic agents appears to be clear according to the in vitro definition, but this only applies under strict laboratory conditions and is inconsistent for a particular agent against all bacteria.

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Secrets of success of a human pathogen: molecular evolution of pandemic clones of methicillin-resistant Staphylococcus aureus. First clinical isolate of vancomycin-intermediate Staphylococcus aureus in a French hospital [letter].

New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae. Tests for bactericidal effects of antibacterial agents: technical performance and clinical relevance.

Serum bactericidal test: past, present, and future use in the management of patients with infections. Google Scholar Google Preview OpenURL Placeholder Text.

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Problems in in vitro determination of antibiotic tolerance in clinical isolates. Determination of minimum bactericidal concentrations of oxacillin for Staphylococcus aureus: influence and significance of technical factors. Importance of bacterial growth phase in determining minimal bactericidal concentrations of penicillin and methicillin.

Bactericidal effects of antibiotics on slowly growing and nongrowing bacteria. Variation in the susceptibility of strains of Staphylococcus aureus to oxacillin, cephalothin, and gentamicin.

In-vitro methods for determining minimum lethal concentrations of antibacterial agents. Importance of minimizing carry-over effect at subculture in the detection of penicillin-tolerant viridans group streptococci.

Teicoplanin and daptomycin bactericidal activities in the presence of albumin or serum under controlled conditions of pH and ionized calcium. Effect of temperature on inoculum as a potential source of error in agar dilution plate count bactericidal measurements.

Special tests: bactericidal activity, activity of antimicrobics in combination, and detection of β-lactamase production. The antibacterial chemotherapy of human infection due to Listeria monocytogenes.

Phenotypic tolerance: the search for beta-lactam antibiotics that kill nongrowing bacteria. Penicillin tolerance and treatment failure in Group A streptococcal pharyngotonsillitis. Comparison of four methods for determination of MIC and MBC of penicillin for viridans streptococci and implications for penicillin tolerance.

Therapeutic failure in pneumonia caused by a tolerant strain of Staphylococcus aureus. Serious staphylococcal infections with strains tolerant to bactericidal antibiotics. Spectrum and mode of action of azithromycin CP, , a new membered-ring macrolide with improved potency against gram-negative organisms.

Bactericidal and bacteriostatic action of chloramphenicol against meningeal pathogens. A comparison of chloramphenicol and ampicillin as bactericidal agents for Haemophilus influenzae type B. Antagonism of ampicillin and chloramphenicol against meningeal isolates of group B streptococci.

Bactericidal activity of five antibacterial agents against Bacteroides fragilis. Antibacterial therapy of experimental endocarditis caused by Staphylococcus aureus.