Which of the following are primary sites for action of antimicrobial drugs in bacteria?

Measuring Performance

Antimicrobial drug prescribing is a process in providing healthcare, and its performance measure must be based on a strong foundation of research showing that the process addressed by the measure, when performed correctly, leads to improved clinical outcomes.

Measuring the performance of antimicrobial drug use (i.e., monitoring and surveillance) gives an insight into the patterns, determinants, and outcomes of use. Patterns of use describe the extent and profiles of use and trends over time that require further qualitative investigation. It enables measuring the effect of stewardship interventions and providing feedback to prescribers and enables regional, national, and international benchmarking. Determinants of use identify reasons that led to prescribing, such as disease prevalence and incidence, socioeconomic factors, drug availability and affordability, prescriber and patient characteristics, etc. Outcomes of antibiotic use besides patient outcomes concern correlations between antibiotic use and resistance, rates of adverse drug reactions, and economic consequences. In addition, antimicrobial pattern of use analysis provides some simple qualitative indices [3].

The Driving re-investment in Research & Development (R&D) and responsible antibiotic use (DRIVE-AB) project is a public–private consortium funded by the EU Innovative Medicines Initiative (IMI). One of the primary objectives was the development of a consensually accepted terminology and a framework to define responsible antibiotic use. Furthermore, the project developed consensually validated quality indicators and quantity metrics for evaluating antibiotic use [4].

Influence of antimicrobial drugs on opsonization of microorganisms

Antimicrobial drugs can change the opsonic requirements of bacteria by inducing changes on the surface of the bacteria. Drugs that inhibit protein synthesis are especially effective in this respect. For example, treatment of Streptococcus pyogenes with clindamycin or lincomycin decreases the expression of M protein on the bacteria. Since M protein inhibits complement activation, decreased expression of M protein results in an increased deposition of C3 molecules on the surface of the bacteria. This explains the enhanced phagocytosis of clindamycin- or lincomycin-treated S. pyogenes by granulocytes and monocytes. Clindamycin has also been shown to increase the phagocytosis of Staphlococcus aureus by granulocytes and macrophages. This has been attributed to a decreased protein A synthesis by clindamycin-treated S. aureus. This may result in more effective opsonization since protein A binds to the Fc part of IgG.

General information

Antimicrobial drugs are widely used in topical medicaments, cosmetics, household products, and industrial biocides. Depending on their concentrations, they can function as disinfectants, antiseptics, or preservatives. The prevalence and rank order of sensitization to antimicrobial allergens in Europe have been reviewed [1,2]. The most frequent antimicrobial allergens in 8521 patients who were patch-tested between 1985 and 1997 in Belgium are given in Table 1 [2].

Table 1. Most frequent antimicrobial allergens in Belgium in 8521 patients in 1985–97

In the multicenter study of the Information Network of Departments of Dermatology, sensitization rates of preservatives in the standard series were all over 1% in the test population of 11 485 patients. Thiomersal was rating highest (5.3%), chloromethyl-isothiazolinone/methyisothiazolinone, formaldehyde, and methyl-dibromo-glutaronitrile/phenoxyethanol were next at about 2%, and parabens rating lowest at 1.6%. Glutaral, a biocide mainly used as a disinfectant, showed a remarkable increase in sensitization from less than 1% in 1990 up to more than 4% at the end of 1994. Health personnel and cleaning personnel were often affected and showed a sensitization rate of 10% [1,3].

12.1 Introduction

Antimicrobial drugs interfere with the life cycle of an organism in various ways. To alter the life cycle, all antimicrobials must bind to a cellular target. Binding of the drug to its target results in alteration of the normal function of the bacterium or fungus, leading to either inhibition of growth or cell death. In addition to the ability of an antimicrobial agent to reach its target site of action (ie, the receptor), the drug must also possess sufficient affinity for its receptor, and it must achieve a sufficient concentration to affect organism function. These pharmacologic characteristics are the primary determinants of antimicrobial activity.

