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Why do antibiotics have a special importance when taking lactulose?

Why do antibiotics have a special importance when taking lactulose?



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Before taking lactulose, tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially antacids, antibiotics including neomycin (Mycifradin), and other laxatives.” (Quote from here)

Why do antibiotics have a special importance when taking lactulose? Why is neomycin (Mycifradin) mentioned separately?


From the Wikipedia article (I'm sure there's a scholarly reference, but I think this is well-known):

Lactulose works by relieving constipation through a number of different methods. Lactulose is made up of sugar molecules and is partly broken down by the bacteria that live in the lower part of the gut.

So, certain antibiotics affect (and reduce) the intestinal flora (and neomycin especially so, which is I believe the reason why it is mainly used in ointments), leaving the lactulose undigested and not as effective in forcing the body to retain water in the colon, which is the mechanism through which the drug acts.


Lactulose is an osmotic laxative. This means it works by drawing water into the colon (i.e. it retains a lot of water with it) and hence softens your stool in cases of constipation. As you can imagine, this interferes with absorption of most drugs including antibiotics and even food. Neomycin is especially toxic to gut flora (as mentioned above) and if taken with lactulose, it will linger in your GI tract for even longer and kill more gut flora. Your gut flora is important in protecting you against other harmful bacteria through competition for food, nutrients, etc. If you kill your flora, you are allowing other harmful organisms a field day in your intestine and they will grow and cause a condition known as pseudomembranous colitis (commonly caused by clostridium difficile infection). Also neomycin is mentioned separately because it has been associated with this condition which can sometimes be fatal (toxic megacolon, GI perforation, severe diarrhoea, etc)

In summary, you shouldn't be taking other medication whilst you're constipated anyway (especially when taking lactulose) because they won't get absorbed and may make the constipation worse.


Amoxicillin

Amoxicillin is used to treat certain infections caused by bacteria, such as pneumonia bronchitis (infection of the airway tubes leading to the lungs) and infections of the ears, nose, throat, urinary tract, and skin. It is also used in combination with other medications to eliminate H. pylori, a bacteria that causes ulcers. Amoxicillin is in a class of medications called penicillin-like antibiotics. It works by stopping the growth of bacteria.

Antibiotics such as amoxicillin will not work for colds, flu, and other viral infections. Taking antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.


Why is this medication prescribed?

Ciprofloxacin is used to treat or prevent certain infections caused by bacteria such as pneumonia gonorrhea (a sexually transmitted disease) typhoid fever (a serious infection that is common in developing countries) infectious diarrhea (infections that cause severe diarrhea) and infections of the skin, bone, joint, abdomen (stomach area), and prostate (male reproductive gland), Ciprofloxacin is also used to treat or prevent plague (a serious infection that may be spread on purpose as part of a bioterror attack) and inhalation anthrax (a serious infection that may be spread by anthrax germs in the air on purpose as part of a bioterror attack). Ciprofloxacin may also be used to treat bronchitis, sinus infections, or urinary tract infections but should not be used for bronchitis and sinus infections, or certain types of urinary tract infections if there are other treatment options. Ciprofloxacin extended-release (long-acting) tablets are used to treat kidney and urinary tract infections however, some types of urinary tract infections should only be treated with ciprofloxacin extended release tablets if no other treatment options are available. Ciprofloxacin is in a class of antibiotics called fluoroquinolones. It works by killing bacteria that cause infections.

Antibiotics such as ciprofloxacin will not work for colds, flu, or other viral infections. Using antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.


Use and administration of antibiotics

The principle governing the use of antibiotics is to ensure that the patient receives one to which the target bacterium is sensitive, at a high enough concentration to be effective but not cause side effects, and for a sufficient length of time to ensure that the infection is totally eradicated. Antibiotics vary in their range of action. Some are highly specific. Others, such as the tetracyclines, act against a broad spectrum of different bacteria. These are particularly useful in combating mixed infections and in treating infections when there is no time to conduct sensitivity tests. While some antibiotics, such as the semisynthetic penicillins and the quinolones, can be taken orally, others must be given by intramuscular or intravenous injection.


7. Interactions

Medicines that interact with amoxicillin may either decrease its effect, affect how long it works for, increase side effects, or have less of an effect when taken with amoxicillin. An interaction between two medications does not always mean that you must stop taking one of the medications however, sometimes it does. Speak to your doctor about how drug interactions should be managed.

Common medications that may interact with amoxicillin include:

  • allopurinol (may increase the incidence of rash)
  • anticoagulants (blood thinners), such as warfarin (may prolong bleeding time)
  • oral contraceptives (may decrease absorption leading to reduced efficacy)
  • other antibiotics, such as chloramphenicol, sulfonamides, macrolides, and tetracycline
  • probenecid (may increase blood concentrations of amoxicillin).

Amoxicillin may cause a false-positive reaction for glucose in the urine with copper reduction tests (eg, Benedict's or Fehling's solution), but not with enzyme-based tests.

Note that this list is not all-inclusive and includes only common medications that may interact with amoxicillin. You should refer to the prescribing information for amoxicillin for a complete list of interactions.


MECHANISMS AND ORIGINS OF ANTIBIOTIC RESISTANCE

The molecular mechanisms of resistance to antibiotics have been studied extensively (Table ​ (Table1) 1 ) and have involved investigations of the genetics and biochemistry of many different facets of bacterial cell function (2, 59, 147). In fact, the study of antibiotic action and resistance has contributed significantly to our knowledge of cell structure and function. Resistance processes are widely distributed in the microbial kingdom and have been well described for a variety of commensals (89) and pathogens most can be disseminated by one or more distinct gene transfer mechanisms. A few of the resistance types that illustrate the difficulties in maintaining effective antibiotic activity in the face of the genetic and biochemical flexibility of bacteria deserve special mention.

