Usually, the health-care challenge in the respiratory infections is due to bacterial infections and their resistance to antimicrobials. These kinds of infections evolve rapidly, and for this reason inappropriate doses (for the broad-spectrum coverage) and extended time of therapy are applied. Inappropriate antimicrobial prescriptions have increased the pathogens resistance. On the other hand, the alternative therapies have grown rapidly over the last two decades to enhance the traditional medical practice in both America and Europe. In this chapter we have addressed different aspects of antimicrobial application against pathogens which cause lower respiratory infections. Moreover, we also discuss natural therapy by plants to treat these infections.
Chapter 14
Antimicrobial approaches against bacterial pathogens which cause lower respiratory system infections
A.F. Jozala*
D. Grotto*
L.C.L. Novaes**
V. de Carvalho Santos-Ebinuma†
M. Gerenutti*
Abstract
Keywords
antimicrobial
natural medicine
plants
bacterial pathogens
1. Introduction
Lower respiratory infections are a leading cause of morbidity and mortality in both children and adults worldwide, especially when caused by Gram-negative pathogens in hospitalized patients. The most common infections usually include bronchitis, bronchiolitis, and especially pneumonia, which is the cause of the most deaths, with four million killed each year worldwide.1–3 The inappropriate doses (for the broad-spectrum coverage) and the extended time of therapy have generated acute problems, such as the emergence of multidrug-resistant microorganisms.4,5
The main problems are the inadequate treatment of multiresistant Gram-negative agents and Staphylococcus aureus oxacillin-resistant. Considering these facts, the clinical characterization of the host, the prevalence of bacterial agents, and their sensitivity profile through quantitative cultures are basic elements applied in order to promote a rational use of antimicrobials.
According to WHO (2015), Antibiotic resistance is occurring everywhere in the world, compromising the treatment of infectious diseases and undermining many other advances in health and medicine. It represents one of the biggest threats to global health today, and can affect any one, of any age, in any country. It leads to longer hospital stays, higher medical costs and increased mortality. Antibiotic resistance occurs naturally, but misuse of antibiotics in humans and animals is accelerating the process. Tackling antibiotic resistance is a high priority for the WHO. As part of implementation of objective of the global action plan on antimicrobial resistance, WHO is coordinating a global campaign to raise awareness and encourage best practices among the public, policymakers, health and agriculture professionals. This survey provides a snapshot of current public awareness and common behaviors related to antibiotics in a range of countries.
On the other hand, efforts should be made on alternative therapy. In fact, there is a need to develop new strategies to subtly manipulate bacterial antimicrobial behavior. There is evidence that antimicrobials do not help acute bronchitis because they often do not require it. Therefore, antimicrobials can be administered to patients with acute exacerbations of chronic bronchitis.
Studies have shown increasing evidence of the important role played by the resident microbiota in offering protection against infectious diseases. Rather than continuing the traditional approach of killing bacteria wherever they occur, there is a need to develop new antimicrobial strategies aimed at subtle manipulation of bacterial behavior. Such therapies would favor natural host defenses and the maintenance of the normal microbiota to keep growth of pathogenic species in check. At the outset the design of strategies for novel antibiotics should include exploration of strategies for exploiting beneficial and commensal bacteria in fighting infections in sites where normal microbiota reside.6,7
In this chapter, we address different aspects of antimicrobial application against pathogens which cause lower respiratory infections. Moreover, natural therapy by plants to treat these infections will also be discussed.
