One must be aware that MICs of chloramphenicol often cluster around the susceptibility breakpoint. Anaerobic Coverage 1,2 All carbapenems have fairly good coverage against anaerobes. Five genes conferring MLS resistance have been identified in anaerobes, including erm(B), erm(C), erm(F), erm(G), and erm(Q). It should be noted that in these animal toxicity studies, the drug has generally been administered for the lifetime of the animal, a situation that may not be relevant for humans. Plates are read after ∼48 h of growth by visually comparing the growths of different strains in the series, and the MIC is designated the lowest antimicrobial concentration that inhibits growth. This review describes current methods for antimicrobial testing in research or reference laboratories. (Right) Series of agar dilution plates. When an MIC is near the breakpoint (e.g., in the case of the B. fragilis group and chloramphenicol as well for as many β-lactam agents), an organism called susceptible on one occasion may be retested and called resistant, all within the accepted variability of the technique. Details for this procedure are described in the CLSI manual (16). 75). The Clinical and Laboratory Standards Institute (CLSI) has standardized many laboratory procedures, including anaerobic susceptibility testing (AST), and has published documents for AST. Most strains of the B. fragilis group and many Prevotella, Porphyromonas, and Fusobacterium spp.  |  He is active in the Anaerobe Society of the Americas, the IDSA, ASM, and the Surgical Infection Society. The choice will be based on published literature and surveys and local or specific patient data. The numbers and choice of species of strains tested should reflect the frequency with which they are isolated. and other Gram-negative organisms as anaerobic pathogens. Agar dilution technique. 64. 1989 Sep;24 Suppl A:73-84 A classification based on amino acid sequence was created by Ambler (102), and a classification based upon substrate-of-inhibition profiles, molecular weight, and isoelectric points was proposed by Richmond and Sykes (103). Antimicrobial agents effective against mixed infection Several tetracycline resistance genes have been described among several anaerobes, which encode protective proteins leading to protection of the ribosomes. These nim genes were found in 50/206 (24%) Bacteroides species isolates and resulted in MICs of 1.5 to >256 μg/ml for metronidazole, including 16 isolates with MICs of ≥32 μg/ml (54). In contrast, MICs for Pseudomonas and Proteus spp. 4, left). The spectrum of efficacy, antimicrobial resistance mechanisms, and resistance patterns against these agents are described. BLA inhibitors cannot inactivate the carbapenemases, which are zinc metalloenzymes encoded by either ccrA or cfiA genes of the B. fragilis group (109). Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. This occurred after the decline in rates anaerobic bacteremia in the 1970s and 1980s, which led many medical centers to discontinue obtaining blood cultures for anaerobic bacteria. Carbapenem (meropenem, ertapenem) Hypersensitivity, GI effects, ... Anaerobic coverage is indicated in a variety of infectious processes, including but not limited to aspiration pneumonia, intra-abdominal infection, gynecologic infection, and diabetic foot ulcer infection. Azithromycin is, in general, the most active macrolide against AGNB such as Fusobacterium spp., Bacteroides spp., Wolinella spp., and Actinobacillus actinomycetemcomitans, including strains resistant to erythromycin. The potential for growing resistance of anaerobes to antimicrobials is especially noted with penicillins, fluoroquinolones, clindamycin, and cephalosporins. Journal of Microbiology & Biology Education, Microbiology and Molecular Biology Reviews, Surveillance Tests for Particular Hospitals or Geographic Regions, Testing in a Research or Reference Laboratory, Factors Contributing to Variability in MIC Results, Detection of Resistance by Using Molecular Methods, The Macrolides: Erythromycin, Azithromycin, and Clarithromycin, Parvimonas micra (Peptostreptococcus micros), The anaerobic microflora of the human body, Anaerobic infections: diagnosis and management, Wadsworth-KTL anaerobic bacteriology manual, Anaerobic infections: update on treatment considerations, Prevalence of antibiotic resistance in anaerobic bacteria: worrisome developments, Cefoxitin in the treatment of aerobic/anaerobic infections: prospective correlation of in vitro susceptibility methods with clinical outcome, Clinical efficacy and correlation of clinical outcomes with, Correlation of various in vitro testing methods with clinical outcomes in patients with. Broth microdilution.In the broth microdilution assay, a polystyrene tray (usually containing 96 wells) is filled with small volumes of serial 2-fold dilutions of different antibiotics (Fig. A consistent observation is the high concentrations achieved in the CNS, even in the absence of inflammation. (37 [80.4%] of 46 patients). Research laboratories that conduct large surveys, as well as pinpointing the mechanisms of resistance that may be relevant in the antibiograms, can help monitor, understand, and perhaps even control these shifts by making recommendations