Genetic Jugglery

The genes for β-lactamase enzymes are probably the most international in distribution random mutations of the genes encoding the enzymes have given rise to modified catalysts with increasingly extended spectra of resistance (63). The archetypical plasmid-encoded β-lactamase, TEM, has spawned a huge tribe of related enzyme families, providing ample proof of this adaptability. The β-lactamase genes are ancient (15) and have been found in remote and desolate environments (4), which implies that novel β-lactamases with altered substrate ranges occur in the environment. As another example, a new extended-spectrum β-lactamase (CTX-M) was acquired from environmental Kluyvera strains and appeared in the clinic in the 1990s this was the first enzyme found to hydrolyze expanded-spectrum cephalosporins at a clinically significant level (86). The CTX-M genes and subsequent variants (upwards of 100 different amino acid substitutions have been identified so far) are highly successful at transmission and are a global phenomenon and threat (Fig. ​ (Fig.3) 3 ) (71). Such epidemics of r genes with efficient HGT and rapid mutational radiation are next to impossible to control.

Worldwide distribution of different classes of CTX-M β-lactamases (first identified in 1989). (Reprinted from reference 71 by permission of Oxford University Press.)

Macrolide antibiotics, such as erythromycin and its successors, were introduced to contend with the problem of methicillin resistance and are widely used for the treatment of Gram-positive infections. Not surprisingly, strains resistant due to a number of different mechanisms are now widely disseminated (120). The macrolides and related antibiotics act by binding at different sites in the peptide exit tunnel of the 50S ribosome subunit. Resistance can occur by modification of the RNA or protein components of the tunnel. A specific rRNA modification that engenders resistance to all antibiotics acting at this site on the ribosome was described recently (88), and this modification is spreading.

Another example of bacterial genetic jugglery comes from the recent appearance of a novel FQ resistance mechanism. When the highly potent FQs were introduced in 1987, a few foolhardy experts predicted that resistance to this new class of gyrase inhibitors was unlikely, since at least two mutations would be required to generate a significant resistance phenotype. It was also suggested that horizontally transmitted FQ resistance was unlikely to occur. However, mutants of the target bacterial gyrase genes and efflux of the FQs from the cell have increasingly been encountered (110). More unexpectedly, a transmissible mechanism of FQ inactivation has made its appearance. This mechanism comes about because one of the many aminoglycoside N-acetyltransferases has the capacity to modify a secondary amine on the FQs, leading to reduced activity (46, 99). The latter does not result in high-level FQ resistance but may impart a low-level tolerance that favors the selection of resistance mutations (121). Another unpredicted FQ resistance mechanism is known as Qnr, a widespread family of DNA-binding proteins (105), and is responsible for low levels of quinolone resistance (133). We have not heard the end of the quinolone resistance saga. The moral of the story … one should not try to second-guess microbes! If resistance is biochemically possible, it will occur.

Intrinsic Resistance

Intrinsic resistance refers to the existence of genes in bacterial genomes that could generate a resistance phenotype, i.e., proto- or quasi-resistance. Different genera, species, strains, etc., exhibit ranges of antibiotic response phenotypes. Since the beginning of this millennium, the availability of genomewide mutagenesis techniques and rapid bacterial genome sequencing has revealed many potential/intrinsic gene functions in bacteria that may lead to resistance phenotypes in clinical situations. For example, a common genetic route to enhanced antibiotic resistance is gene amplification, notably for resistance to the sulfonamides (79) and trimethoprim (25). These studies provide good clues as to what may happen in the future.

Phenotypic analyses of partial or 𠇌omplete” gene knockout libraries by saturation mutagenesis of bacterial genomes permit the identification of specific mutants eliciting hypersensitivity responses to antibiotics. It is assumed that overexpression of the corresponding wild-type gene would generate a resistance phenotype. Such prognostic studies have been carried out with a number of organisms and have led to the prediction of novel resistance classes. This type of analysis was first done with a partial mutant library of Acinetobacter baylyi (64). A more comprehensive survey of the Keio E. coli mutant gene library identified a total of 140 distinct isolates that were hypersensitive to a range of different antibiotic classes (137) related studies have been done with Pseudomonas aeruginosa (51). Many of the putative “susceptibility” genes identified, such as genes that are genetically recessive, might not lead to a resistance phenotype. Nonetheless, such approaches identify potential r genes and provide information on the systems biology of resistance. RNA microarray analyses of the effects of antibiotics have provided similar predictive information (23). Simply put, increasing the number of copies of the target genes for an antibiotic can lead to reduction in the intracellular concentration of the inhibitor as a result of titration.

Yassin and Mankin used a mutant approach to identify putative target sites for inhibitors of ribosome function (151). Studies with rRNA characterized a number of RNA segments that may be novel targets for small-molecule inhibitors of translation. Such innovative analyses indicate that in spite of suggestions to the contrary, many potential drug targets remain to be exploited in antimicrobial discovery. Predicting resistance reliably𠅊nd acting appropriately—would be a valuable approach to extending antibiotic lifetimes (91).

The Resistome

It has been known for some time that bacterial strains resistant to antibiotics can be isolated by plating environmental bacteria on antibiotic-containing media in the laboratory. This is not surprising for antibiotic-producing actinomycetes, since most possess genes encoding resistance to the compounds that they produce. In several cases, the resistance mechanisms have been identified and shown to be specific enzymatic modifications of the antibiotics. Streptomycetes have long been known to produce a variety of β-lactamases that may well be the source of some of the clinical forms of β-lactam resistance (57, 102). As mentioned earlier, environmental Kluyvera species have been found to be the origins of the CTX-M genes. In other cases, resistance of producing organisms to their products has been identified as due to efflux systems (68, 111). Multiple mechanisms of resistance, as found in the tetracycline producer Streptomyces rimosus (109), are frequent in producing bacteria. Based on biochemical and genetic similarities, such resistance mechanisms have presaged those found subsequently in antibiotic-resistant pathogens (18).

In a recent, all-inclusive approach to quantifying the r genes/phenotype density in the environment, Wright and colleagues screened a collection of morphologically distinct spore-forming actinomycetes (including many known antibiotic-producing strains) for resistance to 21 different antibiotics (43). A significant number of strains were resistant to an average of 7 or 8 antibiotics they were naturally multidrug resistant. The population of r genes in nature is referred to as the environmental antibiotic resistome (17, 150). Clearly, different environments would be expected to vary in the number and type of resistances. Novel resistance mechanisms, as well as many mechanisms related to those found in pathogens, were identified in the collection. This is the best evidence available for the presence of a vast environmental pool of genes with the potential to be captured and expressed as resistance determinants for any overused inhibitor. However, more studies are necessary to establish a strong environment-clinic connection (30).

