Treatment Of Community-acquired Respiratory Infections Research Articles

Oral third-generation cephalosporin cefpodoxime in the therapy of respiratory infections

Oral 3rd generation cephalosporin cefpodoxime proxetil has been available in the antibiotic armamentarium for more than 30 years, however, unlike other oral cephalosporins (e.g. cefixime), it has not been given due recognition in clinical practice in Russia due to its low availability on the domestic pharmaceutical market. At the same time, the high activity of cefpodoxime against respiratory pathogens (S. pneumoniae, H. influenzae and S. pyogenes), pharmacological characteristics, results of clinical trials of its safety and efficacy, allow us to discuss the inclusion of this antimicrobial into Russian clinical guidelines for the treatment of community-acquired respiratory infections, primarily in outpatients, as well as for stepdown therapy of these infections in the hospital. In addition, cefpodoxime is a reliable option to replace parenteral therapy, in particular with ceftriaxone, which is unreasonably often prescribed in outpatient practice in Russia, without the threat of loss of the treatment efficacy.

Effective antibiotic therapy for community-acquired otorhinolaryngological respiratory infection (clinical description)

The State Report on the state of sanitary and epidemiological well-being of the population in the Russian Federation speaks of the continued growth of respiratory infections, reaching more than 33 million cases and amounting to more than 606 billion rubles of direct economic damage in 2021. Of particular importance is the new coronavirus infection SARS-CoV-2, and manifestations of its various new genovariants, for example, variant B.1.1.529 called omicron, causes various inflammatory nosologies on the part of the mucous membranes of the ENT organs (acute rhinosinusitis, acute tonsillopharyngitis, acute otitis media). The viral agent, damaging the epithelium of the upper respiratory tract, creates favorable conditions for the activation of the microbial flora. Identification of a respiratory agent is most often carried out only in severe cases of the disease, so the basic diagnosis is based on clinical symptoms. The relevance of studying the rational use of antibacterial drugs in the treatment of community-acquired respiratory infections in practical otorhinolaryngology is associated not only with the frequency of occurrence, but with a high risk of complications. As a rule, antibacterial drugs are actively used in the complex therapy of acute bacterial etiology of the upper respiratory tract. Due to the high variability and increasing antibiotic resistance, antimicrobial agents are not always rationally used for outpatients. In this context, as noted in the clinical guidelines, one of the topical issues is the rational dosed use of antibacterial drugs in accordance with the pharmacokinetics, pharmacodynamics and efficacy of prescribing a cephalosporin antibiotic in the form of dispersible tablets in the treatment of patients with acute inflammatory diseases of the upper respiratory tract and ear, as an example, clinical cases.

Utility of the respiratory viral panel as an antimicrobial stewardship tool.

The development of rapid diagnostics has revolutionized antimicrobial stewardship with efforts targeting earlier de-escalation or discontinuation of antibiotics. The respiratory viral panel (RVP) is one tool quickly able to detect common viral and bacterial pathogens using polymerase chain reaction technology. Utility may be further enhanced in conjunction with procalcitonin (PCT). However, the optimal use of the RVP to the clinical pharmacist in the treatment of community-acquired respiratory infections remains unclear. The purpose of this guide is to review the available literature regarding the impact of the RVP with and without procalcitonin on antimicrobial stewardship efforts and to provide guidance on how to use each of these tools. In total, 13 studies were included, 5 of which utilized PCT in conjunction with RVP and 8 of which did not use PCT. The majority of studies were retrospective in nature, and the most common outcomes evaluated were antibiotic days of therapy (DOT) and time to antibiotic discontinuation. After review, RVP alone has limited value to antimicrobial stewardship; however, when used in conjunction with procalcitonin, RVP has the potential to reduce antibiotic use and duration.

Results from the Survey of Antibiotic Resistance (SOAR) 2015-17 in Pakistan: data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.