Unfortunately, because the interaction between drug and “bug” receptors occurs on a microscopic scale, we cannot directly quantify these effects in patients. Moreover, infection eradication is the desired ultimate outcome, but this is typically delayed by days to weeks after initiation of therapy, and we do not want to wait that long to discover that we chose the wrong drug or dose. As such, we must use surrogate markers in an attempt to reflect the crucial cellular interactions and to predict our desired outcome. These surrogate markers are ideally easily measured, and they substitute for the truly desired outcome, which is eradication of infection.

History

Most antimicrobial drugs are natural products; that is, they are produced by micro-organisms such as bacteria or fungi, often found in the soil. In fact, they can be looked upon as nature’s regulatory principle for microbial society. Resistance to antimicrobial drugs is therefore a natural phenomenon. Before the introduction of penicillin in the 1940s, resistance to antimicrobial drugs was not a clinical problem. At that time, the large majority of commensal and infectious bacteria associated with infections in man were susceptible.

Over the last seven decades, however, increased use of antimicrobial drugs, not only in human medicine, but in other areas, such as veterinary medicine, agriculture, and fish farming, has had an enormous impact on the microbial society. Nearly everywhere, the numbers of susceptible strains have reduced and resistant strains or variants have increased in numbers. It has been repeatedly reported that the susceptibility profile of bacteria in any human compartment, such as the skin, intestine, and respiratory tract, is very different from what it was in the pre-antibiotic era, and even 15 years ago. The same trend is reported from hospitals and homes. Multidrug resistance, that is resistance to several antimicrobial drugs, is commonly found in bacteria that cause infections as well as in commensal organisms.

A few decades ago, it was a common opinion that various compartments in nature have their own flora. As an example, it was claimed that you could use antimicrobial drugs relatively freely in fish farming without increasing the burden of resistance in humans. Now we have learned the lesson. Micro-organisms circulate everywhere, and there is a continuous exchange of strains between all compartments in nature (humans, animals, birds, fish, etc.). Even if a bacterial species is host-specific, the genetic material that codes for resistance is not. In fact, antibiotics have shown that bacteria have great genetic adaptability, in terms of their ability to exchange genetic traits among genera and species which are evolutionarily millions of years apart. Antibiotic resistance genes on plasmids and transposons flow to and from nearly all types of bacteria. Sometimes they leave the plasmid and jump into bacterial chromosomes; sometimes they jump back again.

However, this knowledge is not being heeded everywhere. Small doses of antimicrobial drugs as “growth promoters” are still commonly used, even in countries in which the health authorities should be aware of the problems. It is easy to blame developing countries for using antimicrobial drugs as growth promoters, or for selling antimicrobial drugs over the counter without prescription, but it took the European Community many years before it started to look into the problem of using antimicrobial drugs as growth promoters. The history of cross-resistance between avoparcin and vancomycin may have provided important background for this alteration in attitude.

Avoparcin and vancomycin are glycopeptide antibiotics, large molecules that are produced by a variety of environmental micro-organisms, which may therefore contain genes that code for antimicrobial drug resistance. Both of these drugs are mostly active against Gram-positive bacteria, such as enterococci and staphylococci. In Europe, avoparcin was allowed to be used as an animal food additive in many countries, while the use of vancomycin was limited to humans. Nobody bothered about the possibility of cross-resistance between avoparcin and vancomycin until 10 years ago. After the emergence of vancomycin-resistant enterococci and after more than 2 years of hard lobbying by several groups, avoparcin was withdrawn from the market in the European Community. However, in the meantime, vancomycin-resistant enterococci had become widespread in many European countries.

Instead of focusing on the development of resistance to a specific antimicrobial drug in a specific species, we should focus on the microbial community as a single entity or a “metagenome”. Any use of any microbial agent might cause resistance to develop in one or more microbial species. When such genes have first become established, they may float around and be picked up by other species. This approach to the development and spread of resistance can, and should, be applied to the microbial flora in all mammals, as well as in the environment. The consequence of this approach is that we should, every time we prescribe an antimicrobial drug, try to find a drug that hits nothing but the pathogen in the infected organ(s). Of course, this can be difficult and sometimes even close to impossible. But that should not stop us from trying. For example, in nearly all cases, a third-generation cephalosporin for acute pharyngitis caused by Group A streptococci, or of a fluoroquinolone for acute cystitis, are not the best alternatives.

