The introduction of antibiotics has become a lifesaving breakthrough in the world but due to the emergence of antibiotic resistance, several diseases have become difficult to treat. This study was conducted to assess the concurrent use of clindamycin and metronidazole in Tamale Teaching Hospital (TTH) to help reduce the incidence of resistance.  A review of medical records of all in-patients in the hospital was prospectively conducted between March and September 2019. A total of 25 participants given clindamycin and metronidazole concurrently for the treatment of infections consented and were recruited for the study. Data obtained was analyzed using the IBM SPSS version 26 and compared to clinical practice guidelines. The accident and emergency department recorded the highest incidence of 44% followed by the surgery department with 24% in concurrent use of clindamycin and metronidazole. The highest indication for the double anaerobic coverage was cellulitis (32%) followed by wet gangrene (12%). In 52% of patients, other classes of antibiotics were added with the most common being cephalosporins (84.6%). Overall, 80% of the prescriptions for double anaerobic coverage were by medical house officers. About 84% of the double anaerobic coverage was empiric. Symptoms of 72% of the patients resolved while on clindamycin and metronidazole concurrently. The study showed a common practice of concurrent usage of clindamycin and metronidazole which in most cases was empiric and not supported by susceptibility testing and guideline recommendations. There is, therefore, the need to review the concurrent use of metronidazole and clindamycin in line with guideline recommendations to ensure the rational use of antibiotics and the establishment of an antimicrobial stewardship programme at the TTH.

KEYWORDS

Anaerobes, antibiotic resistance, antibiotic stewardship, clindamycin, metronidazole

Africa including Ghana is under the immense burden of infectious diseases. This not only hinders the achievement of health goals of its populace and in but also affects human development (WHO, 2006). This is a result of antibiotic resistance which has made once-effective agents unable to treat common infections (Peters, 2007; Hutchings et al., 2019).

Antibiotics are agents that exert bactericidal or bacteriostatic activity against a range of Gram-positive and Gram-negative microbes, which may be aerobic, anaerobic, or atypical. Clindamycin and metronidazole are agents useful in the treatment of anaerobic infections like aspiration pneumonia, gynecologic infections, intra-abdominal infections, and diabetic foot ulcers (Njoku, 2010; Hutchings et al., 2019).

Clindamycin, a lincosamide, is a broad-spectrum antibiotic but emerging resistance has become a problem in some clinical settings (Dalhoff, 2021). It can also be used to treat some protozoal diseases, such as malaria in combination with quinine. It is a common topical treatment for acne and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. Clindamycin also has a role in the prophylaxis of endocarditis in penicillin-allergic patients and has been used in babesiosis, toxoplasmosis, and pneumocystis pneumonia (Sweetman, 2014). The most severe common adverse effect of clindamycin is Clostridium difficile-associated pseudomembranous colitis. Although this side-effect occurs with almost all antibiotics, it is classically linked to clindamycin use (Dalhoff, 2021). 

Metronidazole, a 5-nitroimidazole, is used in the treatment and prophylaxis of infections involving gram-negative anaerobes (Sweetman, 2014). Specific bacterial infections treated with metro­nidazole include acute necrotizing ulcerative gingivitis, bacterial vaginosis, pelvic inflammatory disease, nongonococcal urethritis, tetanus, and antibiotic-associated colitis (Kasten, 1999; Hutchings et al., 2019). Additionally, metronidazole is often the drug of choice in treating infections in which Bacteriodes fragilis is a serious concern. Metronidazole is also used in the treatment of susceptible protozoal infections such as amoebiasis, balantidiasis, Blastocystis hominis infections, giardiasis, and trichomoniasis (Sweetman, 2014; Dione et al., 2015).

With few exceptions like tuberculosis, enterococcal endocarditis, intra-abdominal abscess, necrotizing fasciitis, and Clostridium difficile infection, the concurrent use of antimicrobials with the same spectrum of activity provides no extra benefits but only puts patients at risk of adverse drug effects, development of drug resistance, and ultimately financial burden (Kasten, 1999; Bolger et al., 2021).

Ideally, samples from the suspected area of infection suspected should be cultured to identify the causative organism and potential antibiotic susceptibilities before beginning antibiotic therapy (Ebimieowei and Ibemologi, 2016). The benefits of antibiotic therapy, when indicated, are enormous, but the continued use of antibiotics without any clinical evidence or microbiological justification is dangerous and could lead to adverse events and the development of antimicrobial resistance. This trend should be of concern because antimicrobial resistance is putting the gains of Sustainable Development Goal 3 (Good Health and Well-being) at risk (WHO, 2006).

