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ANTIMICROBIAL AGENTS: BACTERIAL/FUNGAL: Edited by Monica Slavin

Anaerobic resistance

should we be worried?

Cooley, Louisea; Teng, Jasmineb

Author Information
Current Opinion in Infectious Diseases: December 2019 - Volume 32 - Issue 6 - p 523-530
doi: 10.1097/QCO.0000000000000595
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Abstract

INTRODUCTION

Anaerobic bacteria are implicated in a broad range of infections, including monobacterial and coinfections with other anaerobes or aerobic bacteria. Anaerobes form part of normal human microbiota and outnumber aerobic bacteria 10–100 : 1. They reside primarily on mucosal surfaces of oropharynx, female genital tract and gastrointestinal tract. Anaerobic bacteria can cause clinical infection such as bacteraemia, intra-abdominal sepsis, diabetic foot infection, empyema and cavitating lung infection, head and neck infection, puerperal sepsis and rarely endocarditis and pericarditis. Despite this, anaerobes are not routinely cultured or identified in clinical microbiology laboratories, and susceptibility testing is infrequently performed.

Antibiotics with activity against anaerobes include penicillins, aminopenicillins, beta-lactam-beta-lactamase inhibitor combinations (BLBLI), cephalosporins (cefoxitin, cefotetan), clindamycin, moxifloxacin, metronidazole, carbapenems and tigecycline. Vancomycin and fidaxomicin are active against Clostridioides difficile only.

Antimicrobial resistance (AMR) in anaerobes is complex and mediated by a number of mechanisms, including but not restricted to target mutation, drug inactivation, multidrug efflux pumps and porin changes. The key genetic mutations are outlined in Table 1. Importantly, the mechanisms underlying high-level resistance for certain antimicrobials, including metronidazole [1] are not yet fully elucidated, and presence of these genes does not always result in phenotypic resistance.

Table 1
Table 1:
Examples for antimicrobial resistance mechanisms exhibited by anaerobes [2]

Surveillance data is of particular importance in anaerobic infection, due to frequent use of empiric therapy. Analysis of temporal trends in global anaerobe AMR is somewhat hampered by variations in survey methodology and susceptibility interpretive criteria (Table 2), range of species and antimicrobials tested as well as taxonomic and breakpoint changes over time.

Table 2
Table 2:
Interpretive categories and MIC breakpoints (mg/L) for anaerobic bacteria according to CLSI M-100 (2018) and EUCAST

Longitudinal surveillance data exemplifies the complex nature of anaerobe resistance. In the United States [3] a study of anaerobes collected between 2007–2009 and 2010–2012 found an increase in all-anaerobe resistance to ertapenem and small increases in Bacteroides fragilis group (BFG) resistance to metronidazole (0–2%) and non-B. fragilis Bacteroides group (NBFBG) to meropenem (0–1%). In the Gram-positive anaerobic cocci (GPAC) there were significant increases in resistance to ampicillin–sulbactam (1–9%), cefoxitin (0–3%), moxifloxacin (11–20%) and ertapenem (0–9%). In the Canadian CANWARD study [4], conducted between 1992 and 2010–2011, resistance increased significantly for amoxicillin–clavulanate (0.8–6.2% resistant) and clindamycin (9–34.1%). Two large surveys have focused on Bacteroides, one US study of isolates collected between 2008–2009 and 2010–2012 [5▪], in which no metronidazole resistance was detected, and resistance in many antibiotics was stable or fell, including cefoxitin, clindamycin, ertapenem, meropenem and moxifloxacin. Resistance was higher in NBFBG than BFG, particularly against moxifloxacin (42.1%) and clindamycin (45.3%). In Europe, a study of BFG [6] conducted over three periods (1998–1999, 1999–2001 and 2008–2009), documented increased resistance in most antibiotic classes, including ampicillin (16–44.5%), amoxicillin–clavulanate (1–10.4%) cefoxitin (3–17.2%) and clindamycin (9–32.4%). Moderate increases in resistance to piperacillin–tazobactam (<1–3.1%) and moxifloxacin (9–13.6%) were noted. Again, NBFBG had higher resistance than B. fragilis.

Box 1
Box 1:
no caption available

Antibiotics of concern

Clindamycin

Clindamycin resistance is mediated by erm genes that encode 23S RNA methylases. Expression may be constitutive or inducible and the genes are often colocated on transferable plasmids with genes encoding tetracycline resistance. A Dutch [7] study of Bacteroides and Prevotella found ermF gene in 15.8 and 9.1%, respectively, and its presence correlated well with resistance. Prevelance of ermF was much higher in Bacteroides ovatus (36.4%) and Bacteroides vulgatus (27.3%) [8]. In contrast, in Costa Rica [9], where clindamycin resistance rates are up to 70%, erm genes remain rare.