9.2 Molecular Mechanism of Nanomedicine for Neuroinfectious Disease

Nanostructured antimicrobial drugs are targeted mainly to the receptors of brain endothelial cells, such as the insulin, leptin, transferrin, and epidermal growth factor receptors for the transfer of lead molecules across the BBB (Gendelman et al., 2015; Hu and Kesari, 2013). In addition, they are also targeted to the receptors of monocytes/macrophages, such as the folate, CD4, mannose, and CD44 receptors, to enhance cellular uptake of the nanomedicine for macrophage-based drug delivery in the brain via the BBB (Irvine et al., 2015). The nanomedicine follows six steps to eliminate microbes from the nervous system and other biological systems (Hollmann et al., 2015). After entry of the nanomedicine into the nervous system it attracts and binds to the microbes. Thereafter, it carries out the following steps: (1) it destroys the peptidoglycan (membrane) layer of the microbe, leading to the control of microbial growth; (2) it releases toxic metal ions into the cytosolic region of the microbe and can cause microbial death; (3) it alters the cellular ionic environment by activating the proton efflux pumps, leading to a change in pH; (4) it enhances the generation of free radicals, especially reactive oxygen species (ROS), leading to raised oxidative stress; (5) it damages the genetic material of the microbial organism, thus stopping the regulation of microbial growth and replication; and (6) it reduces ATP production, thus increasing energy demand and controlling microbial growth and proliferation (Rizzello et al., 2013; Upadya et al., 2011; Watkins et al., 2015; Shah et al., 2015). The molecular mechanism of nanomedicine for the elimination of microbes from the nervous system is illustrated in Fig. 6.4.

Therefore, nanomedicine can achieve therapeutic action against neuroinfection-associated neurodegenerative disease. Based on this discussion, the approach of using nanostructured antimicrobial agents and nanomedicine can be useful in the treatment of neuroinfectious and neurodegenerative disease.

I. Antimicrobial Agents

Several antimicrobial drugs have been reported as causing peripheral neuropathy, although clear evidence of these compounds having a causal role has been demonstrated only for some of the drugs and only after long-term administration [3].

Chloramphenicol, metronidazole, and nitrofurantoin have all been described as causing axonal, length-dependent, sensorimotor neuropathies with a close correlation with chronic use (e.g., for long-term prophylaxis of recurrent urinary tract infections or treatment of inflammatory bowel diseases) and high-dose schedules. Optic neuropathy can precede, follow, or be associated with peripheral neuropathy during chloramphenicol treatment. With all of these drugs, however, the incidence of reported cases is low compared with the number of patients exposed to them, and the availability of safer and effective alternative drugs will further reduce the future occurrence of neuropathy.

More detailed information is available for medications used to treat tuberculosis, such as ethambutol, ethionamide, and isoniazid. Although ethambutol and ethionamide neuropathies are rare, mild, predominantly sensory, and result from axonal damage through an unknown mechanism, isoniazid neuropathy is more common and can be severe, particularly when doses of 300 mg/day or more are used. Optic neuropathy and central nervous system involvement (ataxia, seizures), as well as myalgias and rhabdomyolysis, have also been reported with high doses of isoniazid. Peripheral neuropathy affects around 1% of the treated patients, with a higher risk for people with a slow rate of drug metabolism (slow acetylators), concomitant malnutrition, or alcohol abuse and high-dose schedules. Distal, symmetrical sensory symptoms and signs are predominant over motor impairment, and they are secondary to isoniazid-induced pyridoxine depletion. Prophylactic administration of pyridoxine (25–50 mg/day) prevents the onset of isoniazid neuropathy and allows the planned treatment to be completed in most cases. Pyridoxine administration is also effective in treating isoniazid neuropathy once symptoms and signs have ensued and even if axonal damage is already present.

However, higher-than-recommended doses of pyridoxine can be neurotoxic to the peripheral nerves and they can make the neuropathy worse. The interaction between isoniazid treatment and pyridoxine (which is important for protein, carbohydrate, and fatty acid metabolism and for sphingomyelin synthesis) is not completely understood, and no correlation has been demonstrated between the severity of the neuropathy and the pyridoxine levels. Pure axonal sensory neuropathy is the most common type of pyridoxine-induced damage, but in the most severe cases, because of marked pyridoxine overdose, DRG neuron damage with poor recovery may occur.

