Clinical impact of antibiotic resistance in respiratory tract infections

doi:10.1016/S0924-8579(07)70004-3

International Journal of Antimicrobial Agents

Volume 29, Supplement 1, February 2007, Pages S6-S10

https://doi.org/10.1016/S0924-8579(07)70004-3 Get rights and content

Abstract

Streptococcus pneumoniae is the most common causative pathogen of community-acquired respiratory tract infections. In vitro evidence indicates that S. pneumoniae is increasingly resistant to commonly prescribed antimicrobial agents including the macrolides. The clinical relevance of resistance, however, has not been clearly established. This article reviews the risk factors influencing selection of resistant pneumococci, discusses endpoints used to assess the impact of resistance on clinical outcome, and proposes strategies to minimise the impact of resistance. Evidence demonstrating treatment failures due to macrolide-resistant S. pneumoniae is also reviewed. Increasing rates of resistance among S. pneumoniae present numerous clinical challenges, and require carefully selected treatment strategies to preserve antibacterial efficacy. Antibiotics with a low propensity for stimulating resistance should be chosen wherever possible.

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Cited by (29)

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Citation Excerpt :
If we consider the time before the clearance of free bacteria, NT, as a measure of the efficacy of treatment, this model suggests that if the rate of phagocytosis is great enough, the course of therapy would be relatively insensitive to the PD-based antibiotic categories, and bacteriostatic antibiotics can be as effective as bactericidal ones (Figure 3C). There is no question that, if the dominant population of the target bacteria is genetically resistant to the treating antibiotic, primary treatment will be ineffective – be the infection acute or chronic [59–63]. There is also no doubt that, for chronic infections – like tuberculosis, or those caused by Pseudomonas in cystic fibrosis patients – resistance evolving during the course of therapy, acquired resistance, can thwart effective therapy [64].
Most antibiotic use in humans is to reduce the magnitude and term of morbidity of acute, community-acquired infections in immune competent patients, rather than to save lives. Thanks to phagocytic leucocytes and other host defenses, the vast majority of these infections are self-limiting. Nevertheless, there has been a negligible amount of consideration of the contribution of phagocytosis and other host defenses in the research for, and the design of, antibiotic treatment regimens, which hyper-emphasizes antibiotics as if they were the sole mechanism responsible for the clearance of infections. Here, we critically review this approach and its limitations. With the aid of a heuristic mathematical model, we postulate that if the rate of phagocytosis is great enough, for acute, normally self-limiting infections, then (i) antibiotics with different pharmacodynamic properties would be similarly effective, (ii) low doses of antibiotics can be as effective as high doses, and (iii) neither phenotypic nor inherited antibiotic resistance generated during therapy are likely to lead to treatment failure.
Contradiction between in vitro and clinical outcome: Intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia
2014, Journal of Infection and Chemotherapy
Citation Excerpt :
However, the clinical relevance of macrolide resistance has not been clearly established. A number of studies have reported the treatment failures with macrolides, breakthrough bacteremia, or both in patients infected with macrolide-resistant pneumococci [9–11]. In contrast, other studies have shown an apparent effectiveness of these agents in the treatment of CAP caused by macrolide-resistant S. pneumoniae, which suggests discordance between in vitro susceptibility and clinical efficacy of in vivo macrolide therapy [12,13].
We conducted a multicenter, unblinded, non-comparative, phase 3 trial of azithromycin-intravenous therapy followed by oral administration in Japanese adults to evaluate clinical efficacy and safety against community-acquired pneumonia in order to obtain regulatory approval for the intravenous formulation in Japan. Azithromycin (500 mg, once daily) was intravenously administered for 2–5 days followed by oral 500 mg once daily administration to complete a total of 7–10 days treatment in 102 adults with moderate-to-severe community-acquired pneumonia. The efficacy rate in the Clinical Per Protocol Set overall was 84.5% (60/71 subjects) on Day 15 (primary analysis). The most common causative pathogen was Haemophilus influenzae (17 strains), followed by Streptococcus pneumoniae (14 strains), Moraxella catarrhalis (5 strains) and Mycoplasma pneumoniae (5 strains). Eleven of 14 S. pneumoniae isolates were resistant to azithromycin (MIC ≥2.0 μg/ml), of which 5 strains with a relatively low MIC of <32 μg/ml had only mef A gene and 6 strains with a high MIC of >64 μg/ml had only the erm B gene except for 2 isolates having both the mef A and erm B genes. Despite dominance of macrolide-resistant strains in Japan, clinical efficacy and bacterial eradication were achieved in 10 of 11 patients (90.9%). Intravenous-to-oral azithromycin therapy demonstrated excellent clinical and bacteriological effects on moderate-to-severe pneumococcal pneumonia despite a high MIC and resistance gene development. This discrepancy is referred to as the “in vivo-in vitro paradox”. The current study results provide an insight into this paradox.
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Antibiotic non-susceptibility among Streptococcus pneumoniae and Haemophilus influenzae isolates identified in African cohorts: A meta-analysis of three decades of published studies
2013, International Journal of Antimicrobial Agents
Citation Excerpt :