Clindamycin resistance is increasing globally, to the extent that it is no longer recommended for empiric therapy of serious infections. In the TEST [10] study resistance ranged from 28.4 to 48.1% for Gram-negative anarobes and 10.9–22.1% for Gram-positives. NBFBG were twice as resistant as B. fragilis (up to 48.1 versus 22.1%). Resistance in Prevotella ranged from 10.9 to 32.2% and in Finegoldia magna was 22.9%. Cobo et al.[11] also found high rates of resistance in Finegoldia (54%), Bacteroides (49%) and Prevotella (40%). In Bacteroides, clindamycin resistance rates over 50% were detected in recent studies from Spain and Korea [11,12] and moderate resistance (20–40%) have been reported in Singapore [13], Pakistan [14], Croatia [15], Brazil [16], Australia [17] and Japan [18]. Concerningly, a Russian study of clindamycin resistance in B. fragilis to be almost twice as high in blood-stream compared with nonblood stream isolates (29.8 versus 15.6%) [19▪].

Carbapenems

Carbapenem resistance in anaerobes was first detected shortly after their introduction into clinical practice [20]. Reduced meropenem susceptibility is associated with previous meropenem exposure [21] and in ertapenem, to longer duration of exposure to BLBLI combinations [22].

Carbapenem resistance in B. fragilis is mediated by Zn+ dependent metallo-beta-lactamases, encoded by the cfiA (also known as ccrA) gene. B. fragilis can be classified into two distinct homological groups based on the presence of cfiA; division I isolates (cfiA negative) and division II (cfiA positive). Importantly the presence of cfiA does not confer carbapenem resistance, as constitutive expression is low level and requires upregulation by an upstream promotor insertion sequence. 9.4% European B. fragilis strains harboured cfiA, whereas only 0.8% were imipenem resistant [23].

Carbapenem resistance remains low but is now reported in most surveys. Resistance rates are higher for ertapenem than imipenem or meropenem [3,5▪,15] Within the Bacteroides group, studies have detected low level (<2%) carbapenem resistance in Slovenia [19▪] Spain [11], Australia [17], Brazil [16], Korea [24] and Singapore [13]. Growing resistance in Asia has been noted, with moderate imipenem resistance (3–10%) in Japan [25], and very high resistance in Pakistan [26] (24.1%) and Mongolia [27] (38.5% of B. fragilis).

Importantly, while resistance rates have remain generally low in Europe, an increase in isolates with reduced susceptibility was noted by Nagy et al.[6]. Over a 20-year period isolates with an imipenem minimum inhibitory concentration (MIC) at least 4 increased from 0.1 to 2.7%. The clinical impact of this reduced susceptibility is as yet unclear but is cause for concern.

Metronidazole

Metronidazole is a 5-nitroimidazole antimocrobial introduced in the 1970s. There are multiple mechanisms of resistance [1] of which the nim genes (nimA–nimK) are best studied. nim may be located on plasmids or chromosones, and encode nitroimidazole reductase, which reduces metronidazole to an inactive compound, 5-aminoimidazole. They have been detected in a broad range of anaerobes, but predominate in Bacteroides and Parabacteroides sp. Phenotypic resistance in isolates containing nim genes is unpredictable, with MICs ranging from 0.125 to more than 256 μg/ml, and no association between MIC and the type of nim gene. One larger study of 50 nim-positive Bacteroides strains found only 50% were metronidazole resistant (MIC 16 to >32 μg/ml) [28]. Several studies have reported inducible or heteroresistance to metronidazole, which can be visible after prolonged incubation with metronidazole disks or E tests as small colonies within the inhibition zone, with MICs ranging from 8 to more than 256 μg/ml.

Currently metronidazole resistance in Europe and the United States remains below 2% [3,5▪,10], as well as in Romania [29], Poland [30], Brazil [16], Australia [17], Japan [25], Slovenia [19▪] and Korea [24] Higher resistance has been reported in Croatia (2.9% Bacteroides, 28% other Gram-negatives and GPAC) [15], southern Spain [11] (2.9% all anaerobes), selected anaerobes in Japan [25] (5% Prevotella, 3.6% Clostridium spp. and 3.1% GPAC), Korea [24] (Prevotella spp. 9%, Veillonella 27%, Clostridium spp. 7%) and Karachi [14] (3% all anerobes and 9.7% Prevotella spp.). Concerningly, Mongolia [27] and Pakistan [26] reported resistance rates of 23.1 and 20.6% in B. fragilis, respectively.

