Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks?

BACKGROUND: Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. METHODS AND OBJECTIVE: This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. RESULTS: Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. CONCLUSION: The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

PURPOSE: Advances in structural biology, genetics, bioinformatics, etc. resulted in the availability of an enormous pool of information enabling the analysis of the ancestry of pro- and eukaryotic genes and proteins. METHODS: This review summarizes findings of structural and/or functional homologies of pro- and eukaryotic enzymes catalysing analogous biological reactions because of their highly conserved active centres so that non-antibiotics interacted with bacterial targets. RESULTS: Protease inhibitors such as staurosporine or camostat inhibited bacterial serine/threonine or serine/tyrosine protein kinases, serine/threonine phosphatases, and serine/threonine kinases, to which penicillin-binding-proteins are linked, so that these drugs synergized with ß-lactams, reverted aminoglycoside-resistance and attenuated bacterial virulence. Calcium antagonists such as nitrendipine or verapamil blocked not only prokaryotic ion channels but interacted with negatively charged bacterial cell membranes thus disrupting membrane energetics and inducing membrane stress response resulting in inhibition of P-glycoprotein such as bacterial pumps thus improving anti-mycobacterial activities of rifampicin, tetracycline, fluoroquinolones, bedaquilin and imipenem-activity against Acinetobacter spp. Ciclosporine and tacrolimus attenuated bacterial virulence. ACE-inhibitors like captopril interacted with metallo-ß-lactamases thus reverting carbapenem-resistance; prokaryotic carbonic anhydrases were inhibited as well resulting in growth impairment. In general, non-antibiotics exerted weak antibacterial activities on their own but synergized with antibiotics, and/or reverted resistance and/or attenuated virulence. CONCLUSIONS: Data summarized in this review support the theory that prokaryotic proteins represent targets for non-antibiotics because of a common evolutionary origin of bacterial- and mammalian targets resulting in highly conserved active centres of both, pro- and eukaryotic proteins with which the non-antibiotics interact and exert antibacterial actions.

Comparative evaluation of eight in vitro pharmacodynamic models of infection: Activity of moxifloxacin against Escherichia coli and Streptococcus pneumoniae as an exemplary example.

Use of pharmacodynamic in vitro models provides more clinically relevant information about the activities of antibiotics than static endpoints. Several models are used to simulate pharmacokinetics by dilution of the medium. It is discussed whether this procedure would result in a washout of bacteria, particularly if profiles with a short half-life are simulated. Methods have been developed to minimise the washout of bacteria. Bacteria are retained in the system either by centrifugation and resuspension, use of filters, a capillary unit, dialysis tubing or mathematical correction, versus systems with an unprotected outflow allowing a continuous washout of bacteria. None of these eight models has been directly compared with another. Therefore, an interlaboratory study was performed to address the question of whether or not washout matters. All laboratories used identical batches of media, bacteria, antibiotics and simulated pharmacokinetic profiles with a short or long half-life. Values of area under the bacterial kill-time curve (AUBKC), single-point kill rate and time to 3-log10 reduction of inoculum were calculated. These parameters did not differ significantly between the models. Differences were noted if the inoculum was prepared from the early logarithmic growth phase compared with the late logarithmic or stationary growth phase, resulting either in a pronounced or reduced antibacterial activity. Thus, preparation of inocula affects the results generated, whereas washout of bacteria has apparently a negligible impact on antibacterial activities.

Early Clinical Assessment of the Antimicrobial Activity of Finafloxacin Compared to Ciprofloxacin in Subsets of Microbiologically Characterized Isolates.