2. Bacterial pathogens which cause lower respiratory system infections
Pneumonia is caused by a variety of bacteria, fungi, viruses, and parasites. Numerous factors, including environmental contaminants and autoimmune diseases may cause pneumonia. The pathogens that cause pneumonia are categorized in many ways for the purpose of laboratory testing, epidemiologic study, and choice of therapy. Infections arise while a patient is hospitalized or living in an institution such as a nursing home, which are called hospital-acquired or nosocomial pneumonia. Etiologic pathogens associated with community-acquired and hospital-acquired pneumonia are somewhat different. However, many organisms can cause both types of infections.8
The community-acquired bacterial pneumonia may occur spontaneously or as a complication of viral infections. Its most common agents are Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, and Legionella spp. Bacterial pneumonia acquired in hospitals are the most frequent agents caused by Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and other enterobacteria. In chronic pneumonia, the most frequent cause is Mycobacterium tuberculosis and then other mycobacteria.9
These syndromes, especially pneumonia, can be severe or fatal. For this reason, the initiation of broad-spectrum antimicrobial therapy is important after clinical diagnosis because it is associated with lower mortality rates.10 On the other hand, it is estimated that up to 50% of antimicrobials prescribed may be unnecessary, being important to conduct a clinical trial to evaluate the efficacy, especially for assessment of their broad-spectrum sensibility.11
Bronchitis appears to be caused by a combination of environmental factors, such as smoking, and bacterial infection by S. pneumonia.2 S. pneumoniae is found in 80% of cases and is one of the most dominant species. Recurrence of infections associated with bacterial persistence results in frequent antibiotic courses. This favors the emergence of multidrug resistant species.12,13
Bronchiolitis is a viral respiratory disease of infants and is caused primarily by respiratory syncytial virus. Other viruses, including parainfluenza viruses, influenza viruses and adenoviruses are also known to cause bronchiolitis. Bordetella pertussis, Mycoplasma pneumoniae, and Chlamydia pneumoniae may cause the severe form of the disease, while chronic forms are generally found in association with smoking or pollution. The exacerbation of these processes is often associated with Haemophilus influenzae and S. pneumoniae.14
2.1. WHO’s data about antimicrobial resistance
WHO’s 2014 report on global surveillance of antimicrobial resistance revealed that antibiotic resistance is no longer a prediction for the future; it is happening right now, across the world, and is putting at risk the ability to treat common infections in the community and hospitals. Without urgent, coordinated action, the world is heading toward a postantibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill. Resistance to first-line drugs to treat infections caused by Staphlylococcus aureus—a common cause of severe infections acquired both in health care facilities and in the community—is also widespread.
3. Antimicrobial therapies
Inappropriate antibiotics therapy and overuse of antibiotics may predispose patients to increased resistance and hospital mortality.15 In 2001, WHO published a global strategies for containment of antimicrobial resistance as follows:
The emergence of antimicrobial resistance is a complex problem driven by many interconnected factors, in particular the use and misuse of antimicrobials. Antimicrobial use, in turn, is influenced by an interplay of the knowledge, expectations and interactions of prescribers and patients, economic incentives, characteristics of the health system(s) and the regulatory environment. In the light of this complexity, coordinated interventions are needed that simultaneously target the behaviour of providers and patients and change important features of the environments in which they interact.
More expensive therapies must be used when infections become resistant to first-line drugs. A longer duration of illness and treatment, often in hospitals, increases health-care costs as well as the economic burden on families and societies. Antimicrobial resistance jeopardizes health-care gains to society. The achievements of modern medicine are put at risk by antimicrobial resistance. Without effective antimicrobials for prevention and treatment of infections, the success of organ transplantation, cancer chemotherapy, and major surgery would be compromised (WHO, 2015).
Antimicrobial prescription is affected by acutely ill patient populations, diagnostic uncertainty, a lack of appreciation for the potential harms of antimicrobials, and prescribing by clinically inexperienced physicians in training. The empirical prescription behavior of trainees can be shaped by the practices of senior physicians, who rely on experience and often consider themselves exempt from evidence-based guidelines. To limit inappropriate empirical prescriptions of broad-spectrum agents, interventions can include: the direct education provider; selective formulary restriction; development, dissemination, and enforcement of evidence-based therapeutic guidelines; preprinted order sheets; and use of an audit and feedback program. These strategies are important tools that are available to institutional antimicrobial stewardship programs to improve rational empirical antibiotic prescribing.5
3.1. Antimicrobial approaches following clinical guidelines
Pneumonia: This treatment is community acquired pneumonia (CAP) specific.16 Bacteria and viruses are responsible for the majority of cases. Preponderating: Streptococcus pneumonia and Mycoplasma.17 Empiric therapy. Use CURB65 score.18
Score 1 = Outpatient
Score 2 and over = Impatient treatment
For adults: First choice: Azithromycin 500 mg PO (first dose) then 250 mg/day for 5 days. If the patient has had antibiotic therapy within past three months:
(Azithromycin) + Amoxicillin 1g PO 3 times/day; or,
(Azithromycin) + Levofloxacin 750 mg PO once/day.
Alternatives Doxycycline 100 mg PO twice/daily (5–7 days).