Similarly to carbapenems, isolates with reduced metronidazole susceptibility (MIC ≥ 4) have significantly increased in Europe [6] from 0.3 to 2.7%. Furthermore, a study comparing bacteraemic with nonbacteramaemic isolates found significantly higher metronidazole resistance in the blood stream isolates [14].

Fluoroquinolones

Moxifloxacin, an 8-methyl quinolone, is the only fluoroquinolone registered for treatment of anaerobic infections. Preclinical trials demonstrated activity comparable with metronidazole, with 91–100% of anaerobic isolates studied being susceptible to 2 μg/ml moxifloxacin [31]. Resistance is mediated by efflux pumps, point mutations in gyrA–B and parC genes and quinolone resistance determining regions, that can lead to two to eight-fold increases in MICs for B. fragilis group. Development of resistance is associated with quinolone use, as well as plasmid mediated resistance via qnr (quinolone resistance) encoding plasmids [32].

Moxifloxacin resistance in Bacteroides sp. is of particular concern. In 1998, moxifloxacin resistance was 15% in the United States [33] and 6–9% in Europe [34]. Currently, almost 40% of B. fragilis[35], and more than 80% NBFBG are resistant in the United States. In Europe resistance has increased more slowly [6], reaching 13.6% in 2008–2009. Significant geographic differences were noted, for example no resistance in Italy compared with 28.9% in Sweden. A recent French study found [36] 80% of French isolates were susceptible. Some improvements have been observed such as in Spain [34] where Bacteroides resistance has fallen to 6%, significantly lower than the 25% resistance documented in 2006 [37].

Other species are also of concern. In Belgium, moxifloxacin susceptibility fell in Clostridium spp. (88% susceptible to 66%) and Fusobacterium sp (90% susceptible to 71%) between 2004 and 2011, respectively [38].

Beta-lactam-beta-lactamase inhibitors

The addition of the beta-lactamase inhibitors sulbactam, clavulanate and tazobactam to penicillins confer stability to chromosomal B-lactamases, of which cepA is the most widespread in Bacteroides species. All BLBLI retain good activity against anaerobes although interpretive criteria for Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing differ (Table 1). Susceptibility at least 90% for BLBLI has been reported in United States [3], Europe [6], Japan [18], Australia [17], Korea [24], Karachi [14] and the global TEST programme [10]. Bacteroides in southern Spain demonstrated high BLBLI resistance (20%) [11]. Higher resistance was reported in Bacteroides thetaiotomicron (55.6% piperacillin–tazobactam susceptible) [10] and in Bacteroides with reduced imipenem susceptibility [6], amongst which only 45.5 and 36.4% of isolates were amoxicillin–clavulanate and piperacillin–tazobactam susceptible.

Tigecycline

Tigecycline is a tetracycline derivative and the first drug in the glycylcycline class of antibiotics. MICs are generally higher in Gram-negative than in Gram-positive isolates [10]. In Europe, 1.7% of Bacteroides were resistant [6]. In the United States, 2.4% of all anaerobes, 2.4% of B. fragilis[5▪] and 4.4% of B. thetaiotomicron were tigecycline resistant.

Clostridiodes difficile

C. difficile has a unique resistance profile that is strongly associated with ribotype [39–41]. In the United States [40,41], the prevalence of the highly resistant clone, RT027, has declined. Between the years 2011 and 2017 prevalence fell from 30.6 to 13.5%, and associated moxifloxacin and vancomycin resistance have fallen (37.5–17.5% and 13.6–5%, respectively). Metronidazole and fidaxomicin resistance is rare, however, clindamycin resistance was stable or increasing, at 25–60% [40,41]. A pan-European [39] study also found rare metronidazole and no fidaxomicin or tigecycline resistance; vancomycin resistance was very rare (0.1%).

Emergence of multidrug resistance

Surveillance data has documented the emergence of multidrug and ‘last line’ antibiotic resistance in the most pathogenic anaerobes-Bacteroides, particularly B. fragilis, Bacteroides thetaiotamicron, B. vulgatus and B. ovatus, Parabacteroides and Clostridium species. Two studies [6,42] have reported high rates of multiresistance in isolates with reduced imipenem or metronidazole susceptibility. Clinical cases of infections with dual resistance to metronidazole and carbapenem resistance have been reported due to B. thetaiotamicron[43], B. fragilis[44] and Hartmeyer [42] reported seven cases of multidrug resistant B. fragilis causing severe infections and death. Significantly, a number of surveys have identified greater resistance in invasive versus noninvasive isolates [14,19▪]. It remains to be seen whether this is due to increased virulence in resistant isolates or an inability to control local infection due to resistance.