Dapsone is used mainly to treat leprosy and dermatitis herpetiformis, but in recent years it has also been used as a second-line drug for rheumatoid arthritis and for the prophylaxis of opportunistic infections in immunocompromised patients. It acts by facilitating the conversion of myeloperoxidase into an inactive form and by inhibiting neutrophil adherence to vascular endothelium. The risk of toxic effects on the peripheral nervous system is higher in slow acetylators and with the long-term administration of high doses (i.e., more than 300 mg/day). Neuropathy is predominantly motor, also severely affecting the arms with a symmetrical, distal distribution, and coasting is common. The neuropathy is primarily axonal, but the mechanism of action is unknown.

1 Introduction

Although numerous antimicrobial drugs have been developed to kill or inhibit the growth of pathogenic microbes, infectious diseases continue to be one of the main reasons for death globally for both adults and children (Zhang et al., 2010). The main reason is that many antimicrobials have low transportation rates through cell membranes and low activity inside the cells, thereby imposing negligible inhibitory or bactericidal effects on the intracellular bacteria. Another major challenge is microbial resistance to antimicrobials (Kalhapure et al., 2015a). The increasing resistance of the microorganisms toward antimicrobials has led to serious health problems. An attempt has been made to resolve microbial resistance to antimicrobial drugs by discovering new antibiotics, but there is no assurance that the development of new antimicrobial drugs can catch up with the microbial pathogens' fast and frequent development of resistance in a timely manner (Huh and Kwon, 2011).

Nanotechnology is one of the key technologies of the 21st century. There are increasing prospects of nanotechnology for various applications in fiber and textiles, agriculture, electronics, forensic science, space, and medical therapeutics (Kumari et al., 2010). Development of new and effective medical treatments is one of the greatest values of nanotechnology. A great deal of effort is now focused on the engineering of drug-loaded nanocarriers able to serve as efficient diagnostic and/or therapeutic tools against severe diseases, such as cancer, neurodegenerative disorders, and infections (Mahapatro and Singh, 2011; Nicolas et al., 2013).

Delivery of antimicrobials by novel drug delivery systems such as nanoparticles (NPs) could be a promising strategy to overcome the current challenges associated with antibiotic therapy. NPs are solid, colloidal particles with a size in the range 10–100 nm, prepared from natural or synthetic polymers (Mahapatro and Singh, 2011). They show useful physicochemical features such as ultrasmall size, high surface-to-volume ratios, chemical reactivity, and modifiable platforms (Zhang et al., 2010). These unique physicochemical properties confer numerous advantages for antibiotic delivery such as targeted delivery, relatively uniform distribution in the active site, sustained drug release, minimized side effects, and improved patient compliance (Mahapatro and Singh, 2011; Nicolas et al., 2013). Antimicrobial-loaded NPs can enter cells through endocytosis and accordingly release the drug to eradicate microbe-induced intracellular infections. Furthermore, NPs themselves could inherently overcome existing specific drug-resistance mechanisms by microbes. In fact, a number of NP-based delivery systems for infected cells have been widely investigated as antimicrobial drug delivery platforms (Grottkau et al., 2013).

The aim of this chapter is to summarize various nanocarriers, including liposomes, solid lipid nanoparticles (SLNs), polymeric NPs, dendrimers, and metal NPs as promising tools for antimicrobial drugs. Moreover, the potential application of these nanocarriers is discussed.

Clarithromycin

The macrolide antimicrobial drugs can reportedly interact with digoxin by at least two mechanisms: by reducing its metabolism in the gut before absorption (by inhibiting the growth of the bacterium Eubacterium glenum) and by inhibiting P glycoprotein. However, there have been conflicting reports that clarithromycin can either reduce or increase the renal clearance of digoxin (SEDA-27, 186; SEDA-28, 198). In six men with end-stage renal disease clarithromycin increased serum digoxin concentrations by 1.8–4.0 times (15A). In three cases the increase occurred within 12 days and in the other three at 53–190 days. The authors attributed the increase in serum digoxin to inhibition by clarithromycin of P glycoprotein in the intestine and/or bile capillaries rather than the kidneys, since renal function was dramatically impaired and four of the patients were anuric.