Following the initial detection of penicillin-non-susceptible S. pneumoniae in a few geographic regions, including South Africa, in the 1970s, non-susceptibility spread rapidly worldwide [4,5]. Despite concerns about reported in vitro non-susceptibility of pneumococci to penicillin, there are no reports of microbiologically confirmed clinical failure following intravenous penicillin therapy [6]. However, a multilevel, cross-sectional study among 4888 children with CAP presenting to 33 children's hospitals in the USA found that every 10% increase in penicillin-non-susceptible pneumococcal isolates was associated with a 39% increase in broad-spectrum antibiotic prescribing [7].
Management of community-acquired pneumonia caused by Streptococcus pneumoniae and Haemophilus influenzae type B (Hib) can be complicated by emerging antimicrobial non-susceptibility. We conducted a meta-analysis to examine the antibiotic susceptibility of community-acquired invasive infections with S. pneumoniae and Hib in Africa from 1978 to 2011. With the notable exceptions of widespread trimethoprim/sulfamethoxazole (SXT) and tetracycline non-susceptibility, the majority of pneumococci remain susceptible to ampicillin/amoxicillin. However, 23.8% of pneumococcal meningitis isolates are non-susceptible to penicillin. Similarly, Hib isolates show non-susceptibility to SXT, tetracycline, erythromycin and chloramphenicol. β-Lactamase production among Hib isolates is increasing, a new observation for Africa, but is mitigated somewhat by Hib vaccination scale-up. In summary, pneumococcal susceptibility to amoxicillin remains high throughout Africa, and amoxicillin can be effectively and safely used as first-line treatment for childhood pneumonia. Data support first-line treatment of bacterial meningitis with ceftriaxone or cefotaxime.
Pneumococcal disease manifestation in children before and after vaccination: What's new?
2011, Vaccine
Pneumococcal infections remain a relevant cause of morbidity and mortality in children, especially in countries where vaccination has not been introduced. In contrast to the common belief by many pediatricians, the most important pneumococcal infections are of the respiratory tract and not invasive diseases. The recent pandemic of the H1N1 virus prompted studies to better understand the interaction between the influenza virus, Streptococcus pneumoniae, and pneumonia outcomes. Radiological findings of bacteremic pneumonia have been well investigated and besides the typical alveolar consolidation, a broad spectrum of atypical patterns has been reported. Molecular techniques, such as real-time polymerase chain reaction (PCR), can improve the detection of S. pneumoniae in sterile fluids, mainly in regions where previous antibiotic therapy is a common practice. In the post vaccination era, new manifestations of pneumococcal invasive disease, such as hemolytic uremic syndrome, have increased in association with parapneumonic empyema. Moreover, serotypes not included in PCV7, particularly serotypes 1, 3, 5, 7F, and 19A, have been among the most common isolates in pneumococcal disease. In Latin America, pneumococcal primary peritonitis has been described as an important clinical syndrome in a growing proportion of patients, mainly in girls. The development of newer and more specific diagnostic markers to distinguish bacterial and viral pneumonia are urgently sought, and will be especially pertinent after the introduction of pneumococcal conjugate vaccines with expanded serotypes. Such markers would minimize inappropriate diagnosis of false positive cases and treatment with antibacterial agents, while increasing positive predictive values for diagnosis of bacterial pneumonia. The extension of serotype coverage with the new conjugate vaccines is promising for pneumococcal infections and coverage against antibiotic-resistant strains.
Declining antimicrobial susceptibility of Streptococcus pneumoniae in the United States: Report from the SENTRY Antimicrobial Surveillance Program (1998-2009)
2010, Diagnostic Microbiology and Infectious Disease
How to compare the efficacy of conjugate vaccines to prevent acute otitis media?
2009, Vaccine
Citation Excerpt :
In Canada, approximately 40% of health care costs associated with Sp infections are attributable to AOM and its complications [2]. Resistance to antimicrobial agents is a growing problem worldwide [3,4]. Although pneumococcal conjugate vaccines have been primarily designed for the prevention of invasive pneumococcal disease, they have the potential to prevent other pneumococcal infections, including AOM.
Although the currently available 7-valent pneumococcal conjugate vaccine (PCV7-CRM₁₉₇) has been primarily designed for the prevention of invasive pneumococcal disease, it has also demonstrated the potential to prevent acute otitis media (AOM) and its associated complications. A candidate 11-valent pneumococcal conjugate vaccine (PCV11-HiD), which utilizes Haemophilus influenzae (Hi)-derived protein D as a carrier has demonstrated the ability to prevent AOM caused by not only vaccine serotypes of Streptococcus pneumoniae (Sp), but also those caused by Hi. The methodological, clinical, and epidemiological factors influencing results of vaccine trials for AOM prevention were reviewed and a model-based approach was developed, in order to assess the relative efficacy of different vaccine formulations. Six randomized trials having AOM as a measured outcome were identified. Vaccine efficacy (VE) ranged from −1% to 34% for all-cause AOM and between 56% and 64% for AOM caused by vaccine-type Sp. Using otopathogen-specific VE rates from the FinOM and POET trials and otopathogen distributions observed in three relatively unbiased studies, VE against all-cause AOM episodes under different scenarios was modeled. The most important factor explaining variation in VE estimates was bacterial replacement, which was present in the PCV7-CRM₁₉₇ FinOM study but not in the PCV11-HiD POET study. Another contributing factor was increased protection conferred against Hi AOM by protein D. Geographical variation in the distribution of otopathogens was a third factor explaining differences between trials. More studies on the current aetiology of AOM need to be performed to accurately predict the marginal benefit of a switch from PCV7-CRM₁₉₇ to the newly licensed PCV10-HiD-DiT or to the future PCV13-CRM₁₉₇.

