Metronidazole and Other Antibiotics for Anaerobic Infections

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125 Metronidazole and Other Antibiotics for Anaerobic Infections

Jessica C. Njoku, John C. Rotschafer, Elizabeth D. Hermsen

Metronidazole

Metronidazole [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole], a nitroimidazole antimicrobial, was introduced in 1960 and quickly became the treatment of choice for Trichomonas vaginalis.¹ Initially, metronidazole was regarded as an antiprotozoal agent, proving to be an effective treatment for such infections as trichomoniasis, amebiasis, and giardiasis. The antibacterial activity of metronidazole versus obligate anaerobes was not widely recognized until the 1970s.^2,³ Since then, metronidazole has been used extensively for anaerobic infections such as Clostridium difficile infection (CDI) and those involving Bacteroides spp.

Because metronidazole has been in use for more than 40 years, a plethora of information exists regarding basic knowledge about this antimicrobial, including the mechanism of action, spectrum of activity, pharmacokinetics, adverse drug effects, and clinical uses. The newest addition to the nitroimidazole antimicrobial class is tinidazole, which was approved by the U.S. Food and Drug Administration (FDA) in 2004.⁴ However, this agent is not widely used for infections of a nonparasitic nature, so much of the discussion in the chapter is focused on metronidazole.

Mechanism of Action

Metronidazole possesses bactericidal activity against obligate anaerobes, although the mechanism of action has not yet been thoroughly elucidated. Metronidazole is a prodrug, requiring intracellular nitroreduction to become active; thus metronidazole in the unchanged form is not pharmacologically active.¹ During the process of reduction, cytotoxic intermediates are formed, and these intermediates are thought to be responsible for killing the cells. The reduction process depends on ongoing energy metabolism but not on ongoing cell multiplication, which translates into activity against both dividing and nondividing cells.^1,⁴

Spectrum of Activity and Clinical Uses

Anaerobic bacteria of the Bacteroides fragilis group are known to be the most clinically important anaerobic pathogens, owing to their multidrug-resistant nature and the frequency with which they are involved in infectious diseases including polymicrobial infections such as intraabdominal infections, obstetric-gynecologic infections, and diabetic foot infections.^5,⁶ Nosocomial diarrhea and/or pseudomembranous colitis associated with antibiotic use are frequently caused by Clostridium difficile, another clinically important anaerobe.⁷ Metronidazole is highly effective against both of these medically relevant anaerobes (Table 125-1). Although metronidazole possesses significant antimicrobial activity against several obligate anaerobes, it is not considered to be clinically active versus aerobic bacteria.¹ Tinidazole has similar spectrum of activity to metronidazole against most anaerobic bacteria, including B. fragilis and microaerophilic bacteria such as Helicobacter pylori and Campylobacter spp., but is only currently approved for the treatment of trichomoniasis, giardiasis, amebiasis, and amebic liver abscess. Other uses outside of these indications are considered experimental.⁸

TABLE 125-1 Metronidazole Minimal Inhibitory Concentration and Percent Susceptibility for Various Anaerobes

Anaerobe (No. of Isolates Tested)	MIC90 (mg/L)	% Susceptible
Clostridium difficile (186)	2	100
Peptostreptococcus (49)	2	94
Bacteroides fragilis group* (401)	1	100
Prevotella spp. (65)	2	100
Fusobacterium spp. (22)	2	100
Porphyromonas spp. (19)	2	100

MIC90, minimum inhibitory concentration that inhibits 90% of organisms.

* Includes Bacteroides fragilis, B. distasonis, B. thetaiotaomicron, B. ovatus, B. vulgatus, B. uniformis.

Adapted and modified from Drummond LJ, McCoubrey J, Smith DG et al. Changes in sensitivity patterns to selected antibiotics in Clostridium difficile in geriatric in-patients over an 18-month period. J Med Microbiol 2003;52:259-63; and from Aldridge KE, Ashcraft D, Cambre K et al. Multicenter survey of the changing in vitro antimicrobial susceptibilities of clinical isolates of Bacteroides fragilis group, Prevotella, Fusobacterium, Porphyromonas, and Peptostreptococcus species. Antimicrob Agents Chemother 2001;45:1238-43.

