Introduction

Out of a total of 3,941,000 deaths in the world, respiratory tract infection accounts for 34.60% deaths in the Southeast region of the world. The aetiology and symptomatology of respiratory tract diseases varies based on age, gender, season, type of population at risk and other factors.  Lower respiratory tract infections (LRTIs) are one of the most common infectious diseases in humans worldwide and pose a huge burden on the society. About 4.4% of all hospital admissions and 6% of all general practitioner consultations in the world are mainly due to LRTIs. The mortality and morbidity is comparatively high in all age groups.¹

The term, LRTI, covers a wide spectrum of diseases, including acute bronchitis, acute exacerbations of chronic bronchitis (AECB) and community-acquired pneumonia (CAP).²

A variety of organisms are usually implicated in the aetiology of LRTI. These causative agents vary from area to area and also vary in their antibiotic susceptibility profile. Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, etc., and Gram-negative bacteria such as Haemophilus influenzae, Pseudomonas spp., Acinetobacter spp., and Klebsiella spp. have been recovered from LRTIs. The antimicrobial therapy for LRTIs is frequently empirical and presumptive.¹

Role of Macrolides in Community-Acquired Pneumonia

In many cases with community-acquired pneumonia (CAP), the most common pathogens responsible for hospitalization are Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila and Mycoplasma pneumoniae.³

The macrolides are particularly useful because of their spectrum of activity that covers most of the respiratory pathogens encountered in hospitalized patients as well as in patients who can be treated at home. Their intracellular concentrations and their concentrations in the bronchial mucosa, in lung biopsy specimen, alveolar macrophages, sputum and in the alveolar lining fluid make them excellent antibiotics for the treatment of such infections both in the community and in the hospital.³  If Legionella, Mycoplasma or Chlamydia spp., so-called 'atypical' pathogens, are involved, macrolide antibiotics are the therapy of first choice.⁴

Prognostic Scoring Systems for CAP

The knowledge of relevant prognostic factors might be useful for early identification of CAP patients at high risk requiring intensive care treatment. Two prognostic scoring systems have been developed to address these issues, as shown in Table 1 and Table 2.⁵

Mortality rates progressively increase with increasing risk class in both severity scoring systems.⁵

Parenteral Therapy

Parenteral antibiotic therapy is  essential as  initial therapy for critically ill  patients with severe pneumonia or bacteraemic pneumococcal pneumonia and for patients who are unable to take oral medications.⁷ Intravenous (I.V.) antibiotics rapidly reach bactericidal levels in the serum and cross the alveolar-capillary membrane to reach alveolar lining fluid and interstitium. With I.V. antibiotic therapy, accumulation of antibiotic in the lung is rapid.⁸ Patients treated initially with parenteral antibiotics should be transferred to an oral regimen as soon as clinical improvement occurs and the temperature has been normal for 24 hours, provided there is no contraindication to the oral route.⁹

Current Treatment Guidelines for CAP

Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) Guidelines for CAP in Adults-2007¹⁰

Inpatient, Non-ICU (Intensive Care Unit) Treatment

• A ?-lactam plus a macrolide (Strong recommendation; Level I evidence).*¹⁰
• Patients should be switched from I.V. to oral therapy when they are haemodynamically stable and improving clinically, are able to ingest medications, and have a normally functioning gastrointestinal tract (Strong recommendation; Level II evidence).*¹⁰

*IDSA Guidelines: Level I: High; Evidence from well-conducted, randomized controlled trials. | Level II: Moderate; Evidence from well-designed, controlled trials without randomization (including cohort, patient series, and case-control studies). Level II studies also include any large case series in which systematic analysis of disease patterns and/or microbial aetiology was conducted, as well as reports of data on new therapies that were not collected in a randomized fashion.

Joint Indian Chest Society (ICS) and National College of Chest Physicians (NCCP) Recommendations for CAP-2012¹¹

Antibiotic Therapy in the Hospitalized Non-ICU Setting

• The recommended regimen is a combination of a -lactam plus a macrolide (preferred ? -lactams include cefotaxime, ceftriaxone and amoxycillin-clavulanic acid) (Grade A; Level I evidence).¹¹

Antibiotic Therapy in ICU Setting

The recommended regimen is a ? -lactam (cefotaxime, ceftriaxone or amoxycillin-clavulanic acid) plus a macrolide for patients without risk factors for Pseudomonas  aeruginosa (Grade A; Level II evidence. ¹¹

ICS/NCCP Recommendations: Level I: High-quality evidence backed by consistent results from well-performed randomized controlled trials or overwhelming evidence from well-executed observational studies with strong effects. | Level II: Moderate-quality evidence from randomized trials (that suffer from flaws in conduct, inconsistency, indirectness, imprecise estimates, reporting bias or other limitations). | Grade A: Strong recommendation to do (or not do) where the benefits clearly outweigh the risk (or vice versa) for most, if not all patients.

