Actions of Bacteriostatic And Bacteriocidal Drugs Essay

1. Explain the difference between the actions of bacteriostatic and bacteriocidal drugs.

2. Explain the following terms in relation to antibiotic therapy
I. Identification of the infecting organism
II. Drug susceptibility
III. Host factors
IV. Empiric Therapy Actions of Bacteriostatic And Bacteriocidal Drugs Essay

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3. When caring for a patient with an infection, the nurse may check the following labs. Explain why these labs would be monitored in a patient receiving antibiotics for an infection

CBC with differential

Liver and kidney function tests

Serum drug levels of the antibiotic

The problem of antibiotic resistance requires a solution that relies on more than just the development of new drugs. Pathogens have been unrelenting in evolving mechanisms by which to survive in the face of every drug put on the market. Combination therapy, i.e., the concurrent application of two or more antibiotics, provides an appealing approach that demands closer assessment as a tool to combat this problem. In the treatment of important infectious diseases such as HIV infection, tuberculosis, and malaria, combination therapy has become the standard approach precisely to delay the evolution of drug resistance (1–4). In contrast, for common acute bacterial infections, combinations of drugs are prescribed in only a very limited number of cases and with a different rationale (5). In those specific instances, two drugs are prescribed for their synergistic effects, that is, for the fact that their combined effects exceed the sum of their individual effects. Drug synergy has been demonstrated to result in more-efficient clearance of infections and to achieve clearance at lower drug concentrations (6). Examples of such cases include fusidic acid and rifampin for the treatment of methicillin-resistant Staphylococcus aureus infections and trimethoprim and sulfamethoxazole for the treatment of otitis media (7, 8). Furthermore, recent theoretical work indicates that synergistic drugs can prevent treatment failure even when bacteria resistant to one of the drugs are present at the beginning of therapy (9).Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Just as synergy can be exploited to improve treatment, it is necessary to avoid combinations of drugs that inhibit each other and may prolong infections. Antagonism, when a drug hinders the effect of another drug, was reported early in the history of antibiotics and continues to function as a warning against indeterminate treatment (10). In a study of patients with pneumococcal meningitis, 30% of those treated with penicillin alone failed treatment and died, while 79% of comparable patients who were treated with the same dosage of penicillin plus chlortetracycline, an antibiotic that antagonizes penicillin, died (11, 12).

Despite these findings, an increasing number of laboratory studies indicate that antagonistic drug combinations merit more investigation as clinical options (13). Recent work in this area suggests that the different types of interactions have significant effects on the selection and maintenance of drug resistance mutations. Using a direct competition experiment, Chait and colleagues demonstrated how a hyperantagonistic drug combination was able to select against a bacterial population resistant to one of the drugs and instead favored the completely sensitive wild type (14). Furthermore, the rate of adaptation of laboratory bacteria to multiple drugs has been shown to correlate with the degree of synergism between individual antibiotics (15). Although antagonistic drug combinations are currently eschewed in clinical settings, these studies suggest that antagonism between antibiotics may aid in devising treatment strategies specifically aimed at delaying the emergence of resistance.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

In response to the slow development of new antimicrobials, there is renewed interest in old drugs that have fallen out of use due to toxicity or drawbacks in efficacy (16). One approach that could be implemented to return these drugs to the clinic is to use an old drug in combination with a current drug (17). The advantages of synergism and the diverse nontrivial effects of antagonism will play a central role in determining how best to implement combination therapy in clinical settings.