To determine antibiotic susceptibility of community-acquired respiratory tract infection (CA-RTI) isolates of Streptococcus pneumoniae and Haemophilus influenzae collected in 2015-17 from Pakistan. MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. A total of 94 S. pneumoniae and 122 H. influenzae isolates were collected. Susceptibility to penicillin was noted in 23.4% of the S. pneumoniae isolates by CLSI oral/EUCAST low-dose IV breakpoints, although by CLSI IV and EUCAST high-dose breakpoints all isolates were characterized as susceptible. Susceptibility to trimethoprim/sulfamethoxazole (10.6%), macrolides (33%) and cefaclor (28.7%) was low but higher susceptibility was observed to ceftriaxone (100%), amoxicillin and amoxicillin/clavulanic acid (98.9%), cefuroxime (oral, 97.9%), cefpodoxime (96.8%), fluoroquinolones (93.6%-96.8%) and cefdinir (76.6%) by CLSI breakpoints. However, using EUCAST breakpoints, susceptibility to cefpodoxime (70.2%) and cefuroxime (oral, 61.7%) was reduced. H. influenzae isolates were almost all β-lactamase negative (96.7%). Using CLSI breakpoints, ≥93.4% of isolates were susceptible to all antibiotics tested except fluoroquinolones (75.4%-77.1%) and trimethoprim/sulfamethoxazole (41%). The proportion of isolates susceptible using EUCAST breakpoints was similar or identical for penicillins, trimethoprim/sulfamethoxazole and the cephalosporins that have EUCAST breakpoints; the proportion of isolates susceptible using EUCAST breakpoints was similar or identical to that using CSLI breakpoints except for cefuroxime (oral), where only 1.6% of isolates were considered susceptible. Susceptibility of H. influenzae to fluoroquinolones was also lower by EUCAST breakpoints (33.6%-34.4%). The application of different EUCAST breakpoints for low and higher doses for some of the antibiotics (amoxicillin, amoxicillin/clavulanic acid, ampicillin, penicillin, ceftriaxone, clarithromycin, erythromycin, levofloxacin and trimethoprim/sulfamethoxazole) allowed, for the first time in a SOAR study, the effect of raising the dosage on susceptibility to be quantified. Antibiotic susceptibility in these important respiratory tract pathogens varied in Pakistan based on different breakpoints. These data are important for empirical therapy choices in the treatment of CA-RTIs.

Results from the Survey of Antibiotic Resistance (SOAR) 2016-17 in Ukraine: data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.

To determine antibiotic susceptibility of Streptococcus pneumoniae and Haemophilus influenzae isolates from community-acquired respiratory tract infections (CA-RTIs) collected in 2016-17 from Ukraine. MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. A total of 177 viable clinical isolates, including 78 S. pneumoniae and 99 H. influenzae, were collected. Overall, ∼98% of S. pneumoniae isolates were susceptible to penicillin by CLSI IV or EUCAST high-dose breakpoints and 73.1% were susceptible by CLSI oral or EUCAST low-dose IV breakpoints. Susceptibility rates of 76.9%-100% were observed for most antibiotics by all breakpoints except trimethoprim/sulfamethoxazole (41%-69.2%) and cefaclor, which showed the greatest difference between breakpoints: 0% by EUCAST, 28.2% by PK/PD and 73.1% by CLSI. All S. pneumoniae isolates were susceptible to amoxicillin/clavulanic acid by CLSI and PK/PD breakpoints. H. influenzae isolates were almost all β-lactamase negative (90.9%). One isolate was β-lactamase negative and ampicillin resistant (BLNAR) by CLSI and four isolates were BLNAR by EUCAST criteria. Susceptibility of isolates was high (≥90.9%) by CLSI breakpoints for all antibiotics tested except trimethoprim/sulfamethoxazole (61.6%). Susceptibility using EUCAST breakpoints was similar for ampicillin (90.9%) and amoxicillin/clavulanic acid (95%) but was low for cefuroxime (oral), where only 10.1% of isolates were susceptible. All S. pneumoniae and H. influenzae isolates were susceptible to the fluoroquinolones by all breakpoints. Susceptibility to ceftriaxone was also 100% for H. influenzae and ≥91% for S. pneumoniae isolates by all breakpoints. The application of different EUCAST breakpoints for low and higher doses for some of the antibiotics (amoxicillin, amoxicillin/clavulanic acid, ampicillin, penicillin, ceftriaxone, clarithromycin, erythromycin, levofloxacin and trimethoprim/sulfamethoxazole) allowed, for the first time in a SOAR study, the effect of raising the dosage on susceptibility to be quantified. Antibiotic susceptibility in these respiratory tract pathogens was generally high in Ukraine. These data are important for empirical therapy choices in the treatment of CA-RTIs.