Similar surveys of other antibiotic-producing bacteria, such as the Bacillaceae, pseudomonads, cyanobacteria, and the extensive family of Actinobacteria (144), a phylogenetic group known to produce many low-molecular-weight molecules, will be valuable in extending our understanding of the nature of r genes existing in the wild.

The Subsistome

Dantas and coworkers have taken a complementary approach to that of D'Costa et al. by screening soil bacteria for biochemical processes that degrade or inactivate antibiotics (36). Hundreds of strains were randomly isolated from 11 diverse urban and rural soils and tested for the ability to subsist or grow on one or more of 18 different antibiotics as sole carbon and nitrogen sources. Perhaps surprisingly, many strains were isolated that grew efficiently on common antimicrobials, including aminoglycosides, fluoroquinolones, and other classes. Most of the strains identified in this study were proteobacteria, and more than 40% were Burkholderia spp. pseudomonads were also well represented. Obviously, catabolic pathways responsible for antibiotic digestion in nature provide a rich source of potential resistance determinants additional studies should reveal novel mechanisms of resistance to most antibiotic classes. Work on antibiotic-catabolizing bacteria was reported in the 1970s (53), but the studies of Dantas and colleagues have exposed the full extent and distribution of degradation/r genes in the environment and further verified the roles played by reservoirs of soil bacteria as origins of antibiotic r genes.

Metagenomic Analyses of Environmental Samples

Cloning, PCR, and gene expression techniques have been applied to detect natural r genes in random recombinant clones derived from bacterial DNA libraries from soils and sediments (3, 119). A potential problem is that the identification of functional resistance requires gene expression (transcription and translation) of the cloned genes in a heterologous host to date, only E. coli has been used. Some r genes were identified, but one wonders how many would have been found using a wider range of expression systems and hosts subsequent global sequencing approaches by D'Costa et al. (43) and Dantas et al. (36) indicate that the number would have been large. Taken together, these studies confirm the existence of many potential antibiotic r genes and mechanisms in nature.

Many questions remain. The roles of these environmental reservoirs in clinical resistance development are still hypothetical, and the primary metabolic functions of proto-/quasi-r genes in microbial populations are as yet unknown. We have little or no evidence that any of the putative r genes identified in these environmental studies have been mobilized into pathogenic bacteria and expressed as resistance phenotypes. If concentrations of antibiotic compounds are essentially undetectable in natural environments, what are the selective pressures for the variety of r genes?

Resistance Due to Anthropogenic Activities

The predominant role of human activities in the generation of environmental reservoirs of antibiotic resistance cannot be disputed. Since the 1940s, ever-increasing amounts of antibiotics designated for human applications have been manufactured, used clinically, released into the environment, and widely disseminated, thus providing constant selection and maintenance pressure for populations of resistant strains in all environments. Obtaining accurate figures on the quantities of antimicrobials produced by the pharmaceutical industry is difficult (it is not in the best interest of pharmaceutical companies to provide this information), but it can be estimated that many millions of metric tons of antibiotic compounds have been released into the biosphere over the last half-century. Since the only available evidence indicates that little in the way of antibiotics is contributed by naturally occurring antibiotic-producing strains in their native environments (65), we must assume that commercial production provides the vast bulk of the antibiotics found in the biosphere. Some alternative uses of antimicrobial agents are as follows: (i) growth promotion/prophylactic use in animals (ii) therapeutic/prophylactic use in humans (iii) therapeutic/prophylactic use in aquaculture (iv) therapeutic/prophylactic use in household pets (v) pest control/cloning for plants and agriculture (vi) use as biocides in toiletries and in hand care and household cleaning products and (vii) culture sterility, cloning, and selection in research and industry. It should be noted that therapeutic use in humans accounts for less than half of all applications of antibiotics produced commercially.

Taking into consideration the large-scale disposal of toxic wastes, metals, disinfectants, biocides, and residues of manufacturing processes, the amounts of noxious xenobiotics released into the biosphere are inestimable. The fact that many of the chemicals disposed are recalcitrant to biodegradation only compounds the issue. The dumping of ciprofloxacin into rivers at levels in excess of 50 kg a day by pharmaceutical manufacturers in Hyderabad, in central India (54), is possibly the most extreme of the horror stories concerning irresponsible disposal however, similar levels of pollution probably occur (unreported) elsewhere in the world. Quite apart from providing powerful selection for the formation of resistant strains in all bacterial genera (this information has not yet been published), physiological damage to local resident populations of insects, birds, animals, and humans cannot be overestimated (31).

Numerous types of anthropogenic activity, including antibiotic use in agriculture and aquaculture, other nonhuman applications of antibiotics, and waste disposal, create major environmental reserves of resistance (Fig. ​ (Fig.4) 4 ) (49) and, quite probably, of virulence genes and the organisms that harbor them (95). As other examples, genetic and genomic studies of wastewater treatment plants have shown that they are rich reservoirs of r genes and resistant organisms (123, 136) the genes are frequently carried as genomic islands on transmissible plasmids and provide ready sources of resistance determinants. Do these populations have any relationship with resistance in hospitals? Such treatment plants, established for the common good, have become the common bad (13, 34). Steps to ensure better control of antibiotic release and environmental disposal from all users should be immediate and obligatory.

Dissemination of antibiotics and antibiotic resistance within agriculture, community, hospital, wastewater treatment, and associated environments. (Adapted from reference 49 and reference 83a with permission of the publishers.)

Interesting conundrums have been encountered in investigations of links between antibiotic use and the development of antibiotic resistance. Recent studies have uncovered the presence of antibiotic r genes and even resistance-encoding integrons in the gut flora of peoples who live in isolated areas apparently untouched by modern civilization and not exposed to antibiotic therapies (16, 103, 104). Where did the r genes come from?


Prescribing fewer antibiotics is needed

A reduction in antibiotic consumption leads to a reduction of resistance. The classical Finnish study focusing on macrolide resistant Streptococcus pyogenes clearly showed how a reduction in macrolide use could lead to a reduction in AMR. Antibiotic resistance dropped from 9.2% in 1997 to 7.4% in 2000, with a statistically significant association between regional macrolide resistance and consumption rates [Bergman et al. 2004].