In order to exploit the potential benefits of combination therapy, we need a better understanding of the circumstances under which synergism versus antagonism is expected. Determining how a broader spectrum of drugs interact at inhibitory concentrations and delineating the mechanisms responsible for these effects could allow for a more-prudent application of antibiotics that maintains clinical capability and does not sacrifice the future utility of these drugs.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

In this study, we asked whether basic pharmacodynamic properties of all antibiotics can help predict which pairs would result in antagonism. A widely recognized characteristic of antibiotics is that they are either bacteriostatic and inhibit growth without killing the cells or are bactericidal and result in cell killing (18). Thus, if bactericidal drugs are most potent with actively growing cells, as hypothesized more than 50 years ago (19, 20), then the inhibition of growth induced by a bacteriostatic drug should result in a reduction of drug efficacy. To test this hypothesis, we determined the types of interaction between five different drugs at inhibitory concentrations by estimating death rates using time-kill curves. We then extended our observations and employed screening methods to identify effects across pairs of 21 different drugs at subinhibitory concentrations. Since our hypothesis relies on the decreased antibiotic susceptibility of slowly growing cells and the ability of some drugs to influence this state, we repeated our experiments at the level of individual cells using time-lapse microscopy, in microfluidic devices, to investigate the cellular dynamics underlying combined effects of antibiotics.

MATERIALS AND METHODS
High-throughput combination screening experiments.We selected 21 antibiotics with a wide range of mechanisms of action, including drugs that target cell wall, nucleic acid, protein, and folic acid biosynthesis (Table 1). Fresh antibiotic solutions were prepared from powder stocks on a weekly basis and were filter sterilized before use. All experiments were conducted in Escherichia coli K-12 (BW25113) in minimal medium supplemented with 0.2% glucose and 0.1% Casamino Acids. Combination screens were performed in 384-well plates, using a liquid-handling robotic system (Hamilton Star workstation) to improve reproducibility. The culture volume was 50 μl. Each plate contained two different 6-by-6 dose-matrix blocks (one antibiotic in combination with two other antibiotics), with 4 replicates each. For each pair of antibiotics, we combined 6 different concentrations of the agents in a serially diluted two-dimensional dose matrix, with dose points being centered on the 50% effective concentration (EC50) for each antibiotic. The lowest concentration for each agent was 0 and the highest was above the 90% effective concentration (EC90) (Table 1). In addition to the dose-matrix blocks, each plate included 18 wells containing medium without antibiotics (control wells).Actions of Bacteriostatic And Bacteriocidal Drugs Essay

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TABLE 1
List of all antibiotics used in the study

Antibiotic sensitivity screens were performed by growing cells overnight (optical density at 600 nm [OD600], 4) at 30°C, with shaking at 300 rpm, and diluting the cells to an OD equivalent to 0.04. Next, using a liquid-handling robotic system, cells were transferred into 384-well assay plates (in the presence of antibiotics) to yield 4 × 104 cells/well. Assay plates were incubated for 18 h at 30°C, with shaking at 300 rpm. Bacterial growth was monitored by measuring the optical density (OD600) of the liquid cultures at a single time point. Preliminary experiments showed that a single reading of optical density after 18 h of incubation showed strong linear correlation with the area under the growth curve (a descriptor of overall inhibitory effect that covers the entire growth period) (21). Briefly, this was determined using parallel cultures of E. coli grown in ten 384-well microtiter plates under previously stated conditions. Optical density (OD600) was measured every hour for 24 h, and the areas under the growth curves were determined using custom MATLAB scripts. For a number of different ending time points (e.g., 11, 12, and 13 h), we used a linear regression model to consider whether the last OD measurements predicted the areas under the growth curves (384 × 10 = 3,840 data points). Plates were prepared as multiple (up to 6) biological replicates, and those with quality control problems (e.g., growth in control wells was unusually low or showed large variations or an agent failed to substantially inhibit growth at high concentrations or strongly inhibited growth at even low doses) were omitted from further analysis.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

We had two reasons to study antibiotic interactions in a standard minimal medium at a relatively low temperature (30°C). First, because the culture volume in our study was 50 μl, evaporation was a potential concern. To minimize such a confounding effect, 30°C appeared to be an optimal solution. Second, our experimental setting was similar to that of a prior study (22), allowing direct comparison of the results of the two studies.