Clinically, metronidazole has been used successfully to treat anaerobic bacteremia, endocarditis, meningitis, brain abscesses, intraabdominal infections, and mixed aerobic-anaerobic infections, although the addition of an antibiotic effective against aerobic bacteria is necessary for the latter.^2,⁹^–¹¹ Additionally, although without formal FDA approval, metronidazole remains the drug of choice for mild and moderate CDI due to historical and epidemic BI/NAP1/027 strains, owing to excellent oral bioavailability, low potential for selecting for vancomycin-resistant Enterococcus (VRE), lack of detectable resistance among BI/NAP/027 strains, and low cost.¹² However, in patients with severe CDI, treatment with metronidazole resulted in a less than optimal response compared to oral vancomycin therapy.¹³ Consequently, vancomycin is the preferred agent for severe CDI.¹²

Pharmacokinetics

Given orally, metronidazole is almost completely absorbed, with a bioavailability of greater than 90%.¹⁴ In patients with CDI, absorption of oral metronidazole is reduced due to increased bowel emptying causing fecal concentrations to be high, coupled with secretion from plasma into the colon.¹⁵ However, levels decrease rapidly after treatment of CDI is initiated, from 9.3 mg/g in watery stools to 1.2 mg/g in formed stools to an undetectable level once diarrhea has resolved.¹⁵ Intravenous metronidazole is able to maintain high fecal levels in patients with CDI with toxic megacolon or ileus; otherwise, oral metronidazole is recommended.^12,¹⁵ Metronidazole is a relatively small molecular entity (molecular weight = 171.16 D) with low protein binding (<20%) and is widely distributed throughout the body.¹ The steady-state volume of distribution in adults is 0.51 to 1.1 L/kg.¹³ The elimination half-life of metronidazole is 6 to 8 hours for patients with normal liver function.^1,¹⁴ Metronidazole undergoes metabolism in the liver to form five known metabolites, two of which are 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (the hydroxy metabolite) and 2-methyl-nitroimidazole-1-acetic acid (the acid metabolite). The hydroxy metabolite exhibits 30% to 65% of the anaerobic activity of the parent compound.¹⁴

Adverse Reactions

The most common side effects of metronidazole treatment (at standard doses) are gastrointestinal disturbances including mild nausea, a bad/metallic taste in the mouth, and furring of the tongue. More rare adverse reactions to metronidazole include vaginal and/or urethral burning, dark/discolored urine, and neurologic toxicity such as headache, ataxia, vertigo, somnolence, depression, and peripheral neuropathy.¹ Metronidazole is recognized for causing a disulfiram-like reaction with the concurrent ingestion of alcohol. However, a study conducted by Visapää and coworkers found no evidence of disulfiram-like properties of metronidazole when it was given concomitantly with ethanol,¹⁶ and this reaction has also been disputed by others.¹⁷

Pharmacodynamics

The standard dosing regimen for metronidazole (500-1000 mg q 6-8h) was determined long before pharmacodynamics emerged as a science. Metronidazole exhibits concentration-dependent bactericidal activity along with a significant post-antibiotic effect (>3 h).^14,¹⁸^–²⁰ These factors, in combination with a long half-life and a favorable safety profile, provide a wide corridor to manipulate the metronidazole dose and dosage interval. Much more convenient regimens of larger doses (e.g., 1000-1500 mg) given every 12 hours or once daily are plausible because of the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of this antibiotic.^18,¹⁹ PK analyses show that similar and adequate drug exposure is achievable with metronidazole doses of 500 mg every 8 hours, 1000 mg daily, or 1500 mg daily.^19,²¹ Therefore, from a convenience and cost standpoint, once-daily doses of metronidazole may be adequate when the organism minimum inhibitory concentration (MIC) is less than 2 mg/L.^19,²¹ Knowledge of pharmacodynamic parameters and utilization of such parameters to appropriately dose patients is of utmost importance in the current era of antimicrobial resistance.