Two phase II studies were performed with patients with uncomplicated urinary tract infections (uUTIs) and complicated urinary tract infections (cUTIs) or acute pyelonephritis (PN) to compare finafloxacin (300 mg twice a day [b.i.d.] orally for uUTI and 800 mg once a day [q.d.] intravenously [i.v.] for cUTI/PN) and ciprofloxacin (250 mg b.i.d. orally for uUTI and 400 mg b.i.d. i.v. for cUTI/PN). The early response to the study medications was evaluated in the microbiological intent-to-treat population (mITT) at day 3. A total of 21% of the isolates were ciprofloxacin resistant, 13.7% were primed pathogens carrying a mutation(s) potentially fostering fluoroquinolone resistance development, and 7.1% produced extended-spectrum ß-lactamases (ESBLs). Finafloxacin demonstrated very good early clinical activity, with microbiological eradication rates of 88.6% (n = 132), compared to 78.7% (n = 61) for ciprofloxacin, and 69.6% (n = 23), compared to 35.7% (n = 14) for ciprofloxacin, in patients with ciprofloxacin-resistant uropathogens; 94.1% (n = 17), compared to 80.0% (n = 10) for ciprofloxacin, in patients infected with uropathogens primed for fluoroquinolone resistance uropathogens; and 91.7% (n = 11), compared to 0% for ciprofloxacin, in patients infected with ESBL producers. Finafloxacin demonstrated early and rapid activity against uropathogens, including fluoroquinolone-resistant and/or multiresistant pathogens or ESBL producers, while ciprofloxacin was less active against this subset of resistant pathogens. Susceptibilities of pathogens were quantitated by broth microdilution. Isolates were subgrouped according to their susceptibility patterns, in particular first-step quinolone resistance, quinolone resistance, and ESBL production. Eradication was defined as the elimination or reduction of study entry pathogens to <103 CFU/ml in urine culture. (The studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT00722735 and NCT01928433.).

Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections.

Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally (n = 77) or intravenously (n = 50), and 139 patients with cUTI received finafloxacin intravenously. Plasma (2,824 samples from volunteers and 414 samples from patients) and urine (496 samples from volunteers and 135 samples patients) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). NONMEM was used to build a population pharmacokinetic model, and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression. A two-compartment model with first-order elimination described the data best (central volume of distribution [Vc] and peripheral volume of distribution [Vp] of 47 liters [20%] and 43 liters [67%], respectively, and elimination clearance and intercompartmental clearance of 21 liters/h [54%] and 2.8 liters/h [57%], respectively [median bootstrap estimates {coefficients of variation}]). Vc increased with body surface area, and clearance was reduced in patients (-29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability of 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens. Despite the interindividual variability, the present data set does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.).

Does the use of antifungal agents in agriculture and food foster polyene resistance development? A reason for concern.

Environmental fungicides are used in agriculture to reduce fungal spoilage of crops to a minimum, and the polyene macrolide natamycin is used as a food preservative. The use of natamycin in yoghurt has recently been authorised in the USA and some other countries. However, resistance development is a serious risk associated with the use of antimicrobials as food additives and environmental fungicides. Cross-resistance between agricultural and medical azoles and between azoles and amphotericin B (AMB) not being used in agriculture has been demonstrated in clinical and environmental isolates. Polyene resistance can be elicited in vitro by the use of subinhibitory polyene concentrations and a large number of transfers. This condition may mirror the exposure of faecal Candida spp. to natamycin following consumption of natamycin-containing food. A large number of environmental and clinical isolates are resistant to AMB, and strong evidence linking farm antibiotic use and multidrug resistance, including AMB resistance, in human infections has been provided. In contrast to the acquisition of resistant environmental strains, consumption of natamycin-containing food may expose the gastrointestinal fungal flora directly to resistance selective pressure. So far, whether natamycin itself may cause the emergence of polyene resistance in gastrointestinal fungal flora and/or may act as an AMB resistance selector is probable but speculative. Use of any anti-infective agent as a food preservative should be limited to an absolute minimum as the clinical efficacy of anti-infectives used to treat serious life-threatening infections has to be preserved.

Seventy-Five Years of Research on Protein Binding.