Investigation of Intravenous Azithromycin Treatment Safety When Reducing Solvent for Intensive Care Unit Patients

Intravenous azithromycin (AZM) was approved for use in December 2011 in Japan. In general, intravenous AZM injections are diluted to 1 mg/mL, with a total infusion volume of 500 mL to avoid phlebitis. Patients in intensive care units (ICUs) require small infusion volumes. We retrospectively evaluated the total AZM infusion volume in 65 ICU patients receiving AZM treatment from December 2011 to August 2014. Thirteen patients (20.0%) received a reduced volume [100 mL (5 mg/mL) or 250 mL (2 mg/mL)] using an infusion pump over 2 h. No peripheral phlebitis was observed in any patient. Based on this result, it is assumed that AZM can be safely administered to ICU patients even though the volume of solvent is reduced. AZM is widely recommended for the treatment of community-acquired respiratory infections and is used in patients with severe infections. Further investigation is required in additional patients to understand the effects of AZM volume reduction in greater detail.

Antibiotic Susceptibility of Respiratory Pathogens Recently Isolated in Italy: Focus on Cefditoren

The aim of this study was to evaluate the in vitro antibiotic susceptibility of respiratory pathogens recently isolated in italy to commonly used antibiotics including cefditoren. Six clinical microbiological laboratories collected, between January and September 2009, a total of 2,510 respiratory pathogens from subjects with community- acquired respiratory tract infections (CARTI). Cefditoren, out of all the beta-lactams studied, had the lowest MIC90 against 965 strains of Streptococcus pneumoniae examined, followed by cefotaxime and ceftriaxone (2% resistance in penicillin-resistant S. pneumoniae (PRSP)). Against 470 Haemophilus influenzae, independently of their production of beta-lactamases or ampicillin resistance, cefditoren was the oral cephalosporin with the best in vitro activity, comparable to that of the injectable cephalosporins and levofloxacin. Higher MIC90s were found for the macrolides (4 - 16 mg/L) and cefaclor (4 - 32 mg/L). As was foreseeable, Streptococcus pyogenes (225 strains) was uniformly sensitive to all the beta-lactam antibiotics, but the elevated miC90 values reduced (<75%) susceptibility of this pathogen to macrolides. Beta-lactamase-negative Moraxella catarrhalis (100 strains) had reduced susceptibility only to the macrolides, while the 250 beta-lactamase-producing strains also had reduced susceptibility to cefuroxime. Levofloxacin showed the lowest MIC50/MIC90 values in the producing strains, whereas cefditoren, cefotaxime and ceftriaxone in the non-producers. As regards the enterobacteriaceae, cefditoren and levofloxacin had the lowest MIC90s against Klebsiella pneumoniae. Cefditoren and the third-generation injectable cephalosporins had the lowest MIC90s against Escherichia coli (100% susceptibility) while levofloxacin was less active (86% susceptibility).In conclusion, cefditoren's wide spectrum and high intrinsic activity, as well as its capacity to overcome most of the resistance that has become consolidated in some classes of antibiotics widely used as empiric therapy for CARTI, allows us to suggest that cefditoren might be included in the european guidelines as one of the first-choice antibiotics in the treatment of CARTI.

Newer fluoroquinolones for treating respiratory infection: do they mask tuberculosis?

Possible masking of tuberculosis (TB) in treatment of community-acquired respiratory infection by newer fluoroquinolones has not been examined in randomised controlled trials. We undertook a randomised, open-label controlled trial involving adults with community-acquired pneumonia or infective exacerbation of bronchiectasis encountered in government chest clinics in Hong Kong. 427 participants were assigned by random permutated blocks of 20 to receive either amoxicillin clavulanate (n = 212) or moxifloxacin (n = 215). Participants were followed for 1 yr for active pulmonary TB. Excluding three participants with positive baseline culture, 13 developed active pulmonary TB: 10 (4.8%) out of 210 were given amoxicillin clavulanate, and three (1.4%) out of 214 were given moxifloxacin. The difference was significant by both proportion and time-to-event analysis. Post hoc analysis showed a significant decrease in the proportion with active pulmonary TB from 4.8% to 2.4% and 0% among participants given amoxicillin clavulanate (n = 210), moxifloxacin for predominantly 5 days (n = 127) and 10 days (n = 87), respectively. The log rank test for trend also showed a significant difference between the three subgroups. Regression models reaffirmed the linear effect; the adjusted odds ratio (95% confidence interval) of active pulmonary TB after moxifloxacin exposure up to predominantly 10 days was 0.3 (0.1-0.9). Newer fluoroquinolones appear to mask active pulmonary TB.