What can we do to prescribe fewer antibiotics? Our goal is not just to reduce the amount of antibiotics. It is also to promote a rational use of antibiotics by prescribing antibiotics only to patients who are expected to benefit from the treatment. Many studies have been performed to determine the effectiveness of different types of intervention in promoting a more rational use of antibiotics. According to the last Cochrane review on interventions to improve antibiotic prescribing, multifaceted interventions combining physician, patient and public education in a variety of venues and formats were the most successful. Interactive educational meetings were more effective than didactic lectures, but levels of improvement were limited. Inappropriate antibiotic prescribing was reduced by less than 20% across a broad range of study populations [Arnold and Straus, 2005 Gonzales et al. 2013]. In a recently published paper, van der Velden and colleagues assessed the effectiveness of physician-targeted interventions aiming to improve antibiotic prescribing for respiratory tract infections in primary care. The authors included 58 studies and found that overall antibiotic prescribing was reduced by 11.6%. Within the 59 interventions aiming to decrease overall antibiotic prescribing, it was found that concurrently performed interventions (multiple interventions) were more effective than single interventions focusing on only one issue. Multifaceted interventions that included educational materials for physicians were the most effective strategies. The authors observed that communication skills in training and near-patient testing achieved the largest intervention effects [van der Velden et al. 2012]. The Cochrane review showed that interventions aimed at reducing overall antibiotic prescribing were less effective than interventions focusing on adherence to first choice antibiotics [Arnold and Straus, 2005]. However, other reviews have reported the opposite [van der Velden et al. 2012]. In general, multifaceted interventions were associated with an average increased prescribing of first-choice antibiotics of approximately 10% [Steinman et al. 2006]. The strategies for primary care that have been observed to be most successful are presented in this review.

Enforcement of governmental laws prohibiting over-the-counter sale of antibiotics

Self-medication with antibiotics is common in many parts of the world. In several countries, antibiotics are sold, illegally, without a prescription [Morgan et al. 2011]. This is particularly common in many countries in Asia, Africa, South and Central America, and even in Southern European countries, such as Italy, Spain, Greece and Malta [Borg and Sciclunca, 2002 Väänänen et al. 2006 Carrasco-Garrido et al. 2008 Plachouras et al. 2010]. In some countries, antibiotics are also available on the free market, i.e. outside pharmacies. Law enforcement to prohibit the illegal over-the-counter sale of antibiotics at pharmacies and the sale of antibiotics for humans and animals on the free market should be promoted worldwide.

Antimicrobial stewardship programmes, campaigns and audits

In many countries, there have been educational campaigns that aim to change healthcare professional and patient behaviour in antibiotic consumption. Interventions include the publication of guidelines, educational sessions on appropriate prescribing of antibiotics, educational sessions on the diagnosis and management of infectious diseases, review of prescribing data for practices, local interviews by pharmacists, messages included on TV, radio and other mass media, etc. Although the effects of these public campaigns and primary-care projects are positive, they are not sufficient to reduce the problem of AMR. An analysis of 22 national- or regional-level campaigns in high-income countries from 1990 to 2007 did find a reduction in antibiotic use. However, as all but one campaign targeted the patient and healthcare professional simultaneously [Huttner et al. 2010], it cannot be concluded whether patient education and awareness alone is an effective intervention to decrease antibiotic use. However, some campaigns have been particularly successful. Interventions targeting doctors and patients in primary care with the active participation of GPs in audits with discussion of results obtained have been found to be effective in achieving a reduction of antibiotics prescribed, as was found in the European-funded project Happy Audit [Bjerrum et al. 2011]. The Scottish Antimicrobial Prescribing Group, established by the Scottish Government in 2008, led a national initiative to actively address antimicrobial stewardship with the development of prescribing indicators for hospital and primary care, and observed reductions in antibiotic prescribing with no adverse effect on mortality or AMR patterns [Nathwani et al. 2012]. In Sweden, the Strategic Programme for the Rational Use of Antimicrobial Agents (STRAMA) and Surveillance of Resistance antimicrobial stewardship initiative reported a reduction in antibiotic use and lowered AMR rates over 10 years, without measurable negative consequences [Mölstad et al. 2008].

More evidence from pragmatic studies carried out in primary care is required

GPs often state that the patients attended are special and they need antibiotics in fact, clinicians think their use is associated with a more rapid recovery or because they have an underlying comorbid condition, such as asthma, chronic lung disease, or they are smokers or have purulent sputum, and because of these features they need antibiotics. These are the so-called ‘special situations’, and many GPs claim that published clinical trials published usually do not take these patients into account. However, in recent years some good-quality papers have been published considering these special situations, including patients with outcomes that are of interest to GPs, such as clinical outcomes with length of symptoms and incidence of complications [McNulty et al. 2013]. The publication of these pragmatic studies can help GPs believe the results obtained. One example is the recent study on the low number of complications found in patients with sore throat (quinsy, otitis media, sinusitis, impetigo or cellulitis), observed in 1.3% of the cases, regardless of whether they were treated with antibiotics [Little et al. 2013b].

Promoting the use of valid point-of-care tests

If you visit a primary-care consultation in a Scandinavian country and compare it with a similar consultation in a Southern European country, you soon realize that the most important difference is the number of diagnostic tools available in Scandinavia. GPs in Northern countries usually use rapid antigen detection testing for the diagnosis of streptococcal pharyngitis, C-reactive protein (CRP) devices for ruling out serious respiratory tract infections, equipment capable of determining the number and type of leukocytes and agar plates for urine culture and susceptibility testing of bacteria (e.g. Flexicult plates, Petri plates that give clinicians knowledge about the bacterial aetiology of a urinary tract infection and the susceptibility pattern of the involved microorganisms in less than 24 hours).

The major contribution of point-of-care tests seems to decrease doctors’ uncertainty, adding useful information that helps to identify who to treat or not to treat with antibiotics. However, not all of the rapid tests are useful in primary care only those that are accurate, precise, easy to use and interpret, fast and affordable for a primary care setting are acceptable [Cals and van Weert, 2013] but above all, point-of-care tests should be able to predict prognosis and expected response to antibiotic treatment. In primary care, as opposed to the hospital, knowledge about the aetiological agent of an infection is not the most important thing it is more important to be able to predict the expected evolution of the infectious disease and thereby consider the potential effect of an antibiotic treatment [Llor and Butler, 2014]. Several point-of-care tests have been shown to be effective in reducing the number of antibiotics prescribed. For example, CRP rapid testing, which gives the result in less than 3 minutes, has been shown to significantly reduce antibiotic prescribing in lower respiratory tract infections without compromising the clinical evolution of the patients [Huang et al. 2013]. In a recent trial, carried out in six European countries, Internet-based training on the CRP rapid test was associated with a significant reduction of antibiotics prescribed for acute lower respiratory tract infections [Little et al. 2013c]. Two Dutch studies showed significant decreases in antibiotic prescriptions when GPs used CRP testing to guide antibiotic management in lower respiratory tract infections, observing reductions from 53% to 31% in one study [Cals et al. 2009] and from 56.6% versus 43.4% in the other [Cals et al. 2010]. Furthermore, no differences in clinical outcomes were observed between patients treated and not treated with antibiotics.