For children. (>3 months) antibiotic therapy is not routinely required for preschool-aged children with CAP because of viral etiology. If suspected bacterial infection:
Amoxicillin 90 mg/kg per day (divided in two daily doses)19
Alternatives: Azithromycin 10 mg/kg PO (first dose “maximum 500 mg”) then 5 mg/kg (maximum 250 mg) PO for 4 days.20
Bronchitis: Self-limited inflammation of the upper airways due viral infection (majority), bacterial (5–10%) or irritants. Pharmacological treatment: The etiology of acute bronchitis is almost completely viral, so the treatment should be symptomatic, aiming to guarantee respiratory comfort and removal of secretions. Thus, there is use of cough suppressants or bronchodilators, mucolytics, or corticosteroids. The use of antibiotics is very controversial17,21,22 and there is no indication as recent revisions.
The Cochrane Review from 2014 stated:
There is limited evidence to support the use of antibiotics in acute bronchitis. Antibiotics may have a modest beneficial effect in some patients such as frail, elderly people with multimorbidity who may not have been included in trials to date. However, the magnitude of this benefit needs to be considered in the broader context of potential side effects, medicalization for a self-limiting condition, increased resistance to respiratory pathogens and cost of antibiotic treatment.21
The US Center for Disease Control and Prevention, the American Academy of Family Physicians, the American College of Physicians/American Society of Internal Medicine, and the Infectious Diseases Society of America all recommend not prescribing antibiotics for acute bronchitis.22
Bronchiolitis: Etiology—respiratory syncytial virus (RSV) (50%), parainfluenza (25%); human metapneumovirus.23 Treatment is supportive aiming moisture and oxygen, so the majority of patients with bronchiolitis can be treated as outpatients. In some situations, when there is an association of malnutrition in children, hypoxia, tachypnea, or other immunosuppressive condition, should proceed to hospitalization. The administration of bronchodilators and corticosteroids are not indicated as well as the use of antibacterial agents, unless there are clear signs of bacterial infections.24–27 Children with severe respiratory impairment should fed intravenously or nasogastric tube because of the high risk of food aspiration.28 Only in severe cases, there is an indication of the use of antiviral drugs (ribavirin), aiming to RSV. Ribavirin shows broad antiviral activity that interferes with the RNA metabolism. Typically, ribavirin is administered aerosolized 6 g vial (20 mg/mL) in sterile water by SPAG-2 generator over 18–20 h/day, for 3–5 days.23
Prophylaxis: Immunization with the anti-RSV monoclonal antibody palivizumab. Palivizumab is a humanized monoclonal antibody that binds to the F protein of RSV and inhibits viral infection and replication.29 The prophylaxis indications are as follows:
Preterm infants with chronic lung disease: Prophylaxis may be considered during the RSV season during the first year of life for preterm infants who develop chronic lung disease of prematurity defined as gestational age <32 weeks, 0 days and a requirement for >21% oxygen for at least the first 28 days after birth.
Infants with hemodynamically significant CHD: Infants with haemodynamically significant congenital heart disease can be considered for prophylaxis during the first year of life.
Children with anatomic pulmonary abnormalities or neuromuscular disorder: Infants with neuromuscular disease or congenital anomaly that impairs the ability to clear secretions from the upper airway because of ineffective cough are known to be at risk for a prolonged hospitalization related to lower respiratory tract infection, and therefore, may be considered for prophylaxis during the first year of life.
Immunocompromised children: Prophylaxis may be considered for children younger than 24 months of age, who are profoundly immunocompromised during the RSV season.