Data processing and bias correction steps.To overcome any measurement bias caused by within-plate inhomogeneity, we processed the raw optical density data as follows. We included 18 control wells on each plate, containing medium without antibiotics and inoculated with E. coli. We used these wells both to set a baseline for zero inhibition and to estimate and to eliminate within-plate systematic biases. First we calibrated OD values by applying the transformation ODcalibrated = OD + (0.40449 × OD3), to account for the nonlinear association between OD and cell density at high cell densities (parameters of the calibration formula were derived as in reference 23). Then we calculated relative inhibition values based on the initial OD (maximum inhibition) and the average OD of antibiotic-free control wells (maximum growth). To estimate and to eliminate within-plate spatial effects, first we fitted a linear trend to the control wells to eliminate spatial gradients. Next, for the residuals, we employed Gaussian process regression (24) to eliminate the remaining systematic spatial biases using the control wells. Both steps for bias correction were carried out in MATLAB.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Identification of interacting antibiotic pairs.Synergistic effects between combinations of chemicals, resulting in increased benefits or increased toxicity, have important implications across the fields of biomedicine (25, 26). Correspondingly, many approaches have been devised to quantify drug interactions (27). To assess antagonism and synergy between pairs of antibiotics, we used the Loewe additivity model (28), which assumes that a drug does not interact with itself. Geometrically, Loewe additivity can be represented as lines of equally effective dosages (isoboles) in the two-dimensional linear concentration space for the two drugs. Deviation of the shape of the isoboles from linearity indicates either synergy (concave isoboles) or antagonism (convex isoboles). To identify interactions for each pair of antibiotics, first we merged data from replicate dose-matrix blocks located on the same 384-well plates. Next we fitted sigmoidal dose-response curves (Hill equation) to the single-agent responses using a maximum likelihood fitting procedure. Based on the single-agent response curves for the two antibiotics, we calculated the dose-response relationship for the antibiotic combination expected with the Loewe additivity model. To quantify interactions, we determined the concavity of the set of isoboles inferred from the combination measurements for a given antibiotic pair (“observed” isoboles). To achieve this, we used a mathematical transformation to “bend” the linear isoboles expected under the Loewe additivity model to approximate most closely the observed isoboles (see the report by Cokol and colleagues for a similar approach [29]). The transformation relies on a single parameter to describe the concavity of the observed isoboles, which we used as a measure of antibiotic interaction. This score is zero in the absence of interaction, negative for antagonistic pairs, and positive for synergistic pairs. Finally, interaction scores (B) for each antibiotic pair were calculated by taking the median scores obtained from biological replicates (i.e., independent plates).Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Measurement errors of interaction screens were estimated by testing 5 antibiotics for interactions with themselves in multiple replicates (29). Because under Loewe additivity a drug shows no interaction with itself, deviation of the interaction score from zero provides an estimate of the experimental error of interaction measurements. Thus, we considered two antibiotics as significantly interacting when the score was significantly different from the mean score for self-self antibiotic combinations. For calculation of EC50 values, we followed established protocols (30). EC50 refers to the concentration of drug that induces growth inhibition halfway between the baseline and maximum values after the specified exposure time.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

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Antibiotics and concentrations for time-kill and time-lapse microscopy experiments.Determination of the clinical utility of exploiting different interactions between pairs of antibiotics will require extensive testing across organisms, sites of infection, and the drugs used for particular infections. In contrast, we consider our work a proof-of-principle study, and future work should confirm potential clinical implications. Although some of the antibiotics we used have advanced derivatives in the clinic, the choice of the drugs we used was based on two criteria, i.e., (i) the availability of very detailed literature on the molecular mechanism of action and (ii) the possibility for comparison with the results of an older study (22). Similarly, the antibiotic concentrations used do not reflect clinical recommendations. For example, although the concentration of erythromycin used in our time-kill and time-lapse microscopy experiments is higher than that achievable in blood, this drug was included to illustrate the effect of antagonism between a drug at an inhibitory concentration and a second drug at a subinhibitory concentration. Although the MIC for erythromycin in E. coli MG1655 is well above the concentration we used (500 to 1,000 μg/ml), we were interested in determining whether a subinhibitory concentration of this drug was sufficient to antagonize the killing effect of a second drug whose concentration was above the MIC.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Time-kill curves.Determination of the MICs for the antibiotics used in the time-kill and time-lapse microscopy studies was carried out using a broth dilution protocol similar to that recommended by the Clinical and Laboratory Standards Institute (LB medium was used instead of Mueller-Hinton broth) (31). The concentrations of the drugs used in the following experiments represent fractions of the MICs: 25 μg/ml streptomycin and nalidixic acid (2× MIC), 12.5 μg/ml tetracycline (0.83× MIC), 10 μg/ml trimethoprim, (0.66× MIC), and 200 μg/ml erythromycin (0.4× MIC).