Distinguishing pneumonia from acute bronchitis with only clinical findings is problematic in primary care, and the use of CRP rapid testing has been shown to perform better in predicting the diagnosis of pneumonia than any individual or combination of clinical symptoms and signs in lower respiratory tract infection [Hopstaken et al. 2003 Flanders et al. 2004 van Vugt et al. 2013]. The addition of the CRP level together with the signs and symptoms of a lower respiratory tract infection predicts the diagnosis of pneumonia better [van Vugt et al. 2013]. CRP tests have also proven to be a good predictor of clinical evolution in acute exacerbations of mild-to-moderate chronic obstructive pulmonary disease, being much better than the classic Anthonisen criteria (purulence of sputum, increased coughing or increase of dyspnoea) [Llor et al. 2012]. CRP has also been useful for achieving a reduction of antibiotics prescribed for acute sinusitis [Bjerrum et al. 2004]. The use of procalcitonin has been shown to be effective in reducing the amount of antibiotics in patients with lower respiratory tract infections [Tang et al. 2009]. However, it takes approximately 20 minutes to perform the test.

The utilization of rapid antigen-detection tests or Strep A has been associated with a lower prescribing of antibiotics for patients with sore throat. McIsaac and colleagues reported a 45% reduction in antibiotic prescribing in adults using rapid tests compared with empirical treatment [McIsaac et al. 2004]. Worrall and colleagues reported a proportion of antibiotic prescribing of 58% among physicians who did not use these rapid tests and 27% among those who did use this rapid test [Worrall et al. 2007]. Similarly, in another primary-care study carried out in Switzerland, the use of Strep A reduced antibiotic prescribing from 60% to 37% [Humair et al. 2006]. Curiously, in recent studies carried out in paediatrics, in which the incidence of streptococcal infection is higher, greater reductions were observed, with percentages of antibiotic prescription ranging from 22% to 28% among physicians assigned to rapid testing [Maltezou et al. 2008 Ayanruoh et al. 2009]. However, despite the fact that the use of these rapid antigen detections tests reduces the percentage of antibiotics prescribed, some recent papers cast doubts on the clinical benefit of their use. In a retrospective analysis of 726 patients, post-streptococcal complications were observed in a substantial number of patients with negative results, thereby limiting the usefulness of this rapid point-of-care test [Dingle et al. 2014]. We clearly need new rapid diagnostic instruments that allow clinicians to make a rapid decision on the basis of their results [Laxminarayan et al. 2013].

Promoting delayed prescribing of antibiotics

Delayed antibiotic prescribing means that the prescriber delivers an antibiotic prescription, but recommends the patient not to redeem it the same day. The prescription should only be redeemed if the patient feels worse within a few days. If symptoms reduce spontaneously, the prescription should be discarded. Delayed antibiotic prescribing is a widespread practice in the UK and its use is enforced by national guidelines [National Institute for Health and Clinical Excellence, 2008], but it has been difficult to implement in other countries. However, recent evidence from Norway also indicates that delayed prescribing may lead to a reduction in antibiotic use, mainly for sinusitis and otitis media [Høye et al. 2013].

A Cochrane review evaluated outcomes of delayed antibiotic prescribing compared with immediate antibiotic or no antibiotic prescribing in patients with respiratory tract infections. The study found that delayed prescribing was not superior to no prescribing in terms of symptom control, such as fever and cough, and complications [Spurling et al. 2011]. However, in a recently published study, researchers from Southampton showed a significant reduction in the consumption of antibiotics among patients assigned to delayed antibiotic strategies (less than 40%), without prejudice to the patients’ outcome, compared with the strategy of immediate antibiotic therapy [Little et al. 2014a]. Moreover, the authors pointed out that giving these patients responsibility for their own treatment apparently helps them to consult less frequently in the future. This is a likely and interesting explanation. They concluded that discussing concerns and expectations of patients and informing them of the natural course of an uncomplicated lower respiratory tract infection might reduce reconsultation rates. This has particularly been studied in acute pharyngitis, in which the group of patients assigned to delayed prescribing presented a lower incidence of complications when compared to the group in which antibiotic therapy was withheld and was associated with a lesser re-attendance in subsequent episodes compared with immediate prescribing [Little et al. 2014b].

Enhancing communication skills with patients

Improved communication in primary care can help to bridge this gap between physician and patient expectations. This can be achieved using various approaches. In a pragmatic clinical trial carried out in the Netherlands the authors observed that GPs assigned to CRP testing prescribed fewer antibiotics than those in the control group (30.7% versus 35.7%) and those trained in communication skills treated 26.3% of all episodes of respiratory tract infection with antibiotics compared with 39.1% treated by family physicians without [Cals et al. 2013]. The STAR programme of five sessions of Web-based training in enhanced communication skills, with patient scenarios and an expert-led face-to-face seminar, achieved a 4.2% reduction in global antibiotic use with no significant changes in admissions to hospital, reconsultations or costs [Butler et al. 2012]. Francis and colleagues showed that the use of a brief Web-based training programme and an interactive booklet on respiratory tract infections in children with uncomplicated respiratory tract infections within primary-care consultations led to an important reduction in antibiotic prescribing, with an odds ratio of 0.29 and reduced intention to consult without reducing satisfaction with care [Francis et al. 2009]. Gonzales and colleagues conducted a three-group randomized study at 33 primary-care practices in the United States in acute bronchitis patients, evaluating the effectiveness of two interventions: in one-third of the practices, the intervention was printed decision support in which educational brochures were given by triage nurses to patients with cough as part of routine care, and in another third of the practices a computer-assisted decision support intervention was implemented so that when triage nurses entered 𠆌ough’ into the electronic health record, an alert would prompt the nurse to provide an educational brochure to the patient the remaining practices were control sites. Compared with the baseline period, the percentage of subjects prescribed antibiotics for uncomplicated acute bronchitis during the intervention period decreased from 80% to 68.3% at the printed decision support intervention sites and from 74% to 60.7% at the computer-assisted decision support intervention sites [Gonzales et al. 2013].

