Clinical efficacy of 12-h metronidazole dosing regimens in patients with anaerobic or mixed anaerobic infections

Abstract

Traditional metronidazole dosing regimens utilize an every 8 h dosing strategy to treat anaerobic and mixed anaerobic infections. However, pharmacokinetic data demonstrate that the half-life of metronidazole is 8–12 h and blood levels at 12 h exceed the in vitro minimum inhibitory concentration (MIC) for most anaerobic infections. The primary objective of this study was to evaluate the frequency of clinical cure among patients who received metronidazole every 12 h compared with those who received an every 8 h frequency. Secondary endpoints included duration of antibiotics, hospital length of stay, escalation of antibiotic therapy, microbiologic cure, and mortality.

Methods:

This retrospective, single-center, pre–post intervention study of 200 patients between June 2014 to July 2016.

Results:

No significant differences in clinical cure for every 12 h versus every 8 h metronidazole dosing regimens (85% for both groups, p = 1.00) were found. There were no differences in any of the secondary endpoints, with a mean duration of antibiotic therapy being 5.9 versus 5.8 days and a hospital length of stay averaging 8.1 versus 6.7 days for the 12- and 8-h dosing groups, respectively (p > 0.05).

Discussion:

Findings validate pharmacokinetic data suggesting that an extended metronidazole dosing interval effectively treats anaerobic infections.

Introduction

For over 50 years, metronidazole has been successfully used in practice, and is still considered the drug of choice, for treating many anaerobic infections.¹ Anaerobic bacteria are considered normal human flora in the oral and intestinal spaces but are frequently implicated as causative pathogens when infection occurs at these sites. Obligate anaerobes are often difficult to isolate on solid culture media, making their identification as a pathogen less common in mixed aerobic–anaerobic infections. Infections of the oral and intestinal spaces are often polymicrobial in nature, and as a result, consensus guidelines recommend anaerobic coverage even when anaerobes are not explicitly identified on culture.^2–4 In patients with suspected anaerobic and mixed anaerobic infections, metronidazole is often utilized to empirically treat these pathogens, as it is highly active against gram-negative and gram-positive anaerobic bacteria, has favorable pharmacokinetic and pharmacodynamic properties, is available in both intravenous and oral formulations, and is generally well tolerated.¹

The potent anaerobic activity of metronidazole is associated with its complex metabolism but remains not fully understood. Metronidazole is a prodrug which is activated after bacterial uptake and reduction. It is unclear whether the reduced imidazole or any of the several metabolic products are ultimately responsible for metronidazole’s antibacterial activity. The precise mechanism of toxicity is also debated but is thought to be related to bacterial DNA breakage resulting from nonspecific binding. Similarly, the mechanisms of resistance to metronidazole are unclear but may be associated with changes in reduction potential that eliminate activation of the drug, the ability to repair damaged DNA, drug efflux, or presence of genes that encode reductases that result in inactivation.^1,5 Nevertheless, metronidazole resistance remains uncommon among most anaerobic bacteria.⁶

Metronidazole is commonly administered on an every 8-h dosing frequency. However, pharmacokinetic data demonstrate that the half-life of metronidazole is 8–12 h and blood levels at 12 h exceed the in vitro MIC for most anaerobic organisms, including Bacteroides fragilis, other Bacteroides spp., fusobacterium, and non-difficile Clostridia spp.^7–9 These data provide preliminary evidence to support administration of metronidazole every 12 h. Despite existing pharmacokinetic evidence to support every 12-h dosing, the literature evaluating clinical outcomes with this dosing strategy is limited. A previous study conducted in 1990 by Bunz and colleagues found that the use of an every 12-h metronidazole dosing regimen for both prophylaxis and treatment resulted in no change in postoperative infection rate or death compared with every 8-h dosing. Furthermore, implementation of an every 12-h dosing regimen resulted in a significant drug cost reduction of approximately $28,000 per year.¹⁰ This study is among the few that have been published regarding a longer metronidazole dosing interval, but is limited due to the fact that >50% of patients included were using metronidazole for surgical prophylaxis rather than treatment of infection. Therefore, there is a need to further evaluate clinical outcomes for treatment of infection when dosing metronidazole less frequently.

The primary objective of this study was to evaluate the frequency of clinical cure among patients receiving metronidazole every 12 h compared with those who received an every 8 h frequency. Secondary endpoints included duration of antibiotics, hospital length of stay, escalation of antibiotic therapy, microbiologic cure, and mortality.

Methods

The Novant Health Institutional Review Board approved this pre- and postintervention retrospective chart review as an expedited review provisioning full waiver of the need for informed consent (Protocol ID 16-552). The study was conducted at Novant Health Presbyterian Medical Center, a 531-bed, tertiary care community hospital between June 2014 and July 2016. The preintervention time period observed in this study occurred from June 2014 to June 2015, during which time all patients received metronidazole using the traditional 8-h dosing frequency. In July 2015, a 12-h metronidazole dosing program was implemented and the postintervention period occurred from July 2015 to July 2016. During this time, an every 12-h dosing was utilized for all indications with the exception of C. difficile, central nervous system (CNS), or parasitic/amoebic infections, which are more difficult to treat and require higher concentrations of metronidazole. All data were collected retrospectively.