Resistance

With more than 40 years of clinical use, worldwide resistance of anaerobes to metronidazole is estimated to be less than 5%.²² A recent multicenter study conducted in the United States reported the first confirmed metronidazole-resistant B. fragilis isolate (MIC = 64 mg/mL) in 2002.²³ Following this report, additional data collected revealed two more isolates that were metronidazole resistant, one of which was also a B. fragilis isolate.²² This report is the first to document metronidazole resistance among Bacteroides spp. and, although negligible, still raises concern, since susceptibility testing is not typically performed on anaerobic cultures. The concern with increasing resistance is not limited to metronidazole alone but includes agents such as ampicillin/sulbactam, clindamycin, and moxifloxacin. Susceptibility of carbapenems, cefoxitin, and piperacillin/tazobactam appears stable.²²

Four genes (chromosomally borne nimB and plasmid-borne nimA, nimC, and nimD) of Bacteroides spp. are commonly associated with metronidazole resistance.^1,¹¹ The suggested mechanism of resistance mediated by these genes is the conversion of the nitro group of metronidazole to an amino group, foregoing the formation of the toxic nitroradicals.¹¹ Evidence of gene transfer has also been found within different Bacteroides spp. and between Bacteroides and Prevotella.¹¹

Diniz and associates exposed B. fragilis group species to 4 mg/L of metronidazole and found that exposure to low levels of metronidazole increased both the virulence and the viability of the isolates.⁶ Another factor to consider is the supposed protective effect of Enterococcus faecalis on B. fragilis when exposed to metronidazole.²⁴ The investigators found that E. faecalis was able to negate the bactericidal effect of metronidazole on B. fragilis. However, a more recent study could not confirm these findings.²⁵

Using a resistance breakpoint of 32 mg/L or higher for metronidazole, Peláez and coworkers, when studying 415 C. difficile isolates, found that 6.3% of the isolates were resistant.²⁶ Another study evaluated the susceptibility patterns of 186 C. difficile isolates from a geriatric population.⁷ Contrary to the findings of Peláez and associates, no resistance to metronidazole was documented.

Susceptibility testing of anaerobes is usually either not performed or not used to make clinical decisions because of several limiting factors: the slow growth of anaerobes, convolution of the testing method, questions surrounding the appropriate testing media, involvement of multiple organisms in anaerobic infections, and the generally held belief that susceptibility patterns of anaerobes have not changed over the years and remain forseeable.²⁷ Studies have proven the value and importance of susceptibility testing, showing that appropriate initial therapy is critical to a positive patient outcome²⁸ and that in vitro susceptibility results reliably predict the clinical outcome of patients.²⁷ Therefore, clinicians must realize that susceptibility testing of anaerobes is necessary and that the susceptibility patterns have changed over the years.

Other Agents Effective Against Obligate Anaerobes

Several classes of antimicrobials, including some broad-spectrum penicillins, clindamycin, carbapenems, β-lactam/β-lactamase inhibitor combinations, certain cephalosporins, certain quinolones, and glycylcyclines, exhibit activity versus certain anaerobic bacteria.¹¹ Metronidazole, carbapenems, and piperacillin/tazobactam have proven to be the most reliable agents, whereas clindamycin, moxifloxacin, piperacillin alone, and cephalosporins such as cefotetan and cefoxitin have exhibited significantly decreased susceptibility rates.^5,^11,²² In vitro studies of select compounds (Tables 125-2 and 125-3) from the representative class of antibacterials with anaerobic activity showed better than 15% resistance to B. fragilis group in the United States as well as in other parts of the world.¹¹ The species that are worrisome include Bacteroides ovatus versus carbapenems, Bacteroides vulgatus versus piperacillin/tazobactam, Bacteroides distasonis versus ampicillin/sulbactam and cefoxitin, and Bacteroides ovatus, Bacteroides uniformis, and Bacteroides vulgatus versus moxifloxacin and clindamycin.²² The newest glycylcycline, tigecycline, has extensive activity against anaerobes, with resistance rates that compare to those of the β-lactam class.²⁹ The clinical utility of these agents for intraabdominal infections is extensively reviewed in the intraabdominal guidelines by the Infectious Diseases Society of America (IDSA) and the Surgical Infection Society.³⁰ β-Lactams such as piperacillin/tazobactam and carbapenem monotherapy are reserved for complicated cases of intraabdominal infection, whereas metronidazole is the anaerobic agent of choice for combination therapy with agents devoid of clinically significant anaerobic activity.³⁰