Communicating the possible length of mainly bothersome complaints, such as cough, is important in acute bronchitis, since the mean duration of any cough is between 15 and 20 days. In a recent study, Ebell and colleagues performed a population-based survey in the United States to determine patients’ expectations regarding the duration of acute cough, reporting a median duration of 5𠄷 days [Ebell et al. 2013]. The mismatch between patients’ expectations and reality for the natural history of acute cough illness has important implications for antibiotic prescribing. If a patient expects that an episode will last about 1 week, it makes sense that they might seek care for that episode and request an antibiotic after 5 or 6 days. Notwithstanding, GPs often fail to satisfactorily communicate the mean length of cough to patients with acute bronchitis [Cals et al. 2007]. As physicians, we must avoid sentences such as: ‘With these pills you will feel a rapid remission of your cough’ and, as the cough will not remit the patient will be prone to reconsult again and will probably demand medicine that is perceived as stronger, such as antibiotics. Educating patients about the natural history of infectious diseases is therefore crucial. Patients need to know that antibiotics are probably not going to be beneficial in most self-limiting infections, and that treatment with antibiotics is associated with significant risks and side effects. They should also be told that it is normal to still be coughing 2 or even 3 weeks after onset, and that they should only seek care if they are worsening or if an alarm symptom, such as high fever, bloody or rusty-coloured sputum, or shortness of breath occurs (Box 2). Careful word selection for the infection is also important [Phillips and Hickner, 2005]. One survey showed that patients were less dissatisfied after not receiving antibiotics for a chest cold or ‘viral upper respiratory infection’ than they were for acute bronchitis [Phillips and Hickner, 2005].

Box 2.

Communication tips that can help with patients with self-limiting respiratory tract infections.

Discuss with the patient that antibiotics do not significantly reduce the duration of symptoms of self-limiting respiratory tract infections and that they may cause adverse effects and lead to antibiotic resistance.

Back up the information provided with a leaflet or brochure given to the patient highlighting the most important information.

Set realistic expectations for symptom duration, including the average total duration of symptoms (after seeing the doctor): 4 days for acute otitis media, 1 week for acute sore throat, 1½ weeks for common cold, 2½ weeks for acute rhinosinusitis and 3 weeks for acute cough/bronchitis.

Define the diagnosis as a viral respiratory infection, chest cold, or sore throat instead of using the medical terms �ute bronchitis’ and �ute tonsillitis’.

Clearly explain the red-flag symptoms patients should know about infectious diseases.

Consider delayed prescription of antibiotics in those situations in which an aetiology cannot be clearly established.

Consider the use of rapid tests in cases of doubt, such as C-reactive protein rapid testing or rapid antigen detection tests, and discuss the results with the patient.

The use of information brochures is of aid. In the last few years, many studies on the benefit of discussing the evolution of the infectious conditions with the patient have been published. It is important to talk about the expected duration of symptoms and to deliver written material that explains when the patient should contact again in case of a possible deterioration (Box 2). Some papers have shown that a patient’s awareness of the red-flag signs reassures and helps to better comply with the treatment regimen and the use of fewer antibiotics [Butler et al. 2012]. In a recent clinical trial in which the effect of an online course on improving communication skills along with the use of leaflets was evaluated, the group of GPs assigned to this intervention prescribed 32% fewer antibiotics compared with the control group, and those who were trained in this strategy and at the same time had access to CRP rapid testing in their consultations, reduced antibiotic prescribing by 62% [Little et al. 2013a]. In addition, patients assigned to this strategy better understood why they had to take antibiotics. Communicative aspects have to contemplate what patients are unaware of, such as side effects of antimicrobial agents or their lack of effectiveness in infections that are self-limiting, even in many of these ‘special situations’ [Moore et al. 2014]. Box 2 describes some aspects that GPs should consider when communicating with patients with self-limiting respiratory tract infections.


Natural (Biological) Causes

Selective Pressure

In the presence of an antimicrobial, microbes are either killed or, if they carry resistance genes, survive. These survivors will replicate, and their progeny will quickly become the dominant type throughout the microbial population.

Diagram showing the difference between non-resistant bacteria and drug resistant bacteria. Non-resistant bacteria multiply, and upon drug treatment, the bacteria die. Drug resistant bacteria multiply as well, but upon drug treatment, the bacteria continue to spread.

Mutation

Most microbes reproduce by dividing every few hours, allowing them to evolve rapidly and adapt quickly to new environmental conditions. During replication, mutations arise and some of these mutations may help an individual microbe survive exposure to an antimicrobial.

Diagram showing that when bacteria mulitply some will mutate. Some of those mutations can make the bacteria resistance to drug treatment. In the presence of the drugs, only the resistant bacteria survive and then multiply and thrive.

Gene Transfer

Microbes also may get genes from each other, including genes that make the microbe drug resistant. Bacteria multiply by the billions. Bacteria that have drug-resistant DNA may transfer a copy of these genes to other bacteria. Non-resistant bacteria receive the new DNA and become resistant to drugs. In the presence of drugs, only drug-resistant bacteria survive. The drug-resistant bacteria multiply and thrive.

Diagram showing how gene transfer facilitates the spread of drug resistance. Bacteria multiply by the billions. Bacteria that have drug resistant DNA may transfer a copy of these genes to other bacteria. Non-resistant bacteria recieve the new DNA and become resistant to drugs. In the presence of drugs, only drug-resistant bacteria survive. The drug resistant bacteria multiply and thrive.

Societal Pressures

The use of antimicrobials, even when used appropriately, creates a selective pressure for resistant organisms. However, there are additional societal pressures that act to accelerate the increase of antimicrobial resistance.

Inappropriate Use

Selection of resistant microorganisms is exacerbated by inappropriate use of antimicrobials. Sometimes healthcare providers will prescribe antimicrobials inappropriately, wishing to placate an insistent patient who has a viral infection or an as-yet undiagnosed condition.