Patient selection

Patients were identified for inclusion using a report of all patients treated with metronidazole generated using the hospital’s electronic medical-record system. Patients eligible for inclusion were those greater than or equal to 18 years of age who received metronidazole for at least 3 days for a presumed anaerobic or mixed anaerobic infection. Patients with C. difficile infection, CNS infection, parasitic/amoebic infection, use of metronidazole for surgical prophylaxis, receipt of antibiotics with anaerobic coverage for greater than 24 h prior to the initiation of metronidazole, use of a concurrent medication with anaerobic coverage, those with an organism not susceptible to initial antibiotic selection, or pregnancy were excluded from the study. Informed consent was not obtained due to the retrospective nature of this study.

Definitions

Clinical cure was defined as improvement or resolution of the principle sign/symptom of infection with normalization of white blood cells (WBCs >4000 and <12,000 cells/µl) and temperature (>96.8°F and <100.4°F) at the end of therapy or at discharge, whichever occurred first. Clinical failure was defined by the presence of any of the following parameters: no resolution of the principle sign/symptom, escalation of antibiotics, or no microbiological cure. Elevated WBC in the presence of acute steroid use, with no other clinical rationale for leukocytosis was attributed to steroid use rather than infection. Escalation of antibiotics was defined as an additional antibiotic agent added for coverage. Cultures evaluated included only those relevant to the infectious problem for the index admission. Anaerobic isolation cultures were performed by the microbiology laboratory for all appropriate specimens. Urinary cultures were excluded. Microbiologic cure was defined as the absence of culture growth in the subset of patients with repeat cultures available who grew anaerobes on initial culture. Mortality was defined as death during hospitalization.

Statistical analysis

Assuming an 80% response rate in both groups and α of 0.05, 82 patients were needed in each group in order to meet power of 0.80 and detect a 20% difference in clinical cure rates. Clinical cure and escalation of antibiotic therapy were analyzed using a Chi-square test. Duration of antibiotics and hospital length of stay were analyzed using a Student’s t-test. A p value of 0.05 was considered statistically significant. Data were analyzed using SPSS, version 24.

Results

During the study period, a total of 200 patients meeting inclusion criteria were reviewed, with 100 patients in the 8-h dosing group, and 100 patients in the 12-h dosing group. Baseline characteristics are reported in Table 1. Patients in the 8-h dosing group were significantly older than those in the every 12-h dosing group (62.5 versus 53.9 years, p = 0.002). No other significant differences in baseline characteristics were identified.

Table 1.

Baseline characteristics.

	Q8h dosing (n = 100)	Q12h dosing (n = 100)	p value
Age, mean years (±SD)	62.5 (18.7)	53.9 (19.6)	0.002
Male (%)	44	40	0.567
BMI (%)			0.804
Underweight	4	4
Normal	33	30
Overweight	28	33
Obese	29	24
Morbidly obese	6	9
ICU admission (%)	5	10	0.179
Liver dysfunction* (%)	6	9	0.421

BMI, body mass index (kg/m²); ICU, intensive care unit; SD, standard deviation.

Underweight, <18.5; normal, 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; morbidly obese, >40.

^*The metabolism of metronidazole is decreased in patients with hepatic impairment. Dose reductions of 50% may be needed for Child Pugh Class C.

Infection type, source control, concurrent antibiotic therapy, and signs/symptoms of infection are included in Table 2. Most patients in the 8-h dosing group and 12-h dosing group received metronidazole for treatment of abdominal infections (89% and 79%, respectively) and greater than 90% of patients received concurrent therapy with an additional agent without strong anaerobic activity. Source control was performed on eligible patients; however, only 26% and 31% of patients in the every 8-h and every 12-h dosing groups met clinical criteria for a source control intervention. Common reasons source control was not performed included nonsurgical candidates due to functional status or lack of drainable or accessible foci of infection.

Table 2.

Infection characteristics.

	Q8h dosing (n = 100)	Q12h dosing (n = 100)	p value
Infection type (%)			0.187
Abdominal	89	79
Skin/soft tissue	4	6
Pneumonia	0	2
Other	7	13
Source control performed (%)	26	31	0.434
Concurrent antibiotic therapy (%)	93	95	0.552
Ciprofloxacin	67	46
Ceftriaxone	17	32
Other	9	17
None	7	5
Signs of infection (%)
Abdominal pain	73	64	0.171
Elevated temperature	18	23	0.381
Elevated WBC	51	53	0.777
Radiographic confirmation	77	74	0.622

WBCs, white blood cells.