based on the molecular traits of the pathogen. This increase makes the choice of appropriate empirical therapy even more difficult. The semisynthetic penicillins, the carboxypenicillins (carbenicillin and ticarcillin), and ureidopencillins (piperacillin, azlocillin, and mezlocillin) generally are administered in large quantities to achieve high serum concentrations. New Window. Antibiotics tested should include penicillin, a beta-lactam–beta-lactamase inhibitor combination (BL-BLIC), clindamycin, metronidazole, and a carbapenem (i.e., imipenem, meropenem, or ertapenem). Reliable disk diffusion tests for meropenem do not yet exist for testing streptococci. Resistance has also increased for many non-Bacteroides anaerobes. The production of BLAs is the most common mechanism of resistance to β-lactam antibiotics in anaerobes, especially among the B. fragilis group and Prevotella spp. Tetracycline resistance and the inducible transfer of resistance determinants can occur after exposure to low levels of these agents. Isolates with a positive β-lactamase test should be considered resistant to penicillin and ampicillin. – In general, clinicians recognize the generally good activity of carbapenems against anaerobes and prescribe them appropriately. Fluoroquinolone resistance. He is an editor, associate editor, and member of the editorial board of several medical journals and the Head and Neck Cancer Alliance. It inhibits cell wall synthesis by binding to several penicillin-binding proteins, resulting in defective cell walls & osmotically unstable organisms susceptible to cell lysis. Carbapenem resistance in B. fragilis is associated with cfiA- or ccrA-encoded class B metallo-β-lactamase. Its clinical and bacteriological efficacy is similar to that of imipenem/cilastatin, clindamycin plus tobramycin and cefotaxime plus metronidazole in the treatment of intraabdominal infections; cefotaxime or ceftriaxone in the treatment of meningitis; imipenem/cilastatin, and ceftazidime with or without an aminoglycoside, in lower respiratory tract infections; and imipenem/cilastatin or ceftazidime in the treatment of urinary tract infections. anaerobe. Drugs. 17). J Antimicrob Chemother 1995;36 (Suppl A):S207-223. The antimicrobial susceptibilities of some members of the B. fragilis group vary, especially to the second- and third-generation cephalosporins. To most clinicians, B. fragilis group species are recognized as the major anaerobic pathogen, but the individual B. fragilis group subspecies are less readily recognized. Broth microdilution. The limited medical education that students and residents receive about anaerobes and the limitations of microbiology laboratory culture, with delays in identification and anaerobic susceptibility testing, suggest that at best, the choice of an agent for a serious anaerobic infection is an empirical and educated guess (38). Medical uses Intra-abdominal infections. Chronic Kidney infections.....IV meropenem seems to be the only thing that clears them up. While 89% of B. fragilis strains are susceptible to ampicillin-sulbactam, 98% are susceptible to piperacillin-tazobactam (17), compared to 86% and 92%, respectively, of B. thetaiotaomicron isolates. The carbapenem ertapenem is one of several first-line agents recommended by the Infectious Disease Society of America for the empiric treatment of community-acquired intra-abdominal infections of mild-to-moderate severity. Although these enzymes are generally chromosomally mediated, a plasmid-mediated metallo-BL has been reported in Japan (108). This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Erythromycin is effective in the treatment of mild to moderately severe anaerobic soft tissue and pleuropulmonary infections when combined with adequate debridement or drainage of infected tissue. – 72). Aside from susceptibility patterns, other factors influencing the choice of antimicrobial therapy include the pharmacological characteristics of the various drugs, their toxicity, their effect on the normal flora, and their bactericidal activity (2, 3). Spectrum: best gram negative coverage of FQs, but virtually no gram positive coverage. The newer tetracycline analogs doxycycline and minocycline are more active than the parent compound. The pharmacokinetics of imipenem are characterized by poor absorption from the gastrointestinal tract, high plasma concentrations after intravenous administration, a small degree of systemic metabolism, and renal excretion. – great. – Imipenem has more activity than meropenem against staphylococci and enterococci, but meropenem provides better coverage of aerobic and facultative Gram-negative bacteria such as Pseudomonas, Enterobacter, Klebsiella, Providencia, Morganella, Aeromonas, Alcaligenes, Moraxella, Kingella, Actinobacillus, Pasteurella, and Haemophilus spp. Goldstein et al. Anaerobes. – Unnecessary “Double-coverage” of anaerobes is considered an important target for antimicrobial stewardship programs. Metronidazole and TinidazoleThe nitroimidazoles metronidazole and tinidazole have similar in vitro efficacy against anaerobic bacteria. The carbapenems (imipenem, meropenem, doripenem, and ertapenem) are very effective against all members of the B. fragilis group, and resistance