New Horizons in Mycoplasma genitalium Treatment.

Mycoplasmagenitalium is an important sexually transmitted pathogen responsible for both male and female genital tract disease. Appreciation of its significance in human disease has been hampered by its slow growth in culture, difficulty in isolating it, and lack of commercial molecular-based tests for rapid detection. Comparatively few in vitro data on antimicrobial susceptibility are available due to the scarcity of clinical isolates and difficulty in performing susceptibility tests to determine minimum inhibitory concentrations for M. genitalium. Antimicrobial agents that inhibit protein synthesis such as macrolides, along with fluoroquinolones that inhibit DNA replication, have been the treatments of choice for M. genitalium infections. Even though international guidelines recommend azithromycin as first-line treatment, rapid spread of macrolide resistance as well as emergence of quinolone resistance has occurred. Increasing rates of treatment failure have resulted in an urgent need for new therapies and renewed interest in other classes such as aminocyclitols, phenicols, and streptogramins as treatment alternatives. Limited data for new investigational antimicrobials such as the ketolide solithromycin suggest that this drug may eventually prove useful in management of some resistant M. genitalium infections, although it is not likely to achieve cure rates >80% in macrolide-resistant strains, in a similar range as recently reported for pristinamycin. However, agents with completely new targets and/or mechanisms that would be less likely to show cross-resistance with currently available drugs may hold the greatest promise. Lefamulin, a pleuromutilin, and new nonquinolone topoisomerase inhibitors are attractive possibilities that require further investigation.

Synergy of streptogramin antibiotics occurs independently of their effects on translation.

Streptogramin antibiotics are divided into types A and B, which in combination can act synergistically. We compared the molecular interactions of the streptogramin combinations Synercid (type A, dalfopristin; type B, quinupristin) and NXL 103 (type A, flopristin; type B, linopristin) with the Escherichia coli 70S ribosome by X-ray crystallography. We further analyzed the activity of the streptogramin components individually and in combination. The streptogramin A and B components in Synercid and NXL 103 exhibit synergistic antimicrobial activity against certain pathogenic bacteria. However, in transcription-coupled translation assays, only combinations that include dalfopristin, the streptogramin A component of Synercid, show synergy. Notably, the diethylaminoethylsulfonyl group in dalfopristin reduces its activity but is the basis for synergy in transcription-coupled translation assays before its rapid hydrolysis from the depsipeptide core. Replacement of the diethylaminoethylsulfonyl group in dalfopristin by a nonhydrolyzable group may therefore be beneficial for synergy. The absence of general streptogramin synergy in transcription-coupled translation assays suggests that the synergistic antimicrobial activity of streptogramins can occur independently of the effects of streptogramin on translation.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe (1997-2009).

BACKGROUND: Data on more than a decade of outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 33 countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC), using the WHO Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) methodology. METHODS: For the period 1997-2009, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2011) per 1000 inhabitants per day (DID). Using a classification based on mean plasma elimination half-life, macrolide use was analysed for trends over time, seasonal variation and composition. RESULTS: Total outpatient MLS use in 2009 varied by a factor of 18 between the countries with highest (11.5 DID in Greece) and lowest (0.6 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediate- and long-acting macrolides were the most commonly used agents in 2, 25 and 5 countries, respectively (mainly erythromycin, clarithromycin and azithromycin, respectively). In Sweden, mainly lincosamides (clindamycin) were used. Lincosamide use was observed in all countries, while substantial use of a streptogramin was only seen in France (pristinamycin). For Europe, a significant increase in outpatient MLS use was found, as well as a significant seasonal variation, which increased over time from 1997 to 2009. Relative use of long-acting macrolides and lincosamides significantly increased over time with respect to intermediate-acting macrolides, and relative use of the latter increased with respect to short-acting macrolides. CONCLUSIONS: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this subgroup of antibiotics is still prescribed inappropriately in many countries.

European Surveillance of Antimicrobial Consumption (ESAC): quality appraisal of antibiotic use in Europe.