TABLE 125-2 Antibacterial Activity of Various Antibiotic Agents Against Several Anaerobes

Anaerobe and Antimicrobial Agent (No. of Isolates Tested)	MIC90 (mg/L)	% Susceptible
*Prevotella spp.*^a^,^b
Penicillin G (65)	16	17
Piperacillin/tazobactam (65)	≤0.06	100
Ampicillin/sulbactam (65)	4	100
Cefoxitin (65)	4	100
Doripenem (35)	0.5	100
Ertapenem (35)	0.25	100
Imipenem (65)	0.06	100
Meropenem (65)	0.12	100
Ciprofloxacin (65)	16	35
Clindamycin (65)	4	89.2
*Fusobacterium spp.*^a^,^b
Penicillin G (22)	0.5	91
Piperacillin/tazobactam (22)	0.12	100
Ampicillin/sulbactam (22)	0.25	100
Cefoxitin (22)	0.5	100
Doripenem (15)	1	100
Ertapenem (15)	1	93
Imipenem (15)	0.12	100
Meropenem (15)	0.5	95
Ciprofloxacin (22)	2	96
Clindamycin (22)	0.12	91
*Porphyromonas spp.*^a^,^b
Penicillin G (19)	4	79
Piperacillin/tazobactam (19)	1	100
Ampicillin/sulbactam (19)	1	100
Cefoxitin (19)	4	95
Doripenem (20)	0.5	100
Ertapenem (20)	0.5	95
Imipenem (20)	0.12	100
Meropenem (20)	0. 5	95
Ciprofloxacin (19)	4	90
Clindamycin (19)	8	90
*Peptostreptococcus*^a^,^c
Penicillin G (49)	0.5	94
Piperacillin/tazobactam (10)	0.5	100
Ampicillin/sulbactam (10)	2	100
Cefoxitin (10)	1	100
Doripenem (10)	0.125	100
Ertapenem (10)	0.125	100
Imipenem (10)	0.25	100
Meropenem (10)	0.125	100
Moxifloxacin (10)	32	60
Clindamycin (10)	32	80

MIC90, minimum inhibitory concentration that inhibits 90% of organisms.

Adapted and modified from ^aAldridge KE, Ashcraft D, Cambre K et al. Multicenter survey of the changing in vitro antimicrobial susceptibilities of clinical isolates of Bacteroides fragilis group, Prevotella, Fusobacterium, Porphyromonas, and Peptostreptococcus species. Antimicrob Agents Chemother 2001;45:1238-43; and from ^bWexler HM, Engel AE, Glass D, Li C. In vitro activities of doripenem and comparator agents against 364 anaerobic clinical isolates. Antimicrob Agents Chemother 2005;49:4413-7; and from ^cSnydman DR, Jacobus NV, McDermott LA. In vitro activities of doripenem, a new broad-spectrum carbapenem, against recently collected clinical anaerobic isolates, with emphasis on the Bacteroides fragilis group. Antimicrob Agents Chemother 2008;52:4492-6.

TABLE 125-3 Antibacterial Activity of Various Antibiotic Agents Against B. fragilis Group Isolates

Antibiotic Agent (No. of Isolates Tested)	MIC90 (mg/L)	% Susceptible^a
Penicillin G (160)^a	128	0
Piperacillin (384)^a	128	77
Ticarcillin (137)^a	128	63
Piperacillin/tazobactam (142)^a	8	99.3
Ticarcillin/clavulanate (191)^a	8	96
Ampicillin/sulbactam (382)^a	8	93
Cefoxitin (515)^a	32	84
Cefotetan (473)^a	64	64
Imipenem (378)^a	1	99.5
Meropenem (127)^a	0.5	98
Ertapenem (92)^a	2	94
Doripenem (1351)^b	0.5	98.7
Clindamycin (1351)^b	>128	64
Moxifloxacin (1351)^b	32	59.2
Tigecycline (1351)^b	8	95.3

MIC90, minimum inhibitory concentration that inhibits 90% of organisms.

^a Isolates categorized according to CLSI breakpoints. Nonsusceptible isolates include both intermediate and resistant isolates.