is rare, at <0.1% (27, 112, 113). Resistance to β-lactam antibiotics through changes in the outer membrane protein (OMP)/porin channels, decreased PBP affinity, and efflux pumps (111) is less well studied. nim homologs were found in both Gram-positive and -negative genera of aerobic and anaerobic bacteria and Archaea, suggesting that the nim gene family is ancient and widespread. The routine susceptibility testing of all anaerobic isolates is extremely time-consuming and is not cost-effective. It also possesses excellent activity against beta-lactamase-producing Bacteroides. Antibiotic Spectrum Chart – Coverage for most antibiotics by class As we know, bacteria are classified according to gram stain to positive or negative. Consequently, the most likely agents to cover the vast majority of anaerobes encountered in mixed infections will be either a carbapenem or a BL-BLIC such as piperacillin-tazobactam. These findings emphasize that it is important to perform susceptibility testing of organisms recovered from certain selected cases to guide therapeutic choices. 91). (Courtesy of bioMérieux, reproduced with permission.). express enzymes that are generally inhibited by clavulanic acid (110). Hence, the clinician is likely to consider only the in vitro activity of specific agents against B. fragilis and assume that all the other anaerobes will likely be susceptible as well. In contrast, a study from Europe (147) found an overall fluoroquinolone resistance rate of 15%, with geographic variations from 7% in southern Europe to 30% in northern Europe. Agents to test should include those on the hospital formulary, and the agent that is being considered or used for therapy should be included if at all possible. The CLSI has published an appendix to its recent document that reports the cumulative susceptibilities for B. fragilis group species collected from three U.S. medical centers from 2007 to 2009 (17). Infections caused by these bacteria are seldom reported, as they in most cases are regarded as normal flora or non-pathogenic microorganisms. Treatment of anaerobic bacterial infections is complicated by the relatively slow growth of these organisms (which makes diagnosis in the laboratory possible only after several days), by the frequent polymicrobial nature of the infection, and by the growing resistance of anaerobic bacteria to antimicrobial agents. Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, Noreddin AM, Karlowsky JA. An 8-year study (1997 to 2004) revealed that 19.3% of 2,721 B. fragilis group, 29.6% of P. distasonis, 33.4% of B. ovatus, 33.3% of B. thetaiotaomicron, and 35.6% of B. vulgatus isolates were clindamycin resistant. When selecting antimicrobials for the therapy of mixed infections, their aerobic and anaerobic antibacterial spectrum and their availability in oral or parenteral form should be considered (Table 1). Carbapenems are active synergistically with aminoglycosides against P. aeruginosa. (Left) A Steers replicator is used to apply inocula onto a agar plate. Although not all cfiA-positive B. fragilis strains are resistant to carbapenems, they all have the possibility of becoming resistant to this group of antibiotics by acquisition of an appropriate insertion sequence (IS) element for full expression of the cfiA gene, leading to possible treatment failure. Metronidazole resistance is generally attributed to the nim gene. There are a variety of BLAs which are produced by different organisms. Other antimicrobials, such as doxycycline and minocycline, are more effective than tetracycline. His interests include the diagnosis, pathogenesis, and therapy of anaerobic infections, including intra-abdominal infections, diabetic foot infections, C. difficile, human and animal bites, and the in vitro susceptibility of anaerobic bacteria to new antimicrobial agents. The overall clinical success rate for all anaerobes was 82.3%. PCR is used to detect the presence of the nim gene. A multicenter survey (93) found penicillin resistance for Fusobacterium spp., Porphyromonas spp., and Peptostreptococcus spp. 4). The carbapenems (imipenem, meropenem, doripenem, and ertapenem) have excellent activity against anaerobes . Resistant B. fragilis group isolates carry one of nine known nim genes (nimA-I) on either the chromosome or a mobilizable plasmid that seems to encode a nitroimidazole reductase, which converts 4- or 5-Ni to 4- or 5-aminoimidazole, preventing the formation of toxic nitroso residues necessary for the agent's activity. The tolerance of metronidazole in patients is generally very good. Her work currently includes comparative genomic and transcriptomic studies of multidrug-resistant and virulent strains of Bacteroides fragilis. Doripenem, a synthetic 1-beta-methyl carbapenem, is the newest carbapenem to be commercially released. Trovafloxacin, gatifloxacin, and moxifloxacin yield low MICs against most groups of anaerobes (40). Serum level measurements are often advocated for infants, young children, and occasionally adults, owing to their wide variations (115). Pigmented Prevotella and Porphyromonas spp., Prevotella bivia, Prevotella disiens, and Fusobacterium nucleatum produce primarily penicillinases (107). The Etest is a plastic strip with a predetermined