Overnight cultures of E. coli MG1655 were diluted 1:10,000 into fresh prewarmed LB broth and were incubated for 2 h. A further 1:2 dilution was performed before introduction into flasks containing either a single antibiotic or a pair of bactericidal and bacteriostatic antibiotics. These were then incubated at 37°C with shaking and aeration. Samples were taken at 1-h intervals for up to 5 h. Cell densities for each sample were estimated from colony counts by dilution in phosphate-buffered saline and plating on LB agar. Each time-kill experiment was performed twice.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Time-lapse microscopy.Specific details of the microfluidic system used in this study, the mother machine, have been described previously (32). In brief, this device consists of 4,000 growth channels arranged at right angles against a large trench, through which growth medium is passed. Nutrients then diffuse into the channels and flush out growing cells as they emerge from these channels. An automated microscope stage allows for the monitoring of multiple fields of view, spanning the entire device. This method results in the continuous observation of the growth and division of a large number of individual cells as they experience different antibiotic-containing environments, as well as their survival or death after the drug has been removed.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Time-lapse microscopy experiments were conducted as follows. E. coli MG1655 cultures were grown overnight in LB broth at 37°C. On the following day, 100 μl of culture was diluted in 10 ml of fresh prewarmed LB broth and then was incubated for 2 h at 37°C, with shaking. Eight milliliters of the resulting culture was centrifuged at 10,000 rpm for 5 to 7 min and resuspended in 20 μl of fresh LB broth; 10 μl of the cell suspension was then injected into the mother machine, and the experiment was initiated when more than 80% of the channels were filled with cells via diffusion. A syringe pump was used to pass fresh LB broth supplemented with bovine serum albumin (BSA) and salmon sperm DNA through the device at a rate of 2 ml/h. BSA and salmon sperm DNA are blocking agents that are used to bind to the surface of the microfluidic device to prevent the formation of air bubbles and excessive adhesion of the cells to the channels. Images were acquired from 15 to 25 fields of view at 6-min intervals by using an automated Olympus BX81 microscope with an UPLFN100×O2PH/1.3 phase-contrast oil lens. Samples and the microscope were held at 37°C with a cube-and-box incubation system (Life Imaging Services, Reinach, Switzerland). After at least 4 h of growth in LB broth, the medium was switched to LB broth containing BSA, salmon sperm, and either one or two antibiotics. Cells were exposed to this medium for at least 20 h before being switched back to fresh LB broth supplemented with BSA and salmon sperm DNA for up to 10 h. Each experiment involved fields scanned continuously for at least 30 h.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

The resulting time-lapse images were then analyzed with a custom-designed plug-in for ImageJ, to provide information on cell size and division rates during the three different phases of the experiment. The first step of the analysis consists of defining the length of the cell abutting the end of the channel. The increasing length of the growing cell over succeeding frames is tracked and recorded; division events are also registered based on cell length. Manual verification and annotation were performed after every experiment. In this way, we were able to extract quantitative information on an individual cell’s elongation and division rates. We also tracked the proportion of cells that survived treatment exposure and were able to divide again upon the return to an antibiotic-free environment. The occurrence of filamentation during exposure to the antibiotics erythromycin and nalidixic acid led to elongated cells being pulled out of their growth channels during flow. For this reason, only channels containing cells that could be followed for the entirety of the experiment were considered in the analysis.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