Inadequate Diagnostics

More often, healthcare providers must use incomplete or imperfect information to diagnose an infection and thus prescribe an antimicrobial just-in-case or prescribe a broad-spectrum antimicrobial when a specific antibiotic might be better. These situations contribute to selective pressure and accelerate antimicrobial resistance.

Hospital Use

Critically ill patients are more susceptible to infections and, thus, often require the aid of antimicrobials. However, the heavier use of antimicrobials in these patients can worsen the problem by selecting for antimicrobial-resistant microorganisms. The extensive use of antimicrobials and close contact among sick patients creates a fertile environment for the spread of antimicrobial-resistant germs.

Agricultural Use

Scientists also believe that the practice of adding antibiotics to agricultural feed promotes drug resistance. More than half of the antibiotics produced in the United States are used for agricultural purposes. 1, 2 However, there is still much debate about whether drug-resistant microbes in animals pose a significant public health burden.


Diagnosis

Clinical

It is not usually possible to diagnose streptococcal pharyngitis or tonsillitis on clinical grounds alone. Accurate differentiation from viral pharyngitis is difficult even for the experienced clinician, and therefore the use of bacteriologic methods is essential. However, distinguishing acute streptococcal pharyngitis from the carrier state may be difficult. When documented streptococcal pharyngitis is accompanied by an erythematous punctiform rash (Fig.13-4), the diagnosis of scarlet fever can be made. With streptococcal toxic shock syndrome, unlike staphylococcal toxic shock syndrome where the organism is elusive, there is often a focal infection or bacteremia. Criteria for diagnosis of streptococcal toxic shock syndrome include hypotension and shock, isolation of S pyogenes , as well as 2 or more of the following: ARDS, renal impairment, liver abnormality, coagulopathy, rash with desquamating soft tissue necrosis. The invasive, potentially fatal S pyogenes infections require early recognition, definitive diagnosis, and early aggressive treatment.

Rheumatic fever is a late sequela of pharyngitis and is marked by fever, polyarthritis, and carditis. A combination of clinical and laboratory criteria (Table 13-2) is used in the diagnosis of acute rheumatic fever. Since the original Jones criteria were published in 1944, these have been modified (1955), revised (1965, 1984) and updated (1992). The other late sequela, acute glomerulonephritis, is preceded by pharyngitis or pyoderma is characterized by fever, blood in the urine (hematuria), and edema and is sometimes accompanied by hypertension and elevated blood urea nitrogen (azotemia). Pneumococcal pneumonia is a life-threatening disease, often characterized by edema and rapid lobar consolidation.

Table 13-2

Jones Diagnostic Criteria for Acute Rheumatic Fever a .

Specimens For Direct Examination And Culture

S pyogenes is usually isolated from throat cultures. In cases of cellulitis or erysipelas thought to be caused by S pyogenes , aspirates obtained from the advancing edge of the lesion may be diagnostic. S pneumoniae is usually isolated from sputum or blood. Precise streptococcal identification is based on the Gram stain and on biochemical properties, as well as on serologic characteristics when group antigens are present.Table 13-3shows biochemical tests that provide sensitive group-specific characteristics permitting presumptive identification of Gram-positive, catalase-negative cocci.

Table 13-3

Characteristics for the Presumptive Indentification of Streptococci of Human Clinical Importance.

Identification

Hemolysis should not be used as a stringent identification criterion. Bacitracin susceptibility is a widely used screening method for presumptive identification of S pyogenes however, some S pyogenes are resistant to bacitracin (up to 10%) and some group C and G streptococci (about 3-5%) are susceptible to bacitracin. Some of the group B streptococci also may be bacitracin sensitive, but are presumptively identified by their properties of hippurate hydrolysis and CAMP positivity. S pneumoniae can be separated from other α-hemolytic streptococci on the basis of sensitivity to surfactants, such as bile or optochin (ethylhydrocupreine hydrochloride). These agents activate autolytic enzymes in the organisms that hydrolyze peptidoglycan.

In many instances, presumptive identification is not carried further. Serologic grouping has not been performed as often as it might be because of the lack of available methods and the practical constraints of time and cost however, only serologic methods, as listed inTable 13-4, provide definitive identification of the streptococci. The Lancefield capillary precipitation test is the classical serologic method. S pneumoniae, which lacks a demonstrable group antigen by the Lancefield test, is conventionally identified by the quellung or capsular swelling test that employs type-specific anticapsular antibody. Inspection of Gram-stained sputum remains a reliable predictor for initial antibiotic therapy in community-acquired pneumonia.

Table 13-4

Methods of Serogrouping Streptococci.

New methods for serogrouping that show sensitivity and specificity now are being explored. Organisms from throat swabs, incubated for only a few hours in broth, can be examined for the presence of S pyogenes using the direct fluorescent antibody or enzyme-linked immunosorbent technique. Additional rapid antigen detection systems for the group carbohydrate have become increasingly popular. However, the sensitivity (70-90%) of these currently available rapid tests for group A streptococcal carbohydrate does not allow exclusion of streptococcal pharyngitis without conventional throat culture (sensitivity of a single throat culture is 90-99%). A third generation assay, the optical immunoassay, is currently being evaluated. S pneumoniae can be identified rapidly by counterimmuno-electrophoresis, a modification of the gel precipitin method. The coagglutination test, described in Ch.12, is a more sensitive modification of the conventional direct bacterial agglutination test. The Fc portion of group-specific antibody binds to the protein A of dead staphylococci, leaving the Fab portion free to react with specific streptococcal antigen. The attachment of antibody to other carrier particles in suspension (for example, latex) also is used. The fact that whole streptococcal cells can be used in recently developed methods circumvents the difficulties involved in extracting components that retain appropriate antigenic reactivity. These newer serogrouping methods should make it more practical to identify not only β-hemolytic isolates from the blood or normally sterile sites, but also α-and nonhemolytic strains. It has become increasingly important to identify more of these strains to avoid simply misclassifying them as contaminants. Such information will expand our understanding of the importance of non-group-A streptococci.