antimicrobial concentration gradient on one side and an interpretative MIC scale on the other. Most Enterobacteriaceae (including those that produce AmpC beta-lactamase and extended-spectrum beta-lactamase ... meropenem, and doripenem but are resistant to ertapenem. Carbapenem resistance occurs in <1% of U.S. isolates, and up to 3% of Bacteroides strains harbor one of the genes that is expressed at a very low level. The great majority of B. fragilis group isolates are β-lactamase producers; therefore, testing is generally not recommended for this group. After incubation, endpoints of growth are marked, and the distance is measured in millimeters from the center of the plate to the point where growth stops (Fig. -, Scand J Infect Dis Suppl. Lessons from studies of intra-abdominal sepsis, Treatment of anaerobic infections in children with metronidazole, Safety of metronidazole during pregnancy: a cohort study of risk of congenital abnormalities, preterm delivery and low birth weight in 124 women, Two cases of infections due to multidrug-resistant, Tigecycline: a new glycylcycline antimicrobial, Comparative in vitro susceptibilities of 396 unusual anaerobic strains to tigecycline and eight other antimicrobial agents, The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data, In vitro activities of tigecycline against the, In vitro activity of moxifloxacin against 923 anaerobes isolated from human intra-abdominal infections, Efflux-mediated fluoroquinolone resistance in the, Emergence of fluoroquinolone resistance among, ESCMID Study Group on Antimicrobial Resistance in Anaerobic, Genetic determinant of intrinsic quinolone resistance in, Antibacterial activity of quinupristin/dalfopristin. An additional 40% (8/20) of laboratories surveyed would also perform susceptibility testing by special request. ; Bilophila wadsworthia; and Sutterella wadsworthensis. Thus, a clinical laboratory would have the option of either using Etest (which is FDA approved), using noncommercial panels with CLSI-approved methodology (thus, FDA approval would not be relevant), or sending the isolates to a commercial or reference laboratory for testing. Anaerobic coverage is indicated in a variety of infectious processes, including but not limited to aspiration pneumonia, intra-abdominal infection, gynecologic infection, and diabetic foot ulcer infection. Is a Rapid Test on the Horizon?It would be very appealing to wish that there could be a simple molecular test, or even a complex test, such as multiplex PCR, that would determine the actual or potential resistance of an organism to multiple antibiotics. At this time, the only way to measure these genes in clinical isolates is to quantitatively identify and sequence RNA transcripts, which is not a practical solution. Colitis has also been associated with a number of other antimicrobials, such as ampicillin, cephalosporins, and quinolones, and occasionally also in the absence of previous antimicrobial therapy. Since nearly two-thirds of laboratories do not perform testing (and even those that test do it on only a limited basis), the clinicians often choose therapy based on manufacturers' information, FDA indications, published studies, or their clinical judgment (20). Meropenem has shown clinical and bacteriological efficacy in the treatment of a wide range of serious infections in adults and children which is at least comparable with that of currently available treatment options. Clinical failure (82%) and microbiological persistence (42%) were higher for those who received inactive therapy than for patients who received active therapy (22% and 12%, respectively; P = 0.0002 and 0.06, respectively). Standardization of TestingThe CLSI is a U.S. organization that evolved from a voluntary consensus organization in 1967 to become a World Health Organization Collaborating Center for Clinical Laboratory Standards and Accreditation. For the very resistant P. aeruginosa, doripenem and meropenem are highly potent because they require multiple drug resistance pathways. Resistance to this drug is rare, although it has been reported for some Bacteroides spp. remains good. Drugs. (117). Fortunately, the types of anaerobes involved in many anaerobic infections and their antimicrobial susceptibility patterns tend to be predictable (2, 3). (P. bivia [70% resistant], P. oralis, and P. melaninogenica [both 40% resistant]), although its activity against Fusobacterium and Porphyromonas spp. Active against gram negative organisms, no anaerobe coverage, little to no strep coverage . Lane 0, negative control; lane M, DNA standards. It has a broad spectrum of antibacterial activity in vitro, the majority of Gram-negative, Gram-positive and anaerobic pathogens being highly susceptible to the drug. Quinolones with low activity against anaerobes include ciprofloxacin, ofloxacin, levofloxacin, fleroxacin, pefloxacin, enoxacin, and lomefloxacin. – In cases where other factors that can cause variability are also involved (e.g., differences in techniques or media or different people reading results), it becomes clear that minor changes (e.g., less than 15%) in percent susceptibility may not be significant in reports of large groups of strains; still, survey studies provide useful information on trends and patterns in antimicrobial susceptibility of anaerobes. Resistance to β-lactam antibiotics.Anaerobes manifest three major mechanisms of resistance to β-lactam antibiotics: inactivating enzymes, mainly beta-lactamases (BLAs), which include penicillinases and cephalosporinases; low-affinity penicillin-binding proteins (PBPs); and decreased permeability through alterations in the porin channel (35). However, this may be particularly difficult in anaerobic infections because of the difficulties in obtaining appropriate specimens. 