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Clinical impact of antibiotic resistance in respiratory tract infections

Abstract

Chest

Int J Antimicrob Agents

Streptococcus pneumoniae: epidemiology and patterns of resistance

Am J Med

The need for antimicrobial resistance surveillance

J Antimicrob Chemother

Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997

Am J Public Health

Trends in antibacterial resistance of Streptococcus pneumoniae: PROTEKT global years 1-5

Clin Microbiol Infect

Activity of telithromycin against Streptococcus pneumoniae isolates resistant to other antibacterials: PROTEKT year 5

Clin Microbiol Infect

Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries

JAMA

Management of meningitis caused by penicillin-resistant Streptococcus pneumoniae

Antimicrob Agents Chemother

The emergence of resistant pneumococcal meningitis - implications for empiric therapy

Arch Dis Child

Antimicrobial-resistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalizations

J Infect Dis

Clinical and economic analysis of methicillin-susceptible and -resistant Staphylococcus aureus infections

Ann Pharmacother

Evolving resistance patterns of Streptococcus pneumoniae: a link with long-acting macrolide consumption?

J Chemother

Effect of short-course, high-dose amoxicillin therapy on resistant pneumococcal carriage: a randomized trial

JAMA

Antibiotic consumption and resistance selection in Streptococcus pneumoniae

J Antimicrob Chemother

Predicting antimicrobial resistance in invasive pneumococcal infections

Clin Infect Dis