Clinical Trial Design and Consequences for Drug Development for Community‐Acquired Pneumonia: An Industry Perspective

Antibiotic development has decreased significantly, in part because of recent changes in regulatory requirements in the United States. These changes both decrease the probability of technical and regulatory success for a new antibiotic for which marketing approval is sought and motivate the pharmaceutical industry to focus its research efforts on other therapeutic areas. There is a growing, unmet clinical need for new antibiotics, because of bacterial resistance to approved drugs; however, there are few candidates in development, especially new oral agents for treatment of community-acquired respiratory infections. The answers to important questions about the benefit of antibacterial treatment for community-acquired pneumonia and the publication of clear guidance for future clinical studies will support future investments. We discuss the underlying issues and offer some alternative strategies to enable improvements in clinical trial design for community-acquired pneumonia.

Use of cethromycin, a new ketolide, for treatment of community-acquired respiratory infections

Background: The ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. Ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. Ketolides bind to a secondary region on domain II of the 23S rRNA subunit. Telithromycin was the first ketolide to be approved by the FDA in 2004 for treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) and sinusitis. However, in 2006, after reports of serious hepatotoxicity, the FDA issued a public health advisory followed by a warning. In 2007 the indications for treatment of AECB and sinusitis were removed from the labeling. Cethromycin (ABT-773) is the only other ketolide currently under clinical development. Objective: To review currently available data on cethromycin, including chemistry, in vitro activity, pharmacokinetics, pharmacodynamics, in vivo activity and results of treatment studies in humans. Methods: A search was made in PubMed, pharmaceutical databases and meeting abstracts using the terms ketolides, ABT-773 and cethromycin. Results/conclusions: Cethromycin has comparable tissue penetration, pharmacokinetics and in vitro activity compared with telithromycin to Streptococcus pneumoniae, including multidrug-resistant isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. There is only one published CAP treatment study that compared cethromycin 150 mg q.d. with 150 mg b.i.d. One Phase II and a Phase II/III study have been presented in abstract form, both were non-comparative, dose-ranging studies, which suggested that 150 mg q.d. or 300 mg q.d. were comparable in terms of clinical response and bacterial eradication, although data on the latter are limited. Data on side effects are limited and appear to be mainly gastrointestinal. There have been no reports of serious hepatotoxicity at the time of this writing. Cethromycin may have other uses in addition to treatment of CAP respiratory infections, including treatment of infections due to Neisseria gonorrhoeae and Chlamydia trachomatis and bioterrorism agents including Bacillus anthracis, Yersinia pestis and Francisella tularensis.

Optimizing the management of community-acquired respiratory tract infections in the age of antimicrobial resistance

Community-acquired respiratory tract infections (CARTIs) are the most common reason for prescribing antibiotics in the primary care setting. However, over the last decade, the management of CARTIs has become increasingly complicated by the steady increase in prevalence of drug-resistant pathogens responsible for these infections. As a result, significant attention has been directed at understanding the mechanisms of pathogen acquisition of resistance, drivers of resistance and methods for preventing the development of resistance. Data from recent surveillance studies suggest a slowing or decline in resistance rates to agents, such as β-lactams, macrolides, tetracyclines and folic acid metabolism inhibitors. However, resistance to one antimicrobial family – the fluoroquinolones – while still low, appears to be on the increase. This is of significant concern given the rapid increase in resistance noted with older antibiotics in recent history. While the clinical implications of antibacterial resistance are poorly understood, the overall rates of antimicrobial resistance, as reported in recent surveillance studies, do not correspond to current rates of failure in patients with CARTIs. This disconnection between laboratory-determined resistance and clinical outcome has been termed the in vitro–in vivo paradox and several explanations have been offered to explain this phenomenon. Solving the problem of antimicrobial resistance will be multifactorial. Important factors in this effort include the education of healthcare providers, patients and the general healthcare community regarding the hazards of inappropriate antibiotic use, prevention of infections through vaccination, development of accurate, inexpensive and timely point-of-care diagnostic tests to aid in patient assessment, institution of objective treatment guidelines and use of more potent agents, especially those with a focused spectrum of activity, earlier in the treatment of CARTIs as opposed to reserving them as second-line treatment options. Ultimately, the single-most important factor will be the judicious use of antibiotics, as fewer antibiotic prescriptions lead to fewer antimicrobial-resistant bacteria.