5). This confirmed the role of anaerobes in abscess formation. Organisms that should be considered for individual isolate testing include highly virulent pathogens for which susceptibility cannot be predicted, such as Bacteroides, Prevotella, Fusobacterium, and Clostridium spp. at rates of 9%, 21%, and 6%, respectively. Because of metronidazole's lack of activity against aerobic bacteria, an antimicrobial effective against these organisms (e.g., a cephalosporin or a fluoroquinolone) needs to be added when treating a polymicrobial infection. Like other carbapenems, meropenem is stable against chromosomal and extended-spectrum β-lactamases.  |  Cefoxitin is therefore the most effective cephalosporin against the B. fragilis group. Fusobacterium canifelinum, recovered from cat and dog bite wound infections, is intrinsically resistant to fluoroquinolones because of Ser79 replacement with leucine and Gly83 replacement with arginine on gyrA (148). Carbapenems are active synergistically with aminoglycosides against P. aeruginosa. Routine anaerobic blood cultures: back where we started? The drug has a somewhat unique property of lipid solubility to permit penetration across lipid barriers. An 81 year old woman with a long term, indwelling urinary catheter is admitted with fever and hypotension thought to be due to septicaemia secondary to urinary tract infection. Only about 45% of all B. fragilis strains are presently susceptible to this drug (79). Tigecycline is the first antibiotic approved in a new class called glycylcyclines. (4% and 5% resistance to ampicillin-sulbactam, respectively). what type of organism is clostridium. 82). Among the other resistant anaerobes are various species of clostridia, especially C. difficile. It is indicated for complicated intra-abdominal and skin structure infections, including diabetic foot infections without osteomyelitis, and acute pelvic infections, including postpartum endomyometritis, septic abortion, and postsurgical gynecological infections. The CLSI method specifies the use of control strains including B. fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741, and Clostridium difficile ATCC 700057. For example, metronidazole is active against only anaerobic bacteria and therefore cannot be administered as a single agent for the therapy of mixed infections. Clindamycin does not cross the blood-brain barrier or eye efficiently and should not be administered in CNS infections. Jacobus et al. Isolates from patients likely to undergo long-term therapy should be tested so that any development of resistance can be recognized. Antimicrobial resistance among anaerobes has consistently increased in the past 3 decades, and the susceptibility of anaerobic bacteria to antimicrobial agents has become less predictable. The only commercially available ready-made panel is produced by Sensititre (Trek Diagnostic Systems); it is designated for research purposes only and is not FDA approved for diagnostic testing. However, meropenem and doripenem are less active against E. faecalis than imipenem. Meropenem/imipenem/doripenem Ertapenem Ertapenem ... Gram Positive Cocci Anaerobes Streptococci Gram Negative Bacilli Staphylococci Gram Negative Coccobacilli Atypicals Bacteria Clostridium difficile Mycoplasma pneumoniae, Chlamydophila spp Legionella pneumophila Amoxicillin-clavulanate A negative test does not necessarily predict susceptibility to these drugs, as some anaerobes are resistant to β-lactam antimicrobial agents by other mechanisms. This review describes the current methods for AST in research and reference laboratories. The use of tetracycline is not recommended for patients less than 8 years of age because of the adverse effect on teeth. Several multidrug-resistant isolates appear to have significantly increased efflux pump activity. Double anaerobic coverage is the combination of 2 or more of the following agents: Ampicillin/sulbactam Carbapenems (Doripenem, Ertapenem, Imipenem, Meropenem) Cefotetan Cefoxitin – Increased activity of efflux pumps or changes in penicillin-binding proteins (PBPs) have been shown to affect MICs of β-lactams for many Bacteroides isolates; systematic surveys of these mechanisms have not been conducted, so the percentage of strains that have or utilize these mechanisms is not known (35, 49). The use of trovafloxacin has been limited because of hepatotoxicity. Medical uses Intra-abdominal infections. In many patients the gastrointestinal (GI) tract is the source of Candida dissemination 2, 3, especially in those receiving treatment with broad-spectrum antibiotics as this causes an increase in the GI Candida population 3, 4.
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