Serologic Titers

Antibodies to some of the extracellular growth products of the streptococci are not protective but can be used in diagnosis. The antistreptolysin O (ASO) titer which peak 2-4 wks after acute infection and anti-NADase titers (which peaks 6-8 weeks after acute infection) are more commonly elevated after pharyngeal infections than after skin infections. In contrast, antihyaluronidase is elevated after skin infections, and anti-DNase B rises after both pharyngeal and skin infections. Titers observed during late sequelae (acute rheumatic fever and acute glomerulonephritis) reflect the site of primary infection. Although it is not as well known as the ASO test, the anti-DNase B test appears superior because high-titer antibody is detected following skin and pharyngeal infections and during the late sequelae. Those titers should be interpreted in terms of the age of the patient and geographic locale.

Although not used in diagnosis, bacteriocin production and phage typing of streptococci are employed in research and epidemiologic studies.


Concluding remarks

Drug-resistant bacterial infections are becoming more prevalent and are a major health issue facing us today. This rise in resistance has limited our repertoire of effective antimicrobials, creating a problematic situation which has been exacerbated by the small number of new antibiotics introduced in recent years. The complex effects of bactericidal antibiotics discussed in this review provide a large playing field for the development of novel antibacterial compounds, as well as adjuvant molecules and synthetic biology constructs that could enhance the potency of current antibiotics. It will be important to translate our growing understanding of antibiotic mechanisms into new clinical treatments and approaches, so that we can effectively fight the growing threat from resistant pathogens.


Glossary

Actinomycetes: Soil bacteria that produce the majority of currently identified natural product antibiotics. In particular, the genus Streptomyces has historically been a prolific source of antibacterial agents.

Aerobic Bacteria: All aerobic bacteria require oxygen for growth. Microaerophiles require some oxygen for growth, however they are harmed by high concentrations of it.

Anaerobic Bacteria: Bacteria that do not require oxygen for growth. Obligate anaerobes are incapable of growing in oxygenated environments. Aerotolerant anaerobes can grow in oxygenated environments, but are incapable of utilizing oxygen. Facultative anaerobes are capable of utilizing oxygen for growth, but are also capable of surviving in oxygen free environments.

Bactericidal Agent: An agent that is capable of killing bacteria. These can be antiseptics, disinfectants, or antibiotics.

Bacteriostatic Agent: An agent that stops bacteria from reproducing while not harming them otherwise. Unlike bactericidal agents they are not capable of killing bacteria on their own.

Biofilm: A sessile community of microorganisms that adhere to a surface. Some biofilm forming bacteria produce exopolysaccharide sheaths that make them dramatically less susceptible to antibiotics and other environmental toxins.

Center for Disease Control and Prevention (CDC): An agency of the United States Department of Health and Human Services that is in charge of monitoring and maintaining the health safety of its residents in regard to both noncommunicable and communicable disease.

Commensal Bacteria: Bacteria that benefit from their host environment without causing harm to the host. These bacteria are non-pathogenic.

Cytotoxin: Substances that are toxic to cells. They can induce cell death through apoptosis or necrosis or they can simply reduce cell viability.

Efflux Pump: Protein or glycoprotein complexes located in the cell membrane that are responsible for energy-dependent, active transport of toxins out of cells. These structures play a major role in bacterial antibiotic resistance. Bacterial efflux pumps are categorized by five sub-families: Major facilitator superfamily (MFS), ATP-binding cassette superfamily (ABC), small multi-drug resistance family (SMR), resistance-nodulation cell-division superfamily (RND), and multi-antimicrobial extrusion protein family (MATE).

Endotoxin: Toxins that are not secreted by bacteria, but rather are a part of their cellular membrane and are released only upon its degradation. These toxins are most often lipopolysaccharides.

Enterobacteriaceae: A family of gram-negative bacteria that includes many non-pathogenic species as well as many problem pathogens including Klebsiella, Shiegella, Enterobacter, Salmonella, E. coli, and Y. pestis.

Enterotoxin: Protein exotoxins that target the intestines.

Exotoxin: A broad term referring to any toxin that is secreted by the bacteria. Many exotoxins are highly potent and can be potentially lethal to humans.

Food and Drug Administration (FDA): An agency of the United States Department of Health and Human Services that regulates food, drugs, and cosmetic products. One of the duties of the FDA within the context of pharmaceuticals is the approval of new drugs for public consumption.

Gram-negative Bacteria: Bacteria that have a lipopolysaccharide / protein outer cell membrane and an inner cell membrane with a peptidoglycan layer sandwiched between the two. Their outer cell membrane does not retain Gram stain allowing them to be differentiated from gram-positive bacteria.

Gram-positive Bacteria: Bacteria that have a thick peptidoglycan cell wall surrounding their cell membrane which is capable of retaining Gram stain.

Infectious Diseases Society of America (IDSA): An association based in the United States that represents health care professionals and scientists from around the world that specialize in infectious diseases. The society promotes research, education, and initiatives related to this field.

Methylase: Otherwise known as methyltransferases, these enzymes are highly relevant in many aspects of biology and medicine. In the context of antibiotics they are a common bacterial resistance mechanism. Bacteria utilize them to modify drug targets with methyl groups thereby decreasing the affinity of the antibiotic.

Nosocomial Infection: Also referred to as hospital acquired infections (HAIs), these infections occur in hospital associated environments.

Opportunistic Pathogen: A microorganism that is normally commensal, but can become pathogenic in hosts with compromised immune systems.

Penicillin-binding Proteins: A large group of proteins essential for cell wall biogenesis that are all characterized by their ability to irreversibly bind β-lactam antibiotics.

Peptidoglycan: A polymeric saccharide and amino acid structure. In a cross linked form it is the primary constituent of the cell wall of bacteria. Gram positive bacteria have a thick peptidoglycan layer outside of their cell membrane. Gram negative bacteria have a much thinner peptidoglycan layer located between an inner and an outer cell membrane.

Porin: Beta-barrel, transmembrane, transport proteins that allow small to medium sized molecules to pass through cell membranes.

Structure-activity Relationship (SAR): The relationship between the chemical structure of a molecule and its biological activity. Medicinal chemists probe this relationship by manipulating functional groups or even larger portions of a molecule and then observing the changes to biological activity that result.

World Health Organization (WHO): An agency of the United Nations with a focus on international public health. The WHO monitors and advises on all aspects of public health including trends in communicable diseases.

Zoonotic Infection: A disease transmitted from animals to humans. These infections can occur via contact with living animals or through the consumption of foods that are either products of animals or have been contaminated by animals.