This review summarizes evidence that the impact of protein binding of the activity of antibiotics is multifaceted and more complex than indicated by the numerical value of protein binding alone. A plethora of studies has proven that protein binding of antibiotics matters, as the free fraction only is antibacterially active and governs pharmacokinetics. Several studies have indicated that independent from protein binding of immunoglobulin G, albumin, α1-acid-glycoprotein, and pulmonary surfactant acted synergistically with antibacterial agents, thus suggesting that some intrinsic properties of serum proteins may have mediated serum-antibiotic synergisms. It has been demonstrated that IgG and albumin permeabilized Gram-negative and Gram-positive bacteria and facilitated the uptake of poorly penetrating antibiotics. Alpha-1-acid-glycoprotein and pulmonary surfactant also exerted a permeabilizing activity, but proof that this property results in a sensitizing effect is missing. The permeabilizing effect of serum proteins may explain why serum-antibiotic synergisms do not represent a general phenomenon but are limited to specific drug-bug associations only. Although evidence has been generated to support the hypothesis that native serum proteins interact synergistically with antibiotics, systematic and well-controlled studies have to be performed to substantiate this phenomenon. The interactions between serum proteins and bacterial surfaces are driven by physicochemical forces. However, preparative techniques, storage conditions, and incubation methods have a significant impact on the intrinsic activities of these serum proteins affecting serum-antibiotic synergisms, so these techniques have to be standardized; otherwise, contradictory data or even artifacts will be generated.

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers.

Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 µg · h/ml and 2.56 to 20.2 µg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.).

Does use of the polyene natamycin as a food preservative jeopardise the clinical efficacy of amphotericin B? A word of concern.

Natamycin is a poorly soluble, polyene macrolide antifungal agent used in the food industry for the surface treatment of cheese and sausages. This use is not of safety concern. However, highly soluble natamycin-cyclodextrin inclusion complexes have been developed for the protection of beverages. This practice leads to high drug exposures exceeding the safety level. Apart from the definition of an acceptable daily dietary exposure to natamycin, its effect on the faecal flora as a reservoir for resistance has to be examined. Consumption of food to which natamycin has been added and mixed homogeneously, such as yoghurt, and in particular the addition of cyclodextrin inclusion complexes to beverages and wine generates high faecal natamycin concentrations resulting in high drug exposures of faecal Candida spp. Development of natamycin resistance has been observed in Candida spp. colonising the intestinal tract of patients following natamycin treatment of fungal infections. Horizontal gene transfer among different Candida spp. and within Aspergillus fumigatus spreads resistance. Therefore, it cannot be denied that use of natamycin for preservation of yoghurt and beverages may foster development of resistance to polyenes in Candida spp.

Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients.

Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

In vitro activity of MCB3681 against Clostridium difficile strains.

One hundred fourteen Clostridium difficile strains were collected from 67 patients and analyzed for the presence of C. difficile toxin B by the cell cytotoxoicity neutralization assay, genes for toxin A, toxin B, binary toxin and TcdC deletion by PCR. All strains were also PCR-ribotyped. The MICs of the isolates were determined against MCB3681 and nine other antimicrobial agents by the agar dilution method. All isolates were positive for toxin B as well as for toxin A and B genes. In addition, 13 isolates were positive for the binary toxin genes. Thirty-two different ribotypes were identified. No strain of ribotype 027 was found. All 114 isolates were sensitive to MCB3681 (0.008-0.5 mg/l), cadazolid (0.064-0.5 mg/l), fidaxomicin (0.008-0.125 mg/l), metronidazole (0.125-2 mg/l), vancomycin (0.125-1 mg/l) and tigecycline (0.032-0.25 mg/l). Three isolates were resistant to linezolid (8 mg/l), 12 isolates were resistant to moxifloxacin (8-32 mg/l), 87 isolates were resistant to clindamycin (8-256 mg/l) and 107 isolates were resistant to ciprofloxacin (8-256 mg/l). No association between toxins A, B and binary toxin, ribotypes and the sensitivity to MCB3681 could be found. MCB3681 has a potent in vitro activity against C. difficile.

Ecological impact of MCB3837 on the normal human microbiota.