4. Probiotic treatment
Instead of continuing the traditional approach to kill bacteria wherever they occur, the new criteria for successful antiinfective chemotherapeutics are to preserve the efficacy of each agent as long as possible by delaying the emergence of drug resistance and to spare the normal microbiota as much as possible. The normal microbiota is viewed as containing invaluable allies in combating microbial pathogenesis by protecting niches against new microbial competitors and sustaining the species diversity that impedes virulence.4,5
Antibiotic development has focused on the identification of “essential” targets whose inhibition is lethal under conditions of maximal microbial proliferation. A fresh approach would be to revise the operational definition of essentiality so that it more accurately reflects the biological reality: Which genes are essential to the pathogen in vitro under conditions that are relevant in the host? Which genes are essential to the pathogen in specific host environments, including polymicrobial communities on epithelial surfaces, where the microorganism of interest may represent a relatively minor planktonic population, in monomicrobial populations deep in tissues?4
Araújo and colaborators5 reviewed several studies and found that they were heterogeneous regarding strains of probiotics, the mode of administration, the time of use, and outcomes. In the same work, they identified 11 peer-reviewed, randomized clinical trials, which include a total of 2417 children up to 10 incomplete years of age. In their analysis of these studies, the reduction in new episodes of disease was a favorable outcome for the use of probiotics in the treatment of respiratory infections in children. It is noteworthy that most of these studies were conducted in developed countries with basic sanitation, health care and strict, well-established, and well-organized guidelines on the use of probiotics. Adverse effects were rarely reported, demonstrating probiotics to be safe. They concluded that the encouraging results—that is, reducing new episodes of respiratory infections—emphasize the need for further research, especially in developing countries, where rates of respiratory infections in children are higher when compared to the high per capita-income countries identified.
5. Natural medicines
Complementary and alternative therapies have grown rapidly over the last two decades to increment or replace the traditional medical practice in both America and Europe,30,31 especially to multidrug resistant strains of bacteria such as Escherichia coli and K. pneumoniae, which are for example widely distributed in hospitals. Thus, herbal medicines have often been recommended in the treatment of many diseases, including in lower respiratory system infections, as follows.
Regarding bronchitis, a large number of plants were found in the literature indicating its treatment, which are presented in Table 14.1. Bronchitis treatment includes, in the most studies, antitussive, expectorant, and antiinflammatory outcomes.
Table 14.1
Plants Indicated to the Bronchitis Treatment
| Scientific Name | Doses/Extracts | Constituents | Observations/Results | References |
| Tussilago farfara L. | • Aqueous extract from flower buds (2.8 g/kg) and rachis (3.5 g/kg) | Caffeic acid, chlorogenic acid, sinapic acid, rutin and kampferol, Maleic acids, formic acid, tussilagone, and others. | • Preclinical study; ICR mice of either sex (19–24 g); • Antitussive and expectorant activities. | a |
| Citri grandis (L.) Osbeck | • Aqueous extract: 1005 mg/kg • 50% ethanolic extract: 568 mg/kg • 70% ethanolic extract: 247, 493, and 986 mg/kg • 90% ethanolic extract: 501 mg/kg | Not identified | • Preclinical study; NIH mice of either sex (18–22 g); • 70% ethanolic extract of C. grandis demonstrated the best antitussive, expectorant and antiinflammatory effects in vivo. | b |
| Pyrrosia petiolosa (Christ et Bar.) Ching | • Ethanol extract and fractions (petroleum ether, ethyl acetate, N-butanol and aqueous); • Test with microorganisms: ethanol extract or fractions at 0.25, 0.50, 0.625, 1.25, 2.50, 5.0, 10.0, and 20.0 mg/ mL • Antiinflammatory test: ethanol extract at 2.5, 5.0, and 10.0mg/kg | Anthraquinones, flavonoids, terpenoids, steroids, reducing sugars, and saponins. | • In vitro study with bacterial ad fungi strains, and preclinical study (Kunming mice); • The minimum inhibitory concentration (MIC) of the ethanol extract and fractions ranged from 1.25 to 10.00 mg/mL • Antibacterial activity ranging from 1.25 to 10.0 mg/mL for ethanol extract and fractions) and antiinflammatory property (ethanol extract at 5.0 and 10.0 mg/kg) | c |
| Hedera helix L. | • Ivy leaves extract with 50% ethanol (Hedelix—reference natural medication), 260 patients; • Ivy leaves extract with 30% (m/m) ethanol (Prospan), 258 patients; • Doses: adults and children (from 10-years old) 24 drops; children (4–10-years old) 16 drops; children (2–4-years old) 12 drops. | A minimum of 6.75% of hederacoside C | • Male or female Caucasian patients at least 2 years of age with a confirmed clinical diagnosis of acute bronchitis; • Children under 2 years of age were excluded as well as medication possibly influencing symptoms of acute bronchitis; • Patients took one of the medications 3x/daily during 7 days; • Bronchitis severity score subscale cough, sputum, rhales/rhonchi, chest pain during coughing, and dyspnea improved to a similar extent in both treatment groups.
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