OBJECTIVES: To assess quality of outpatient antibiotic use in Europe in 2009 based on the 12 European Surveillance of Antimicrobial Consumption (ESAC) drug-specific quality indicators and to evaluate changes in quality between 2004 and 2009. METHODS: Quality of outpatient antibiotic use in 2009 was compared between 32 countries by calculating the indicator values for 2009 for each of the 12 ESAC drug-specific quality indicators based on outpatient antibiotic use data expressed in defined daily doses per 1000 inhabitants per day (DID). For each of the indicators we grouped the 2009 indicator values into four quartiles. To evaluate changes in quality between 2004 and 2009, based on their respective indicator values, countries were also grouped according to the quartile distribution of the 2004 indicator values. Only countries able to deliver data for both years were included in this analysis. RESULTS: In 2009 a difference in the quality of outpatient antibiotic use between Nordic and Southern European countries was observed. Quality of outpatient antibiotic use decreased between 2004 and 2009. In particular, there were increases in the quality indicators [J01F_DID], [J01M_DID], [J01CR_%] and [J01_B/N], i.e. the use of macrolides, lincosamides and streptogramins in DID, the use of quinolones in DID, the proportional use of combinations of penicillins, including ß-lactamase inhibitors and the ratio of broad- to narrow-spectrum antibiotics. CONCLUSIONS: Quality of outpatient antibiotic use in DID decreased between 2004 and 2009. A continuous effort to improve outpatient antibiotic consumption seems to be essential to reduce outpatient antibiotic use in general and the use of broad-spectrum antibiotics in particular.

Part VII. Macrolides, azalides, ketolides, lincosamides, and streptogramins.

In this article we describe antimicrobials that are grouped by their similar mechanism of action, namely inhibition of protein synthesis at the bacterial 50S ribosomal subunit. Macrolides, azalides, and ketolides are primarily used to treat community acquired respiratory tract infections. A lincosamide antibiotic, clindamycin, is primarily used to treat anaerobic infections. A combination of streptogramins, quinupristin/dalfopristin, is used to treat infections due to multiple drug resistant Gram positive cocci.

Antibiotic use in ambulatory care in Europe (ESAC data 1997-2002): trends, regional differences and seasonal fluctuations.

PURPOSE: The ESAC project (European Study on Antibiotic Consumption) aims to collect antibiotic-use data through a European network of national surveillance systems. This paper reports on the retrospective data collection in ambulatory care for the period 1997-2002. METHODS: Valid data of antibiotic consumption of 24 European countries for 2002 and of 18 countries for the entire 6-year period was classified according to the Anatomical Therapeutic Chemical Classification (ATC) and expressed in defined daily dose (DDD) per 1000 inhabitants per day (DID). Overall and subgroup comparison of antibiotic consumption over time as well as between geographical clusters was performed. RESULTS: Total use of antibiotics in Europe remained at a median level of 20 DID in the period 1997-2002 with a wide variation between countries ranging from 9.8 DID in The Netherlands to 32.2 DID in France. A substantial increase in subclass consumption of co-amoxiclav and fluoroquinolones was noted while the use of narrow-spectrum penicillins, erythromycin, quinolones and sulfonamides decreased. Total consumption as well as seasonal fluctuations showed remarkable geographical clustering with low consumption and low variation between summer and winter in the North, high consumption patterns in the South and a mixed model in the East. CONCLUSIONS: Within the ESAC project, valid time series of antibiotic-use data are publicly available now, enabling to improve the study of determinants of use, the evaluation of governmental antibiotic consumption policies and the investigation of the associated emergence of antibiotic resistance.

Antibiotics--past, present, and future.

The drug therapy for diseases other than those caused by microbial agents involves treating the host. In infectious diseases therapy, the goal is to rid the host of the pathogen. Hence, drug therapy is aimed at the pathogen. Because a second living agent is involved in the triangle, drug therapy is affected by the pathogen's nature, its tissue specificity, and, most importantly, the changes it undergoes to survive. The history of antimicrobial therapy has clearly demonstrated that the drugs that are used to treat infections are also responsible for making them more difficult to treat in future. The only way to keep antimicrobial agents useful is to use them appropriately and judiciously.

[Clinically significant toxicity and tolerance of the main antibiotics used in lower respiratory tract infections]. / Toxicité et tolérance cliniquement significatives des principales familles antibiotiques utilisées pour le traitement des infections des voies respiratoires basses.