RESULTS
Time-kill curves.To quantify interactions between antibiotics at clinically relevant concentrations, we measured death rates at inhibitory drug levels based on time-kill curves. We tested every possible bactericidal-bacteriostatic pair among five antibiotics at concentrations above the MIC. The antibiotics used in the time-kill experiments were selected for their differing mechanisms of action and because, to the best of our knowledge, there are no reports of cross-resistance mutations for these drugs in E. coli.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

In the presence of a bactericidal drug that alone is capable of clearing a bacterial population, the addition of a bacteriostatic drug resulted in a decrease in killing rates and a significant number of survivors at the end of the experiment (Fig. 1). We also noted that the degree of antagonism differed depending on the bactericidal drug employed in the experiment. Acquisition of a resistance mutation over the course of the time-kill curve experiment could be a confounding effect explaining the reduced death rate observed in bacterial cultures treated with a bactericidal-bacteriostatic pair. In order to control for this possibility, the colonies obtained at the end of every time-kill curve experiment were replica plated on antibiotic-containing plates. We found no evidence for the evolution of single-drug or multidrug resistance in any replicate, to any of the drugs used in the experiment (data not shown). These time-kill curves provide confirmation that the antagonistic interactions found between drugs at inhibitory concentrations manifest as decreases in the rate of killing and the presence of significant proportions of sensitive bacteria at the end of the experiment.

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Several factors are important in choosing the most appropriate antimicrobial drug therapy, including bacteriostatic versus bactericidal mechanisms, spectrum of activity, dosage and route of administration, the potential for side effects, and the potential interactions between drugs. The following discussion will focus primarily on antibacterial drugs, but the concepts translate to other antimicrobial classes.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Bacteriostatic Versus Bactericidal
Antibacterial drugs can be either bacteriostatic or bactericidal in their interactions with target bacteria. Bacteriostatic drugs cause a reversible inhibition of growth, with bacterial growth restarting after elimination of the drug. By contrast, bactericidal drugs kill their target bacteria. The decision of whether to use a bacteriostatic or bactericidal drugs depends on the type of infection and the immune status of the patient. In a patient with strong immune defenses, bacteriostatic and bactericidal drugs can be effective in achieving clinical cure. However, when a patient is immunocompromised, a bactericidal drug is essential for the successful treatment of infections. Regardless of the immune status of the patient, life-threatening infections such as acute endocarditis require the use of a bactericidal drug.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Spectrum of Activity
The spectrum of activity of an antibacterial drug relates to diversity of targeted bacteria. A narrow-spectrum antimicrobial targets only specific subsets of bacterial pathogens. For example, some narrow-spectrum drugs only target gram-positive bacteria, whereas others target only gram-negative bacteria. If the pathogen causing an infection has been identified, it is best to use a narrow-spectrum antimicrobial and minimize collateral damage to the normal microbiota. A broad-spectrum antimicrobial targets a wide variety of bacterial pathogens, including both gram-positive and gram-negative species, and is frequently used as empiric therapy to cover a wide range of potential pathogens while waiting on the laboratory identification of the infecting pathogen. Broad-spectrum antimicrobials are also used for polymicrobic infections (mixed infection with multiple bacterial species), or as prophylactic prevention of infections with surgery/invasive procedures. Finally, broad-spectrum antimicrobials may be selected to treat an infection when a narrow-spectrum drug fails because of development of drug resistance by the target pathogen.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

The risk associated with using broad-spectrum antimicrobials is that they will also target a broad spectrum of the normal microbiota, increasing the risk of a superinfection, a secondary infection in a patient having a preexisting infection. A superinfection develops when the antibacterial intended for the preexisting infection kills the protective microbiota, allowing another pathogen resistant to the antibacterial to proliferate and cause a secondary infection (Figure 14.2.1 ). Common examples of superinfections that develop as a result of antimicrobial usage include yeast infections (candidiasis) and pseudomembranous colitis caused by Clostridium difficile, which can be fatal.