Adapted and modified from Alridge KE, Ashcraft D, O’Brien M et al. Bacteremia due to Bacteroides fragilis group: distribution of species, β-lactamase production, and antimicrobial susceptibility patterns. Antimicrob Agents Chemother 2003;47:148-53; and from ^bSnydman DR, Jacobus NV, McDermott LA et al. Lessons learned from the anaerobe survey: historical perspective and review of the most recent data (2005-2007). Clin Infect Dis 2010;50:S26-33.

Beta-Lactam Antibiotics

Some β-lactam antibiotics, including some broad-spectrum penicillins (piperacillin, ticarcillin), β-lactam/β-lactamase inhibitors (piperacillin/tazobactam, ticarcillin/clavulanate, ampicillin/sulbactam, amoxicillin/clavulanate), certain cephalosporins (e.g., cefoxitin, cefotetan), and carbapenems (imipenem, meropenem, ertapenem, doripenem), possess activity versus various anaerobic bacteria.^5,^11,²² Because β-lactams are generally regarded as concentration-independent or time-dependent antibiotics, the free drug concentration must remain above the MIC (%fT>MIC) for a certain proportion of the dosing interval. Although several investigators have demonstrated antibacterial activity of β-lactams with percent time free drug fraction is above MIC being as little as 40% of the dosing interval,¹⁸ the pharmacodynamic characteristics of β-lactam antibiotics against anaerobic bacteria have not been well characterized. However, owing to the existing knowledge of β-lactam pharmacodynamics, once-daily regimens are unlikely to be effective. However, when comparing the β-lactams, some agents do have more convenient regimens than others because of differences in their pharmacokinetics (e.g., ertapenem 1000 mg q 24 h versus cefoxitin 1000 mg q 6 to 8 h).

Several β-lactam antibiotics have circumvented much of the resistance among anaerobes, maintaining relatively high susceptibility rates. Aldridge and associates showed that the susceptibility of Prevotella spp., Fusobacterium spp., Porphyromonas spp., and Peptostreptococcus was the highest and the most consistent for piperacillin-tazobactam, imipenem, and meropenem (see Table 125-2).³¹ In vitro data for doripenem, the newest addition to the carbapenem class, show that its activity mirrors that of meropenem in terms of gram-negative activity, and that of imipenem with respect to gram-positive activity (see Tables 125-2 and 125-3).³²

Resistance of B. fragilis group isolates to β-lactams can be caused by β-lactamase production, alteration in penicillin-binding proteins, changes in outer membrane permeability, and efflux.¹¹ Aldridge and associates found the order of activity of cephalosporins-cephamycins against B. fragilis group species to be cefoxitin > ceftizoxime > cefotetan = cefotaxime = cefmetazole > ceftriaxone, whereas no isolates were susceptible to penicillin G.⁵ Piperacillin and ticarcillin alone exhibited 77% and 63% susceptibility, respectively, whereas piperacillin-tazobactam and ticarcillin-clavulanate showed 99.3% and 96% susceptibility, respectively. Ampicillin-sulbactam, another β-lactam/β-lactamase inhibitor combination, exhibited 93% susceptibility. All carbapenems had favorable activity (see Table 125-3).^5,³² In the study by Snydman et al., a resistance rate of 1.5% was documented for doripenem versus B. fragilis, but no resistance was documented for other Bacteroides spp. or gram-positive anaerobes, including Clostridium spp.³² These rates were not significantly different compared to the other carbapenem agents. In general, the carbapenem agents maintained excellent activity against the tested clinical anaerobes. In the same study, the susceptibility pattern to piperacillin/tazobactam remained stable, with resistance rates similar to those of carbapenems (0.9%-2.3%); however, this was not the case for ampicillin/sulbactam, which showed an increasing resistance trend, particularly to B. distasonis at 20.6%.²²

Clindamycin

Clindamycin has been used in clinical practice for many years and exhibits concentration-independent activity against anaerobes. In the first study to establish this pharmacodynamic property, clindamycin was evaluated against B. fragilis in an in vitro model.³ The findings of the study of concentration-independent activity would suggest an alternate dosing regimen than what is currently utilized in practice. Standard dosing for clindamycin ranges from 600 mg every 6 to 8 hours to 900 mg every 8 hours to 1200 mg every 12 hours, but the findings of Klepser and colleagues imply that doses of 300 mg every 8 to 12 hours may be more appropriate. The investigators further confirmed the effectiveness of this dosing regimen (300 mg q 8 to 12 h) against B. fragilis by obtaining serum inhibitory and bactericidal titers (SIT, SBT) from the sera of 12 healthy volunteers.³³ The advantages of using a lower total dose include less drug exposure and decreased likelihood of adverse events.