MCB3837 is a novel, water-soluble, injectable prodrug that is rapidly converted to the active substance MCB3681 in vivo following intravenous (i.v.) administration. Both MCB3837 and MCB3681 are oxazolidinone-quinolone hybrid molecules. The purpose of the present study was to investigate the effect of MCB3681 on the human skin, nose, oropharyngeal and intestinal microbiota following administration of MCB3837. Twelve healthy male subjects received i.v. MCB3837 (6 mg/kg body weight) once daily for 5 days. Skin, nose, saliva and faecal samples were collected on Day -1 (pre dose), during administration on Days 2 and 5, and post dose on Days 8, 12 and 19. Micro-organisms were identified to genus level. No measurable concentrations of MCB3681 were found in any saliva samples or in the faecal samples on Day -1. On Day 2, 10 volunteers had faecal MCB3681 concentrations between 16.5 mg/kg faeces and 275.1mg/kg faeces; no MCB3681 in faeces could be detected in two of the volunteers. On Day 5, all volunteers had faecal concentrations of MCB3681 ranging from 98.9 to 226.3 mg/kg. MCB3681 caused no ecological changes in the skin, nasal and oropharyngeal microbiota. The numbers of enterococci, bifidobacteria, lactobacilli and clostridia decreased in the intestinal microbiota during administration of the drug. Numbers of Escherichia coli, other enterobacteria and Candida were not affected during the study. There was no impact on the number of Bacteroides. The faecal microbiota was normalised on Day 19. No new colonising aerobic or anaerobic Gram-positive bacteria with MCB3681 minimum inhibitory concentrations of ≥4 mg/L were found.

Alternative strategies for proof-of-principle studies of antibacterial agents.

The proof that a new antibacterial agent is not only active in vitro but also effective in vivo under clinically relevant conditions is currently provided (i) by using appropriate nonclinical models of infection and pharmacokinetic-pharmacodynamic (PK-PD) analysis providing evidence of the likelihood of clinical efficacy and (ii) by examining the study drug in exploratory clinical trials, as well as dose and schedule finding during phase II of clinical development. This approach is both time-consuming and costly. Furthermore, PK-PD targets for any novel antibacterial agent cannot be derived from studies with experimental animals. Therefore, alternative strategies have to be identified to prove the principle that a novel antibacterial agent is active under clinically relevant conditions. This review summarizes evidence that the quantitative analysis of shifts in the viable counts of pathogens in infected patients or the evaluation of the PD effect of an investigational agent on indicator organisms of the human resident microflora or colonizers of healthy volunteers, if paralleled with PK monitoring of serum and the target site, provides an alternative to a classical proof-of-principle study in the course of a phase II study program.

Global fluoroquinolone resistance epidemiology and implictions for clinical use.

This paper on the fluoroquinolone resistance epidemiology stratifies the data according to the different prescription patterns by either primary or tertiary caregivers and by indication. Global surveillance studies demonstrate that fluoroquinolone resistance rates increased in the past years in almost all bacterial species except S. pneumoniae and H. influenzae, causing community-acquired respiratory tract infections. However, 10 to 30% of these isolates harbored first-step mutations conferring low level fluoroquinolone resistance. Fluoroquinolone resistance increased in Enterobacteriaceae causing community acquired or healthcare associated urinary tract infections and intraabdominal infections, exceeding 50% in some parts of the world, particularly in Asia. One to two-thirds of Enterobacteriaceae producing extended spectrum ß-lactamases were fluoroquinolone resistant too. Furthermore, fluoroquinolones select for methicillin resistance in Staphylococci. Neisseria gonorrhoeae acquired fluoroquinolone resistance rapidly; actual resistance rates are highly variable and can be as high as almost 100%, particularly in Asia, whereas resistance rates in Europe and North America range from <10% in rural areas to >30% in established sexual networks. In general, the continued increase in fluoroquinolone resistance affects patient management and necessitates changes in some guidelines, for example, treatment of urinary tract, intra-abdominal, skin and skin structure infections, and traveller's diarrhea, or even precludes the use in indications like sexually transmitted diseases and enteric fever.

Activity of moxifloxacin, imipenem, and ertapenem against Escherichia coli, Enterobacter cloacae, Enterococcus faecalis, and Bacteroides fragilis in monocultures and mixed cultures in an in vitro pharmacokinetic/pharmacodynamic model simulating concentrations in the human pancreas.