A Review of New Fluoroquinolones

The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.

Telithromycin-induced acute interstitial nephritis: A first case report

Telithromycin, a ketolide antibiotic used for the treatment of community-acquired respiratory infections, is widely prescribed in primary care practice. Treatment-related adverse events are mainly of gastrointestinal origin and generally mild in intensity. The authors report the first case of telithromycin-induced severe acute interstitial nephritis. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure.

Comparative in vitro activity of telithromycin and beta-lactam antimicrobials against community-acquired bacterial respiratory tract pathogens in the United States: Findings from the PROTEKT US study, 2000–2001

Background: Telithromycin is a new ketolide antimicrobial that was developed to provide good activity against resistant respiratory tract pathogens. PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) is a multicenter in vitro surveillance study that was initiated in 2000 to chart the emergence and spread of antimicrobial-resistant pathogens in patients with community-acquired respiratory tract infections (CARTIs). Objective: This article reports first-year results from PROTEKT US pertaining to the comparative in vitro activity of telithromycin and beta-lactam antimicrobials against community-acquired bacterial respiratory tract pathogens. Methods: Data were compiled on the comparative in vitro activity of telithromycin and beta-lactams against Streptococcus pneumoniae (10,103 isolates), Streptococcus pyogenes (3918 isolates), and Haemophilus influenzae (2706 isolates). Minimum inhibitory concentrations (MICs) and susceptibilities were determined according to National Committee for Clinical Laboratory Standards methods. Results: In total, 38.8% (3920/10,103) of pneumococcal isolates were not susceptible to penicillin (12.5% [1266] intermediate [MIC, ⪰0.12–1.0 mg/dL], 26.3% [2654] resistant [MIC, ⩾2 mg/dL]). Telithromycin was highly active against S pneumoniae (MIC required to inhibit 90% of isolates [MIC 90], 0.5 mg/L), with 99.6% (10,062/10,103) of isolates fully susceptible (MIC, ⩽1 mg/L). Based on MIC 90s, the rank order of antimicrobial activity was telithromycin (0.5 mg/L), followed by amoxicillin/clavulanate (2 mg/L), penicillin (4 mg/L), and cefuroxime (8 mg/L). Telithromycin retained high activity (MIC 90, 1 mg/L) against penicillin-resistant penumococci that showed high levels of coresistance to beta-lactams. All isolates of S pyogenes were fully susceptible to the beta-lactams tested. Beta-lactamase production was common among H influenzae isolates (28.3% [ 765 2706 ]). Telithromycin was active against H influenzae (MIC 90, 4 mg/L), irrespective of beta-lactamase production. Conclusion: Overall, these findings from the first year of PROTEKT US support the potential value of telithromycin in the treatment of CARTIs.

Comparative Activity of Telithromycin Against Macrolide-Resistant Isolates of Streptococcus pneumoniae: Results of Two Years of the PROTEKT Surveillance Study

The increase in resistance to macrolides has been linked with increasing use of these agents as empirical therapy for community-acquired respiratory tract infections (CARTIs). As part of the ongoing PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance program, over 7600 Streptococcus pneumoniae isolates were collected worldwide from 1999-2001 and evaluated for macrolide resistance. Globally, macrolide resistance was 31-33%, with considerable inter-country variation (<10-88%) and particularly high prevalence in the Far East (>71%). In Europe, France had the most resistant isolates (>53%). The highest rates of macrolide resistance were seen in 0-2 year olds. Co-resistance to clindamycin (64%) and all b-lactams (14-79%) was seen among macrolide-resistant isolates, but >99% of these isolates were susceptible to telithromycin, vancomycin and linezolid. There was considerable variation in the prevalence of erm(B) (56-64%) and mef(A) (30-35%): erm(B) was prevalent in Europe and mef(A) in North America. Globally, 5-7% isolates carried both mechanisms (erm(B)+mef(A)); of these, 47-65% were from South Korea. These double resistance isolates were >90% resistant to the b-lactams, except amoxicillin-clavulanate. Clindamycin was active against >98% mef(A) but poorly active against erm(B) and erm(B)+mef(A) isolates. Telithromycin, vancomycin and linezolid were highly active (>99.5%) across all three genotypes. Conclusions: In vitro, telithromycin, vancomycin and linezolid are highly active against antibiotic-resistant strains of S. pneumoniae. Telithromycin may be a useful therapeutic alternative to macrolides for the treatment of CARTIs.