Diagram of process of superinfection. 1: Normal microbiota keeps opportunistic pathogens in check. Image shows many different bacteria, only 1 of which is labeled pathogen. 2: Broad-spectrum antibiotics kill nonresistant cells. Image shows all cells but pathogen being killed. 3: Drug-resistant pathogens proliferate and can cause a superinfection. Image shows many of the pathogen.
Figure 14.2.1 : Broad-spectrum antimicrobial use may lead to the development of a superinfection. (credit: modification of work by Centers for Disease Control and Prevention)Actions of Bacteriostatic And Bacteriocidal Drugs Essay
Exercise 14.2.1

What is a superinfection and how does one arise?

Dosage and Route of Administration
The amount of medication given during a certain time interval is the dosage, and it must be determined carefully to ensure that optimum therapeutic drug levels are achieved at the site of infection without causing significant toxicity(side effects) to the patient. Each drug class is associated with a variety of potential side effects, and some of these are described for specific drugs later in this chapter. Despite best efforts to optimize dosing, allergic reactions and other potentially serious side effects do occur. Therefore, the goal is to select the optimum dosage that will minimize the risk of side effects while still achieving clinical cure, and there are important factors to consider when selecting the best dose and dosage interval. For example, in children, dose is based upon the patient’s mass. However, the same is not true for adults and children 12 years of age and older, for which there is typically a single standard dose regardless of the patient’s mass. With the great variability in adult body mass, some experts have argued that mass should be considered for all patients when determining appropriate dosage.1 An additional consideration is how drugs are metabolized and eliminated from the body. In general, patients with a history of liver or kidney dysfunction may experience reduced drug metabolism or clearance from the body, resulting in increased drug levels that may lead to toxicity and make them more prone to side effects.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

There are also some factors specific to the drugs themselves that influence appropriate dose and time interval between doses. For example, the half-life, or rate at which 50% of a drug is eliminated from the plasma, can vary significantly between drugs. Some drugs have a short half-life of only 1 hour and must be given multiple times a day, whereas other drugs have half-lives exceeding 12 hours and can be given as a single dose every 24 hours. Although a longer half-life can be considered an advantage for an antibacterial when it comes to convenient dosing intervals, the longer half-life can also be a concern for a drug that has serious side effects because drug levels may remain toxic for a longer time. Last, some drugs are dose dependent, meaning they are more effective when administered in large doses to provide high levels for a short time at the site of infection. Others are time dependent, meaning they are more effective when lower optimum levels are maintained over a longer period of time.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

The route of administration, the method used to introduce a drug into the body, is also an important consideration for drug therapy. Drugs that can be administered orally are generally preferred because patients can more conveniently take these drugs at home. However, some drugs are not absorbed easily from the gastrointestinal (GI) tract into the bloodstream. These drugs are often useful for treating diseases of the intestinal tract, such as tapeworms treated with niclosamide, or for decontaminating the bowel, as with colistin. Some drugs that are not absorbed easily, such as bacitracin, polymyxin, and several antifungals, are available as topical preparations for treatment of superficial skin infections. Sometimes, patients may not initially be able to take oral medications because of their illness (e.g., vomiting, intubation for respirator). When this occurs, and when a chosen drug is not absorbed in the GI tract, administration of the drug by a parenteral route (intravenous or intramuscular injection) is preferred and typically is performed in health-care settings. For most drugs, the plasma levels achieved by intravenous administration is substantially higher than levels achieved by oral or intramuscular administration, and this can also be an important consideration when choosing the route of administration for treating an infection (Figure 14.2.2 ).Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Graph with time on the X axis and Plasma Concentration of Drug on the Y axis. IV route increases plasma concentration very quickly and then tapes off. Intramuscular rout and oral route increase concentrations more slowly with the intramuscular route being a bit faster than oral but also dropping off more quickly.
Figure 14.2.2 : On this graph, t0 represents the time at which a drug dose is administered. The curves illustrate how plasma concentration of the drug changes over specific intervals of time (t1 through t4). As the graph shows, when a drug is administered intravenously, the concentration peaks very quickly and then gradually decreases. When drugs are administered orally or intramuscularly, it takes longer for the concentration to reach its peak.
Exercise 14.2.2

List five factors to consider when determining the dosage of a drug.
Name some typical side effects associated with drugs and identify some factors that might contribute to these side effects.Actions of Bacteriostatic And Bacteriocidal Drugs Essay
Drug Interactions
For the optimum treatment of some infections, two antibacterial drugs may be administered together to provide a synergistic interaction that is better than the efficacy of either drug alone. A classic example of synergistic combinations is trimethoprim and sulfamethoxazole (Bactrim). Individually, these two drugs provide only bacteriostatic inhibition of bacterial growth, but combined, the drugs are bactericidal.