Primary and secondary outcomes are reported in Table 3. Frequency of clinical cure was the same in each group, with 83% of patients achieving cure (p = 1.00). Escalation of antibiotic therapy did not significantly differ between groups (p = 1.00). One patient in the 8-h dosing group required escalation to a carbapenem and one patient in the 12-h dosing group was switched to piperacillin/tazobactam. Duration of antibiotic therapy was 5.8 days for the 8-h dosing group and 5.9 days for the 12-h dosing group (p = 0.891). When specifically looking at metronidazole, mean duration of therapy was 4.8 versus 4.9 days for patients receiving every 8 h versus every 12 h, respectively (p = 0.827). Hospital length of stay averaged 6.7 days in the 8-h dosing group, compared with 8.1 days in the 12-h dosing group, but was not significantly different (p = 0.110). Mortality rates also did not differ significantly, with two deaths in the 8-h dosing group and three deaths in the 12-h dosing group (p = 0.651). For microbiologic cure, there was a low rate of positive anaerobic culture results (n = 2 in the 8-h group and n = 0 in the 12-h group), with no positive repeat anaerobic cultures.

Table 3.

Outcomes.

	Q8h dosing (n = 100)	Q12h dosing (n = 100)	p value
Clinical cure (%)	83	83	1.00
Escalation of antibiotic therapy (%)	1	1	1.00
Duration of all antibiotic therapy, days (±SD)	5.8 (4.0)	5.9 (4.3)	0.891
Duration of metronidazole, days (±SD)	4.8 (2.8)	4.9 (2.4)	0.827
Hospital length of stay, days (±SD)	6.7 (5.2)	8.1 (7.0)	0.110
Death (%)	2	3	0.651

SD, standard deviation.

Discussion

This large, retrospective chart review of 200 patients found no difference in clinical cure rates among patients who received metronidazole every 12 h compared with a traditional every 8-h dosing frequency. Additionally, there were no significant differences in secondary endpoints such as duration of antibiotics, hospital length of stay, escalation of antibiotic therapy, microbiologic cure, or mortality.

Among patients who failed therapy, the primary reason for failure was abnormal WBC count at the end of therapy or discharge. Notably, a higher frequency of leukopenia was seen in the every 8-h group [7/17 patients (41.2%)]. As leukopenia is a side effect of metronidazole, using a longer dosing interval does have the potential to avoid this adverse reaction, as well as others.¹¹ While the side effects that are seen with metronidazole are usually mild to moderate in severity (such as the gastrointestinal side effects that are most commonly seen), having reduced plasma concentrations does have the potential to avoid rare adverse reactions, including seizures, encephalopathy, as well as optic peripheral neuropathies.^1,12,13

Hospital length of stay was not statistically different between the two different groups (6.7 versus 8.1 days), but was 1.6 days longer among patients receiving every 12-h metronidazole dosing. This finding may be confounded by severity of illness. More patients required initial admission to the intensive care unit in the every 12-h group as compared with the 8-h dosing group suggesting that patients in the 12-h group had more severe infections and possible comorbidities upon initial presentation.

Strengths of this study include that it is the largest reported study to date using a longer metronidazole dosing interval. Additionally, this study was powered to detect a difference in clinical cure between the different dosing groups. Besides age, there were no significant differences in baseline characteristics between groups and infection types were comparable between groups. Overall failure rates found in this study were similar to those previously reported in other studies of metronidazole. Limitations of this study include the retrospective nature of the study design. In order to be included in this study, patients needed at least 3 days of therapy with metronidazole and during the screening process, many patients were excluded as they had coverage with an agent with anaerobic coverage (mainly piperacillin/tazobactam) prior to the start of metronidazole. Many patients were also not eligible for this study as they had 2 days of inpatient therapy and were subsequently discharged on oral therapy before the 72-h inclusion criterion was met. Despite attempts to isolate anaerobes from appropriate culture specimens, there were a lack of positive anaerobic culture results, making it difficult to determine whether anaerobes were true causative pathogens. However, anaerobic pathogenesis is often presumed for certain intra-abdominal and wound infections as anaerobes are difficult to isolate on culture media.

Utilization of a 12-h dosing frequency for metronidazole has been shown in previous studies to reduce drug costs and medication waste.¹⁰ While this study was unable to assess a reduction in hospital spending due to a change in contract pricing during the time period for inclusion, there is a potential for savings when using a longer dosing interval. In addition to reductions in side effect incidence, a longer dosing interval may reduce the potential for development of antimicrobial resistance. Specifically, with reduced metronidazole drug exposure, bacteria may be less likely to accrue non-nim-mediated mechanisms of resistance.^1,5

In conclusion, no differences in clinical outcomes for patients receiving every 12-h metronidazole dosing interval were identified among patients receiving metronidazole for presumed anaerobic or mixed anaerobic infections. These findings validate existing pharmacokinetic data and add to the limited clinical literature that currently exists for this dosing strategy. In addition to effectively treating infections, utilizing a 12-h dosing interval has the potential to reduce drug costs, adverse drug effects, and antibiotic resistance.