Contemporary evaluation of the in vitro activity and spectrum of cefdinir compared with other orally administered antimicrobials tested against common respiratory tract pathogens (2000-2002)

Cefdinir is an oral cephalosporin approved by the Food and Drug Administration in 1997 for the treatment of acute exacerbation of chronic bronchitis, pharyngitis-tonsillitis, community-acquired pneumonia, acute maxillary sinusitis, and uncomplicated skin and skin structure infections in adults and adolescents, and acute otitis media, pharyngitis-tonsillitis, and uncomplicated skin and skin structure infections in children. Although cefdinir showed similar activity to other cephalosporins in the early studies, very limited data has been generated over the last decade. In this report, we summarize the contemporary in vitro activity and spectrum of cefdinir in comparison to numerous other orally administrated antimicrobials available for treatment of community-acquired respiratory infections. A total of 8,326 non-duplicate recent clinical isolates, including Haemophilus influenzae (3,438), Moraxella catarrhalis (1,688), and Streptococcus pneumoniae (3,200), were collected from 35 medical centers in North America during 2000 through 2002, and susceptibility tested by reference broth microdilution methods. Pneumococcal susceptibility patterns for β-lactams and macrolides were also analyzed according to the year of isolation and the age group of the patients. Cefdinir had the greatest activity against H. influenzae among the cephalosporins tested with susceptibility rates of 97.1 to 99.0%. All of the agents tested had complete or near complete activity against M. catarrhalis. Against S. pneumoniae, cefdinir and other cephalosporins showed similar susceptibility patterns, but improved rates were observed in 2002 (78.5-79.4%) when compared to the previous monitored period (71.8-74.5%). This increase in susceptibility was mainly because of a declining the occurrence of high-level penicillin resistance (MIC ≥2 μg/ml) across all age groups. Macrolide resistance also decreased among S. pneumoniae in 2002 when compared to 2000 through 2001; however, resistance to levofloxacin continued to increase from 0.9% in 2000 to 1.4% in 2002. These results indicate a significant change in emerging β-lactam resistance patterns (including cefdinir) with a decrease possibly influenced by greater pneumococcal vaccine use in children and the elderly. These rates of increased susceptibility could sustain and enhance the clinical activity of orally administered β-lactams such as cefdinir.

Fluoroquinolone-associated tendinopathy: a critical review of the literature.

With the expanded use of fluoroquinolones for the treatment of community-acquired respiratory infections and reports of tendon injury linked to the use of these agents, we reviewed the literature to investigate the frequency and strength of this association. Ninety-eight case reports were available for review. The incidence of tendon injury associated with fluoroquinolone use is low in a healthy population but increases in patients who have renal dysfunction, who are undergoing hemodialysis, or who have received renal transplants. Pefloxacin and ciprofloxacin were most frequently implicated, but tendon injury was reported with most fluoroquinolones. The median duration of fluoroquinolone treatment before the onset of tendon injury was 8 days, although symptoms occurred as early as 2 hours after the first dose and as late as 6 months after treatment was stopped. Up to one-half of patients experienced tendon rupture, and almost one-third received long-term corticosteroid therapy. Tendon injury associated with fluoroquinolone use is significant, and risk factors such as renal disease or concurrent corticosteroid use must be considered when these agents are prescribed.

A critical review of the fluoroquinolones: focus on respiratory infections.