Whereas synergistic drug interactions provide a benefit to the patient, antagonistic interactions produce harmful effects. Antagonism can occur between two antimicrobials or between antimicrobials and nonantimicrobials being used to treat other conditions. The effects vary depending on the drugs involved, but antagonistic interactions may cause loss of drug activity, decreased therapeutic levels due to increased metabolism and elimination, or increased potential for toxicitydue to decreased metabolism and elimination. As an example, some antibacterials are absorbed most effectively from the acidic environment of the stomach. If a patient takes antacids, however, this increases the pH of the stomach and negatively impacts the absorption of these antimicrobials, decreasing their effectiveness in treating an infection. Studies have also shown an association between use of some antimicrobials and failure of oral contraceptives.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Exercise 14.2.3

Explain the difference between synergistic and antagonistic drug interactions.

RESISTANCE POLICE

In the United States and many other countries, most antimicrobial drugs are self-administered by patients at home. Unfortunately, many patients stop taking antimicrobials once their symptoms dissipate and they feel better. If a 10-day course of treatment is prescribed, many patients only take the drug for 5 or 6 days, unaware of the negative consequences of not completing the full course of treatment. A shorter course of treatment not only fails to kill the target organisms to expected levels, it also selects for drug-resistant variants within the target population and within the patient’s microbiota.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

Patients’ nonadherence especially amplifies drug resistance when the recommended course of treatment is long. Treatment for tuberculosis (TB) is a case in point, with the recommended treatment lasting from 6 months to a year. The CDC estimates that about one-third of the world’s population is infected with TB, most living in underdeveloped or underserved regions where antimicrobial drugs are available over the counter. In such countries, there may be even lower rates of adherence than in developed areas. Nonadherence leads to antibiotic resistance and more difficulty in controlling pathogens. As a direct result, the emergence of multidrug-resistant and extensively drug-resistant strains of TB is becoming a huge problem.

Overprescription of antimicrobials also contributes to antibiotic resistance. Patients often demand antibiotics for diseases that do not require them, like viral colds and ear infections. Pharmaceutical companies aggressively market drugs to physicians and clinics, making it easy for them to give free samples to patients, and some pharmacies even offer certain antibiotics free to low-income patients with a prescription.Actions of Bacteriostatic And Bacteriocidal Drugs Essay

In recent years, various initiatives have aimed to educate parents and clinicians about the judicious use of antibiotics. However, a recent study showed that, between 2000 and 2013, the parental expectation for antimicrobial prescriptions for children actually increased (Figure 14.2.3 ).Actions of Bacteriostatic And Bacteriocidal Drugs Essay

One possible solution is a regimen called directly observed therapy (DOT), which involves the supervised administration of medications to patients. Patients are either required to visit a health-care facility to receive their medications, or health-care providers must administer medication in patients’ homes or another designated location. DOT has been implemented in many cases for the treatment of TB and has been shown to be effective; indeed, DOT is an integral part of WHO’s global strategy for eradicating TB.3,4 But is this a practical strategy for all antibiotics? Would patients taking penicillin, for example, be more or less likely to adhere to the full course of treatment if they had to travel to a health-care facility for each dose? And who would pay for the increased cost associated with DOT? When it comes to overprescription, should someone be policing physicians or drug companies to enforce best practices? What group should assume this responsibility, and what penalties would be effective in discouraging overprescription? Actions of Bacteriostatic And Bacteriocidal Drugs Essay