The main concerns with clindamycin are resistance, which based on many reports ranges from 14.3% to 66.7%, and resultant superinfection with C. difficile.^7,²² The resistance pattern also appears to increase with time. Serial national susceptibility surveys of B. fragilis group initiated in the early 1980s provide a good framework for such trends.^22,²³ At study inception, Bacteroides spp. had only around 6% resistance rate to clindamycin. By 2004, the resistance rate had increased to 31.6%, and the most recent data for time period 2005-2007 shows a resistance rate as high as 49.2%. Resistance to clindamycin is isolate specific, and the isolates with highest resistance rates are B. ovatus, B. vulgatus, B. uniformis, and B. thetaiotaomicron at 45.5%, 42.6%, 49.2%, and 39.8%, respectively. Of note, these isolates were among the most frequent clinical isolates (order of frequency: B. fragilis [48%] > B. thetaiotaomicron [19.3%] > B. ovatus [10.3%] > B. vulgatus [6%] > B. uniformis [4.4%]), highlighting the need for specific pathogen identification and susceptibility testing. Drummond and coworkers examined the susceptibility of 186 C. difficile isolates to clindamycin and found that 66.7% of the isolates were resistant and 24.7% were intermediate.⁷ Interestingly, Alridge and associates showed that clindamycin-intermediate or clindamycin-resistant isolates are more likely to have decreased susceptibility to other agents.⁵ Representative antimicrobial agents tested in the study that are presented in Table 125-3 exhibited further decreased susceptibilities when tested against isolates with decreased clindamycin susceptibility. Metronidazole was the only agent tested that did not show decreased susceptibility when exposed to these isolates.

Fluoroquinolones

The utility of fluoroquinolones for the treatment of mixed aerobic and anaerobic infections is limited by increasing resistance in the Bacteroides group and their impact on CDI.³⁴ The first agent in this class to receive approval for treatment of anaerobic infections was trovafloxacin, which has since been withdrawn from the market. Levofloxacin and ciprofloxacin do not have clinically significant activity against anaerobes.³⁴ The one fluoroquinolone currently in the market with in vitro potency similar to that of trovafloxacin against a broad spectrum of anaerobic bacteria is moxifloxacin.³⁴ Limited data exist regarding the pharmacodynamics of fluoroquinolones against anaerobic bacteria. Peterson and colleagues conducted a study to explore whether the AUC/MIC ratio was predictive of quinolone activity versus B. fragilis.³⁵ Interestingly, the investigators found that the quinolones demonstrated concentration-independent activity versus B. fragilis, with an AUC/MIC ratio greater than or equal to 44 being predictive of activity. Furthermore, the authors suggest that the potential for the selection of resistant isolates may increase with an AUC/MIC ratio that is less than 44.

Resistance is a major concern with fluoroquinolones and gram-negative anaerobes. One study showed an increase from 0% to 12% fluoroquinolone resistance among B. fragilis isolates in just 3 years.³⁶ Data from another study demonstrated significantly increased moxifloxacin resistance (>30%) among B. fragilis group species, with the highest resistance rate among B. vulgatus at higher than 50%.²² Furthermore, the new epidemic strain of C. difficile (BI/NAP1/027) is notable for its resistance to fluoroquinolones in addition to a novel mutation (an 18 base pair deletion in its tcdC gene) and hyperproduction of toxins A and B as compared to historical strains.³⁷ The inciting event for the BI/NAP1/027 outbreak is thought to be the over-utilization of fluoroquinolones, which then selected for the fluoroquinolone-resistant BI/NAP1/027 strain.³⁷ Decreased susceptibility to fluoroquinolones (ciprofloxacin and moxifloxacin) among other anaerobic bacteria is evident from Tables 125-2 and 125-3.