British Thoracic Society (BTS) Guidelines for the Management of CAP-2009, annotated 2015¹²

Clarithromycin I.V. in the Treatment of CAP

Clarithromycin,  a macrolide antibiotic, is highly effective, achieves acceptable serum levels and reaches concentrations  in pulmonary tissue that exceed the minimum inhibitory concentrations (MICs) for  atypical  and  typical  pathogens, including  most macrolide-resistant  Streptococcus pneumonia. ¹³

Mode of Action

Other Beneficial Actions of Clarithromycin

• Macrolides exert local immunomodulatory effects and have anti-inflammatory properties. Clarithromycin  has  shown in  vitro suppression of  cytokines and  can  modulate cytokine production in vivo in humans with CAP.^15,16
• Macrolides have been shown to inhibit biofilm formation and decrease mucus hypersecretion, leading to improved mucociliary clearance.¹⁷
• Additionally, clarithromycin has a post-antibiotic effect.¹⁸

Pharmacokinetics (PK)

• Steady state is achieved by 3 days of IV dosing. ²⁰
• In patients with renal impairment,  an increase in clarithromycin  plasma levels and its active metabolite can be observed.²⁰

Pharmacodynamics

Spectrum

Clarithromycin is a macrolide antibiotic whose spectrum of activity includes many Gram-positive organisms such as Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes; Gram-negative aerobic bacteria such as  Haemophilus influenzae, Haemophilus parainfluenzae and  Moraxella catarrhalis; and  Atypical aerobic organisms, including Legionella pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae. It also has activity against many anaerobic bacteria, some mycobacteria and other organisms, including  Ureaplasma, Chlamydia, Toxoplasma and Borrelia. Clarithromycin is usually bacteriostatic, but may be bactericidal depending on the organism and drug concentration.^13,21

Clarithromycin has demonstrated bactericidal activity against both typical and atypical respiratory pathogens. ²²

Aerobic Gram-negative micro-organisms such as Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa are inherently resistant to clarithromycin.²⁰

Clinical Efficacy and Safety Evidence

Clarithromycin – an Ideal Antibiotic for the Treatment of CAP23

Study Design

A total of 290 CAP patients were treated with clarithromycin from January 1992 to December 1997, out of which

• 163 were males (98 smokers) and 127 were females (41 smokers);
• 87 were over 65 years old and 203 had concomitant diseases (mainly cardiovascular); and,
• 172 patients were admitted after unsuccessful therapy (122 cephalosporins and 48 penicillins).

Study Dose

Clarithromycin I.V. 500 mg was first given b.i.d. in 250 or 500 mL of saline solution and then switched after 4–5 days to the same dosage given orally.

Results

Conclusions

Clarithromycin showed good antimicrobial spectrum, PK profile and the possibility of I.V. to oral sequential administration. Hence, it can be used as an ideal antibiotic in the treatment of CAP.

Combination  of  ?-lactam  and  Clarithromycin  in  the  Treatment  of  Moderately  Severe CAP Offers Early Clinical Stability²⁴

Study Design

An open-label, multicentre, non-inferiority, randomized trial (n=580) in immunocompetent adult patients hospitalized for moderately severe CAP. Mean PSI score was 84.

Study Dose

Patients were randomized into two groups:

1. 291 patients in the monotherapy arm received initial treatment with ?-lactam alone (I.V. cefuroxime 1.5 g t.d.s or I.V. amoxycillin and clavulanic acid 1.2 g q.d.s).
2. 289 patients in the combination arm received a ?-lactam and a macrolide (clarithromycin 500 mg BD intravenously or orally).

Urine samples were systematically tested for the presence of Legionella pneumophila (an atypical pathogen) antigen, and a macrolide was added to the monotherapy arm in case of a positive test result.  Median time before administration of  clarithromycin  was  47  hours in  patients with Legionella pneumophila infection in the monotherapy arm. Streptococcus pneumoniae was the most common pathogen.

Results

1] Higher number of patients did not reach clinical stability in the monotherapy arm as compared with the combination arm (41.2% vs 33.6%, P = 0.07) after 7 days of treatment.

 2] At 30 days after discharge, more patients in the monotherapy arm had been re-admitted than those in the combination arm (7.9% vs. 3.1%, P = 0.01).

Conclusion

• Initial empirical treatment with ?-lactam monotherapy delays the clinical stability for patients infected with atypical pathogens. The superiority of combination therapy may be attributed to the timely coverage of Legionella infection.
• Patients with higher severity of pneumonia (PSI category IV or CURB-65 score of ≥2) seemed also to benefit from combination therapy.
• Better control of the host inflammatory response through a non-antibiotic effect of clarithromycin might have protected patients in the combination arm from adverse events that led to readmission.