The new fluoroquinolones (clinafloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin) offer excellent activity against Gram-negative bacilli and improved Gram-positive activity (e.g. against Streptococcus pneumoniae and Staphylococcus aureus) over ciprofloxacin. Ciprofloxacin still maintains the best in vitro activity against Pseudomonas aeruginosa. Clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin display improved activity against anaerobes (e.g. Bacteroides fragilis) versus ciprofloxacin. All of the new fluoroquinolones display excellent bioavailability and have longer serum half-lives than ciprofloxacin allowing for once daily dose administration. Clinical trials comparing the new fluoroquinolones to each other or to standard therapy have demonstrated good efficacy in a variety of community-acquired respiratory infections (e.g. pneumonia, acute exacerbations of chronic bronchitis and acute sinusitis). Limited data suggest that the new fluoroquinolones as a class may lead to better outcomes in community-acquired pneumonia and acute exacerbations of chronic bronchitis versus comparators. Several of these agents have either been withdrawn from the market, had their use severely restricted because of adverse effects (clinafloxacin because of phototoxicity and hypoglycaemia; grepafloxacin because of prolongation of the QTc and resultant torsades de pointes; sparfloxacin because of phototoxicity; and trovafloxacin because of hepatotoxicity), or were discontinued during developmental phases. The remaining fluoroquinolones such as gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin have adverse effect profiles similar to ciprofloxacin. Extensive post-marketing safety surveillance data (as are available with ciprofloxacin and levofloxacin) are required for all new fluoroquinolones before safety can be definitively established. Drug interactions are limited; however, all fluoroquinolones interact with metal ion containing drugs (eg. antacids). The new fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin) offer several advantages over ciprofloxacin and are emerging as important therapeutic agents in the treatment of community-acquired respiratory infections. Their broad spectrum of activity which includes respiratory pathogens such as penicillin and macrolide resistant S. pneumoniae, favourable pharmacokinetic parameters, good bacteriological and clinical efficacy will lead to growing use of these agents in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis and acute sinusitis. These agents may result in cost savings especially in situations where, because of their potent broad-spectrum activity and excellent bioavailability, they may be used orally in place of intravenous antibacterials. Prudent use of the new fluoroquinolones will be required to minimise the development of resistance to these agents.

Pharmacokinetics and pharmacodynamics of the new fluoroquinolones: focus on respiratory infections.

High occurrence of penicillin-resistant and multidrug-resistant Streptococcus pneumoniae and reports of resistance with Haemophilus influenzae and Moraxella catarrhalis are influencing the empiric treatment of community-acquired respiratory infections and allowing the new fluoroquinolones to serve as important treatment alternatives. Recent analysis of the pharmacokinetic and pharmacodynamic properties of the new fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin) have shown high bioavailability (> or = 70%) and long serum half-lives (> or = 7 h), allowing for once-daily dosing. They concentrate in respiratory tract tissues and fluids at levels that exceed serum concentrations. Concentration-dependant killing is evident and the pharmacodynamic parameters that best correlate with bacteriological eradication, clinical efficacy and minimization of resistance have now been identified. The new fluoroquinolones display excellent pharmacokinetic and pharmacodynamic properties against community-acquired respiratory pathogens, making them ideal agents for the empirical treatment of community-acquired respiratory infections.

In vitro pharmacodynamic modelling simulating free serum concentrations of fluoroquinolones against multidrug-resistant Streptococcus pneumoniae.

An in vitro pharmacodynamic model was used to compare bacterial killing and the development of resistant mutants in the presence of respiratory fluoroquinolones and ciprofloxacin. Free (protein unbound) serum concentrations were simulated using peak serum concentrations and AUC(24), achieved after standard oral doses for treatment of community-acquired respiratory infections. Respiratory fluoroquinolones reduced the inoculum of isolates of multidrug-resistant Streptococcus pneumoniae below the level of detection in the model at 12 h and did not allow regrowth to occur over 48 h. In contrast, ciprofloxacin had a bacteriostatic (<3 log(10) reduction of the initial inoculum) effect, with rapid regrowth occurring over 48 h. Bacterial regrowth and the development of resistant mutants did not occur with any of the respiratory fluoroquinolones. Rapid regrowth and the development of resistant mutants, with MICs two- to eight-fold higher than the MIC before treatment, occurred with ciprofloxacin. These data suggest that the new respiratory fluoroquinolones with a free AUC(24)/MIC of 35-63 reduce the inoculum of multidrug-resistant S. pneumoniae below the level of detection without regrowth or development of resistance over 48 h. This study also demonstrated the poor activity of ciprofloxacin against S. pneumoniae.