Glycylcycline

The newest class of antibiotic with a broad spectrum of activity including anaerobic coverage is the glycylcycline class, with tigecycline as the representative agent.²⁹ Tigecycline was approved by the FDA in 2005 for the treatment of skin and skin structure infections and intraabdominal infections. Tigecycline has excellent activity against multidrug resistant (MDR) gram-positive and gram-negative pathogens, atypical bacteria, and anaerobes including Clostridium spp., Fusobacterium spp., Prevotella spp., Porphyromonas spp., and B. fragilis group. However, it does not have activity against Pseudomonas aeruginosa, Proteus spp., Providencia spp., or Morganella morganii owing to constitutive high expression of tigecycline-specific multidrug efflux pump systems that renders these organisms intrinsically resistant to this agent.²⁹

Pharmacokinetic and pharmacodynamic studies show that tigecycline exhibits time-dependent killing properties and prolonged post-antibiotic effects. The pharmacodynamic predictor of in vivo activity is AUC/MIC, which is 7 for anaerobes.³⁸ The FDA MIC susceptibility breakpoint for tigecycline versus anaerobes is ≤ 4 mg/L; however, typical MICs of Bacteroides spp. in in vitro studies ranged from 1 to 8 mg/L. Tigecycline is widely distributed in tissues, achieving only minimal peak serum concentration. Depending on the site of infection, the high tissue binding of tigecycline may be advantageous.^11,³⁸ Conversely, if the infection is endovascular, the concentration of tigecycline in the serum (∼1 mg/L) is likely at or below the MIC of the infecting organism, which will impede the effectiveness of the drug.

Several in vitro studies have evaluated the activity of tigecycline versus anaerobic pathogens, specifically the Bacteroides spp.^11,^22,^23,³⁹ In the survey by Snydman and colleagues, tigecycline outperformed clindamycin, linezolid, and moxifloxacin among the non-β-lactam agents.^22,²³ However, about 7.2% of the group Bacteroides “other” (B. caccae, B. eggerthii, B. merdae, and B. stercoris) was resistant to tigecycline compared to an average resistance rate of ≤ 5% for other species.²³ Tigecycline also outperformed cefoxitin and ampicillin/sulbactam but was less active than carbapenems and piperacillin/tazobactam among the β-lactam class (see Tables 125-2 and 125-3). Thus, tigecycline may have a role in the treatment of anaerobic infections, particularly when mixed infection with MDR pathogens is suspected in a patient intolerant to preferred regimens.

Investigational Agents

Several investigational agents have shown potential for the treatment of anaerobic infections. Ednie and colleagues found ranbezolid, a new oxazolidinone, to possess significant anaerobic activity.⁴⁰ Snydman and associates tested the in vitro activity of NVP-LMB415 against clinical anaerobic isolates. The compound had excellent in vitro activity against all species of B. fragilis group isolates, including B. fragilis group strains resistant to β-lactams, quinolones, or clindamycin, and exhibited lower MICs than linezolid, tigecycline, and garenoxacin against the strains tested. However, MICs for Clostridium spp. were higher than the MICs for other anaerobes.⁴¹ Additionally, DX-619; PTZ601, an intravenous carbapenem; sulopenem, an oral and intravenous carbapenem; and fidaxomicin, a novel macrolide antibiotic for CDI, have demonstrated potential for use in anaerobic infections.¹¹ Experimental treatments for CDI include tolevamer (a toxin-binding polymer); two poorly orally absorbed antimicrobials, CB-183,315 and ramoplanin; monoclonal antibodies; and a C. difficile vaccine.⁴² Preliminary data with tolevamer does not show it to be significantly better than metronidazole or oral vancomycin for the treatment of CDI. Nitazoxanide and rifaximin have been used successfully for the treatment of CDI.⁴³^–⁴⁶ However, according to the CDI treatment guidelines, nitazoxanide should be reserved as alternative therapy, and caution is recommended with use of rifaximin due to emergence of resistance in clinical studies.¹² Tigecycline has been used anecdotally in combination with metronidazole for CDI treatment.^47,⁴⁸ However, the role of tigecycline in the treatment of CDI is still a matter for debate and was not recognized in the CDI treatment guidelines.¹²