The purpose of this article was not to review all reported adverse reactions of antibiotics used in the treatment of lower respiratory tract infections but rather to focus either on those which might have an impact on observance, efficacy, and resistance, or on rare but life-threatening adverse effects such as torsade de pointe. The latter are mostly predictable and prescribers should adhere to precautions and contraindications. For new antibiotics, the number of patients enrolled in phase I to III clinical trials is far to small to detect such rare adverse effects and large post registration tolerance surveys are mandatory. ss-lactams are well tolerated. The risk of anaphylactic reaction is magnified by patient reports and can be reduced by skin testing. Macrolides are well tolerated as well. The risk of cardiac toxicity should be reduced by assessing individual susceptibility and avoiding drug interactions. The tolerance to telithromycin, a new ketolide, is similar to that of macrolides. Serious toxic reactions such as convulsions, tendon rupture, torsade de pointe, and hypoglycemia are associated with the use of fluoroquinolones. Most of these adverse reactions can be often circumvented by avoiding exposure patients at risk. Quinupristin/dalfopristin can induce arthralgia and myalgia and the major adverse effects of linezolid are IMAO like reactions, reversible myelosuppression, and peripheral neuropathy. Most of the adverse antibiotic reactions are reported when precautions of use in susceptible patients are not taken into account. When they are, the safety/risk ratio is good.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe.

BACKGROUND: Data on outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Macrolide use was analysed in detail, using a classification based on their mean plasma elimination half-life. RESULTS: Total outpatient MLS use in 2003 varied by a factor of 11 between the country with the highest (9.36 DID in Greece) and lowest (0.85 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediate- and long-acting macrolides were used most in 6, 18 and 1 countries, respectively (mainly erythromycin, clarithromyin and azithromycin, respectively). Lincosamide use was observed in all countries (mainly clindamycin) and substantial streptogramin use only in France (pristinamycin). From 1997 to 2003, MLS use increased in 14 countries and was most pronounced in Greece (increase of >5 DID). Except for Sweden, a relative increase of intermediate- (mainly clarithromycin) and/or long-acting (mainly azithromycin) macrolide use was observed, at the expense of short-acting macrolide (mainly erythromycin) use. CONCLUSION: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this class of antibiotics is prescribed inappropriately in many countries. The MLS classification developed here facilitates a more comprehensive description of macrolide use in Europe. These data (collected as part of ESAC) could promote investigations that lead to a deeper understanding of the link between macrolide use and resistance.

Pharmacodynamics of a new streptogramin, XRP 2868, in murine thigh and lung infection models.

XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 10(6.8) to 10(8.4) CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with S. pneumoniae strain ATCC 10813 and -1.5 to 10.7 h with S. aureus strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 10(6.1) to 10(7.8) CFU/thigh of four isolates of S. aureus (three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of S. pneumoniae (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 microg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs +/- standard deviations (SDs) for S. pneumoniae and S. aureus isolates were 14 +/- 10 and 31 +/- 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.

A re-emerging class of antimicrobial agents: streptogramins (quinupristin/dalfopristin) in the management of multiresistant gram-positive nosocomial cocci in hospital setting.

Multiresistant gram-positive cocci, including Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium, are emerging pathogens in the setting of immunocompromised, hospitalized patients, especially when surgery or invasive procedures are of concern, and patients are admitted in intensive care units. The spectrum of antimicrobial compounds available for an effective treatment of these infection is significantly threatened by the emerging and spread of glycopeptide-resistant strains. Quinupristin/dalfopristin is a novel streptogramine association, which represents an effective response to most of these problems, due to its innovative mechanim of action, its maintained activity against multiresistant pathogens, and its possibility of synergistic activity with other compounds. Problems related to the epidemiology of multiresistant gram-positive infection, potential clinical indications of quinupristin/dalfopristin, and updated data on efficacy and tolerability of this compound and its derivatives, are outlined on the ground of a review of available literature evidences.

Antibiotics: what's new?