Clinical significance

Over the past 2 decades, in-vitro resistance trends of anaerobic bacteria raise concerns of antimicrobial treatment failure. The impact of emerging resistance can be difficult to elucidate as anaerobic infections are often polymicrobial and mixed. Concurrent surgical debridement of necrotic tissue or abscess drainage and antibiotic therapy against concurrent aerobic pathogens often confound outcome data.

Mortality associated with anaerobic bacteraemia approximates 20% [45,46]. The association between reduced antimicrobial susceptibility of anaerobes, inappropriate therapy and adverse clinical outcome been established in several studies. A pivotal study by Nguyen et al. demonstrated higher clinical failure (82%) and microbiological persistence (42%) in patients with Bacteroides bacteraemia who received inactive antimicrobial therapy than those who received active therapy (22 and 12%, respectively; P = 0.0002). Similarly, Kim et al. showed that the survival rate of anaerobic bacteraemia was significantly worse in patients who had inappropriate antimicrobial therapy compared with those treated appropriately [hazard ratio, 5.4; 95% confidence interval (CI), 1.7–6.9; P = 0.004] [47]. In another study by Umemura et al.[48], Kaplan–Meier analysis of mortality showed that the 30-day survival rate was 83% in clindamycin susceptible and 38.1% in clindamycin resistant anaerobes causing bacteraemia.

Emerging data on Eggerthella lenta, an anaerobic nonsporulating anaerobic Gram-positive bacilli associated with intra-abdominal sepsis and bacteraemia, deserves special mention [49,50]. In retrospective cohort study of E. lenta infections in Canada, Ugarte-Torres et al.[50] described 30-day mortality of 23% for blood stream infection which was independently associated with empiric piperacillin–tazobactam therapy (odds ratio 4.4; 95% CI 1.2–16; P = 0.02). In this series, the piperacillin–tazobactam MIC50 and MIC90 for E. lenta isolates (n = 100) were 32 and 64 mg/l, respectively.

In the paediatric and neonatal population, anaerobic bacteraemia is considered rare (<0.5%) and the impact of anaerobic resistance in this population requires further study.

Antimicrobial stewardship

Appropriate usage of antianaerobic antimicrobials and unnecessary double anaerobic coverage (DAC) has been low hanging fruits for antimicrobial stewardship programmes (ASP). Briefly, DAC refers to the redundant concurrent use of two or more antimicrobials with antianaerobic activity and has been associated with increased hospital costs, risk of adverse reaction and theoretical risk of driving AMR [51–53]. To date, multiple studies continue to confirm the value of well structured ASP resulting in improved prescribing practices [54,55]. While outcome measures such as reduction in healthcare cost and antimicrobial consumption are easily captured, whether this translates to reduction in AMR in anaerobes is yet to be established.

Data on the impact of broad-spectrum antimicrobial use on gut anaerobic flora is emerging. In a recent Danish study, Hansen et al.[21] investigated B. fragilis group anaerobes from stool samples of patients with suspected infectious diarrhoea under the care of haematology, oncology and infectious diseases departments with high level of antibiotic use. Consistent with previous reports, metronidazole resistance was less than 1% whereas reduced susceptibility to meropenem was 5%, primarily in B. ovatus/xylanisolvens and was associated with meropenem exposure.

Emerging resistance in anaerobic bacteria poses a unique challenge for ASP in assessing antimicrobial appropriateness and suitability. While the impetus is to restrict unnecessary antimicrobial use, reports of clinical failure due to drug-resistant anaerobic infections is a cause for concern. Nakamura et al.[56] published a case in point of a patient with intra-abdominal sepsis due to B. fragilis harbouring a cfiA4 metallo-beta-lactamase and upstream insertion sequence, treated empirically with a carbapenem who ultimately died of septic shock. Furthermore, in areas such as Pakistan where of very high rates of metronidazole and imipenem resistance are reported, DAC may be necessary [26]. Knowledge of local antibiograms through routine testing and periodic surveillance is paramount to guide empirical therapy.

CONCLUSION

Collectively, surveillance data and clinical studies document worrying trends in anaerobe AMR. Globally the trend is towards increasing resistance, although this is not homogenous, necessitating country, hospital and species-specific data. Important antianaerobe antimicrobials are under threat – moxifloxacin and clindamycin – and that the previous reliable metronidazole and meropenem are now at risk. Furthermore, patients with invasive infections due to resistant anaerobes have increased mortality.

As a result, anaerobic culture and identification must become routine in the clinical microbiology laboratory. Susceptibility testing should be performed for sterile site, deep or nonresponding anaerobic infections as well as for determining local antibiograms. The role of stewardship is not well defined and needs to be tailored to local antibiograms and clinical settings. Close collaboration between stewardship teams, microbiologists and clinicians is paramount.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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    Keywords:

    anaerobe; antimicrobial resistance; multidrug resistance

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