Advantages of Clarithromycin over Azithromycin

• Clarithromycin is more active when compared with azithromycin in terms of MIC values.²⁵
• Although both drugs are highly active against typical and atypical pathogens, several studies have found the MICs of clarithromycin to be 1 to 2 dilutions lower than the MICs of azithromycin against pathogens commonly encountered in CAP.¹³
• Clarithromycin seems to be more active than azithromycin against atypical pathogens such as Legionella pneumophila and Chlamydia pneumoniae.²⁶
• The levels of clarithromycin achieved in the epithelial lining fluid and alveolar macrophages are higher than those of azithromycin.²⁷
• Azithromycin attains lower serum concentrations than clarithromycin. So, it should not be used in patients suspected of having bacteraemic pneumonia.²⁶
• The lower mutant prevention concentration (MPC) values for clarithromycin (MPC90=0.5 mg/L) vs azithromycin (MPC90=4 mg/L) reduces the likelihood for resistance selection from susceptible populations.²⁵
• Azithromycin was found to be generally somewhat less active than clarithromycin in terms of inhibition of the production of total (intracellular+extracellular) pneumolysin, a pneumococcal toxin, by the macrolide susceptible- and two macrolide-resistant  strains of Streptococcus pneumoniae.²⁸
• In the time-kill experiments against Streptococcus pneumoniae, clarithromycin showed significantly greater killing effects at 1 hour than did azithromycin. Also, azithromycin had a significantly lower mean post-antibiotic effect than clarithromycin in clinical isolates of Streptococcus pneumoniae. ²⁹

Clarithromycin I.V.: Place in Therapy for CAP

Several retrospective studies suggest superiority of beta lactam-macrolide combination therapy in hospitalized CAP patients, particularly those with more severe CAP. As a rule of thumb, the more severely the patient presents, the stronger is the recommendation for such combination treatment.³⁰

Clarithromycin has an established efficacy, safety and tolerability in the treatment of CAP.^13,23  As per the recommendations by the current guidelines, I.V. clarithromycin can be added to a ?-lactam agent (e.g. amoxycillin/clavulanic acid) in the empirical treatment of moderate-to-severe CAP in patients who require hospital admission in non-ICU as well as ICU settings.^9,10,11

Role of Macrolides in Acute Exacerbations of Chronic Bronchitis/Acute Exacerbation of Chronic Obstructive Pulmonary Disease

• Approximately 5–10% of  the adult world population is  suffering from chronic obstructive pulmonary disease (COPD).³¹
• The progressive course of COPD is accelerated by acute exacerbations (AECOPD), which are episodes of worsening symptoms, and are the most frequent causes of hospitalizations and death among COPD patients.³²
• Bacterial infection is likely aetiologic in approximately 50% of AECOPD patients.³³
• The pre-eminent pathogens associated with acute exacerbation of chronic bronchitis (AECB) are  Haemophilus influenzae, Streptococcus  pneumoniae and  Moraxella catarrhalis, which together account for 85–95% of bacterial exacerbations.³⁴
• As per the guidelines, AECB (or AECOPD) should be treated with oral or, occasionally, I.V. antibiotics if repeated episodes of cough and dyspnoea occur and if there is evidence for increased sputum production, and if this sputum is purulent.^3,35
• Macrolide antibiotics provide adequate coverage for the most frequently identified pathogens in AECB/AECOPD.³³
• Macrolide antibiotics have assumed an  important role in the management of  AECOPDs because of their broad-spectrum coverage and excellent safety profile.³³

^?

Clarithromycin in the Treatment of AECB/AECOPD

The effects of clarithromycin on the inhibition of inflammatory cytokine production by COPD sputum cells is more potent than that of azithromycin.³¹

Clarithromycin I.V.: Place in Therapy for AECB/AECOPD

I.V. clarithromycin might be used in hospitalized patients with severe COPD exacerbations who have clinical signs of a bacterial infection, according to the guidelines for COPD.^30,35

Take-Home Message

• CAP and AECB or AECOPD are the leading causes of mortality and morbidity that require immediate treatment with empirical therapy. 
• Macrolides are considered as a part of primary treatment in moderate-to-severe CAP and also as an additional treatment option for severe AECB/AECOPD due to their safety and efficacy.
• Clarithromycin  I.V. can be  recommended for wide application due to  the following properties:
  • Safety and efficacy
  • Wide antimicrobial spectrum and superior PK profile
  • Immunomodulatory and anti-inflammatory properties
  • High serum concentration and better penetration into pulmonary tissues
  • Post-antibiotic effect

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