In addition to the traditional antibiotic choices for skin and skin structure infections, such as beta-lactams, macrolides, and clindamycin, newer broad-spectrum antibiotics are available to treat resistant pathogens that can cause severe infections. The pharmacologic profiles of 3 newer classes of these antibiotics are reviewed briefly, and the role of these agents in treating skin and skin structure infections is discussed.

Assessing risks for a pre-emergent pathogen: virginiamycin use and the emergence of streptogramin resistance in Enterococcus faecium.

Vancomycin-resistant enterococci (VRE) are an important cause of hospital-acquired infections and an emerging infectious disease. VRE infections were resistant to standard antibiotics until quinupristin/dalfopristin (QD), a streptogramin antibiotic, was approved in 1999 for the treatment of vancomycin-resistant Enterococcus faecium infections in people. After that decision, the practice of using virginiamycin in agriculture for animal growth promotion came under intense scrutiny. Virginiamycin, another streptogramin, threatens the efficacy of QD in medicine because streptogramin resistance in enterococci associated with food animals may be transferred to E faecium in hospitalised patients. Policy makers face an unavoidable conundrum when assessing risks for pre-emergent pathogens; good policies that prevent or delay adverse outcomes may leave little evidence that they had an effect. To provide a sound basis for policy, we have reviewed the epidemiology of E faecium and streptogramin resistance and present qualitative results from mathematical models. These models are based on simple assumptions consistent with evidence, and they establish reasonable expectations about the population-genetic and population-dynamic processes underlying the emergence of streptogramin-resistant E faecium (SREF). Using the model, we have identified critical aspects of SREF emergence. We conclude that the emergence of SREF is likely to be the result of an interaction between QD use in medicine and the long-term use of virginiamycin for animal growth promotion. Virginiamycin use has created a credible threat to the efficacy of QD by increasing the mobility and frequency of high-level resistance genes. The potential effects are greatest for intermediate rates of human-to-human transmission (R0 approximately equal 1).

[Macrolides, ketolides and streptogramins]. / Macrólidos, cetólidos y estreptograminas.

Macrolides, ketolides and streptogramins are three families of antibiotics with different chemical structures, sharing the same mechanism of action. All three bind to distinct bases of the peptidyl transferase center of ARNr 23S. Their antibacterial spectrum practically overlaps, but dissimilarities in affinity and/or number of binding sites determine differences in the intensity of their antibacterial effects (bacteriostatic or bactericidae) and in their activity against strains with acquired resistance mechanisms. These agents are active against the majority of gram-positive microorganisms and many intracellular microorganisms for growth. Over the last five years in our country, the percentage of macrolide-resistant pneumococci and S. pyogenes strains has increased substantially. Telithromycin (ketolide) and Synercid (streptogramin) have shown maintained activity against these strains. Macrolides, ketolides and streptogramins are metabolized in the liver through CYP 3A4 and they can partially block the activity of the enzyme, interfering with the metabolism of other drugs that use the same metabolic pathway. There is little elimination through the urine, with the exception of clarithromycin. High concentrations are reached in the cellular cytoplasm, but they do not diffuse to the CSF. These agents are included among class B drugs for use during pregnancy. Tolerance to macrolides and telithromycin is good and they have few associated adverse effects. The main clinical indication for these drugs is in empirical treatment of mild to moderate, community-acquired, upper and lower respiratory tract infections. Synercid is indicated in the treatment of infections due to methicillin-resistant staphylococci and glycopeptide-resistant enterococci.

What is the role of streptogramins in intensive care?

The combination of two injectable streptogramins, quinupristin/dalfopristin, provides a new pharmacological choice proven to be therapeutically efficacious against most Gram-positive, multi-resistant microorganisms. They have been shown to be efficacious above all in critically ill patients hospitalized in intensive care who have unique alterations in homeostasis that makes tissue penetration of various pharmacological antimicrobials difficult. In cases of infection localized in difficult-to-treat sites, the combination with other drugs, such as cefepime, a glycopeptide or linezolid, is able to potentiate the action of the streptogramin with positive results which allow resolution of the illness. In this article, we review data from the literature on the use of quinupristin/dalfopristin in the treatment of Gram-positive, multi-resistant infections in critically ill patients.