The activities of moxifloxacin, imipenem, and ertapenem against pathogens causing severe necrotizing pancreatitis were studied in an in vitro pharmacokinetics/pharmacodynamics (PK/PD) model. Escherichia coli, Enterobacter cloacae, Enterococcus faecalis, and Bacteroides fragilis were exposed in monocultures and mixed cultures to concentrations of the three agents comparable to those in the human pancreas. Moxifloxacin was more active than the two carbapenems in monocultures and mixed cultures, reducing the numbers of CFU more drastically and more rapidly.

Urinary pharmacokinetics and bactericidal activity of finafloxacin (200 and 800 mg) in healthy volunteers receiving a single oral dose.

BACKGROUND: Finafloxacin is a novel 8-cyano-fluoroquinolone under investigation for treatment of urinary tract infection. METHODS: Urinary concentrations and urinary bactericidal titers (UBT) of finafloxacin 200- and 800-mg single doses in 6 healthy volunteers were measured up to 48 h. UBT were determined for a reference strain and 9 selected clinical uropathogens at the pH of native, acidified (pH 5.5) and alkalinized (pH 8.0) urine. RESULTS: The mean maximum urine concentrations for 200 and 800 mg finafloxacin were 69.3 mg/l (0-2 h) and 150 mg/l (4-8 h). Median UBT were between 0 and 1:>2,048 and were in general agreement with minimal inhibitory concentrations of strains and urinary pH values. UBT in alkaline urine were significantly lower than those in native or acidic urine, except for Enterococcus faecalis. CONCLUSIONS: Finafloxacin exhibited significant bactericidal activity against susceptible uropathogens. The urinary bactericidal activity of finafloxacin was enhanced in acidic urine and significantly lower in alkaline urine.

Comparative in vitro activities of the novel antibacterial finafloxacin against selected Gram-positive and Gram-negative bacteria tested in Mueller-Hinton broth and synthetic urine.

Kill kinetics and MICs of finafloxacin and ciprofloxacin against 34 strains with defined resistance mechanisms grown in cation-adjusted Mueller-Hinton broth (CAMHB) at pH values of 7.2 and 5.8 and in synthetic urine at pH 5.8 were determined. In general, finafloxacin gained activity at low pH values in CAMHB and remained almost unchanged in artificial urine. Ciprofloxacin MICs increased and bactericidal activity decreased strain dependently in acidic CAMHB and particularly in artificial urine.

German multicentre survey of the antibiotic susceptibility of Bacteroides fragilis group and Prevotella species isolated from intra-abdominal infections: results from the PRISMA study.

OBJECTIVES: To determine the susceptibility of Gram-negative anaerobic bacteria of the family Bacteroidaceae from hospitalized patients with intra-abdominal infections (IAIs) to moxifloxacin and other antimicrobial agents with known activity against anaerobes. METHODS: Four hundred and thirty anaerobic bacterial isolates of the family Bacteroidaceae obtained from patients with IAIs were collected from 32 centres in Germany in 2007. MICs were determined using microbroth dilution for the following antimicrobials: ampicillin/sulbactam; ertapenem; meropenem; levofloxacin; moxifloxacin; clindamycin; and metronidazole. EUCAST and CLSI guidelines (for moxifloxacin) were used for interpretation. RESULTS: Overall, metronidazole exhibited the lowest resistance rates against the study isolates (four isolates, 0.9%), while the resistance rate was 4.9% for ampicillin/sulbactam, 5.3% for ertapenem and 4.9% for meropenem. Moxifloxacin showed good activity against most Bacteroides species. Resistance rates ranged between 10% and 22% for the various species except Bacteroides vulgatus, with 59% of isolates being resistant. Clindamycin had only poor activity, with 9%-56% of Bacteroides isolates being resistant. CONCLUSIONS: Resistance among Bacteroides spp. involved in IAIs to antimicrobials with known activity against anaerobes does occur and the resistance rate observed for the carbapenems is a cause of concern. These data emphasize the need not only for periodic monitoring of the susceptibility of anaerobic pathogens to guide empirical treatment but also for species identification and susceptibility testing in selected patients with severe infections involving anaerobic bacteria.