Combination antibiotic therapy is often overused in clinical practice (Katzung et al., 2012) except in conditions with large bacterial loads and to limit the development of resistant strains (e.g. tuberculosis or enterococcal endocarditis) (Bolger et al., 2021). The essence of combination therapy is to achieve synergism with initial empirical coverage, especially in severely ill patients, where broad-spectrum coverage is needed for bacteriostatic or bactericidal activity (Tepekule et al., 2017). Monotherapy is mostly adequate once antibiotic susceptibilities are established (Chamot et al., 2003).

Double anaerobic coverage entails the use of any combination of antibiotics such as clindamycin, metronidazole, amoxicillin/clavulanic acid, ampicillin/sulbactam, meropenem, piperacillin/tazobactam, cefoxitin, ertapenem, moxifloxacin, tigecycline among others. (Njoku, 2010). Though useful in Clostridium difficile infection and necrotizing fasciitis (Njoku, 2010), available susceptibility and clinical data do not support the concurrent use of clindamycin and metronidazole, which is prevalent at TTH (Njoku, 2010).

There was therefore a need to study the rationale behind the concurrent use of clindamycin and metronidazole at TTH since the practice was routinely observed in the hospital. It is worth noting that no such study has been done to assess this practice in Ghana. This study examined the concurrent use of clindamycin and metronidazole in clinical practice at TTH.

Study site

The study was conducted at TTH in the Northern Region of Ghana. It is a tertiary health facility with an 812-bed capacity, which receives referral cases from health facilities in the five regions of northern Ghana. The study was conducted in all in-patient wards in the hospital.

Study design

A review of patients' records with concurrent use of clindamycin and metronidazole was carried out from March to September, 2019.

Target population

Purposive sampling was used to recruit in-patients diagnosed with infection and treated with the concurrent use of clindamycin and metronidazole.

Inclusion criteria

Patients admitted, diagnosed, and treated concurrently with clindamycin and metronidazole against infectious disease at TTH were included in the study.

Exclusion criteria

Patients who refused to be included in the study and those admitted outside the study period. Medical records of admitted patients prescribed either clindamycin or metronidazole alone were also excluded.

Data collection instrument

A data collection tool was used to extract data on the patient's demographics, diagnosis, type of antibiotics prescribed, treatment outcomes, culture, and sensitivity requests, together with the prescriber’s expertise.

Data analysis

The data was analysed using IBM SPSS version 26. Data was presented with descriptive statistics.

Ethical consideration

The study was approved by the Research and Development Unit (TTH/R&D/SR/19/58) of TTH. Informed consent was sought from the participants after explaining to them the purpose of the study.

Demographics of participants

Twenty-five (25) respondents were considered for the study, with an average age of 44.7 years and an average length of stay of 21.1 days. Most of the respondents were housewives (20%, n=5) followed by farmers (16%, n=4) and teachers (16%, n=4). About 60% (n=15) of the respondents were females and 40% (n=10) males. Most of the respondents came from the A&E Department (44%, n=11), followed by Surgery Department (24%, n=6), whilst Internal Medicine and O&G Departments had the same number of respondents (16%, n=4) (Table 1).

Table 1: Descriptive statistics of participants

* SD= standard deviation

Diagnoses                                                                                                            

Cellulitis (32%, n=8) was the most common medical condition treated concurrently with clindamycin and metronidazole followed by wet gangrene (12%, n=3) (Table 2).

Table 2: Diagnoses

Antibiotics Added to Clindamycin and Metronidazole

About 52% (n=13) of the patients were given additional antibiotics which included amoxicillin/clavulanic acid injection and tablet, cefotaxime injection, ceftriaxone + sulbactam injection, cefuroxime injection and tablet, doxycycline capsule, and gentamicin injection. The remaining 48% (n=12) of patients were not given additional antibiotics.

Table 3: Antibiotics added to clindamycin and metronidazole

Prescriber expertise

Of the 25 respondents, 80% (n=20) of the respondents had their prescriptions written by House Officers, 12% (n=3) by Medical Officers, and 8% (n=2) by Specialist Consultants.

Table 4: Prescriber expertise

Culture and sensitivity request

Most (84%, n=21) respondents did not have a culture and sensitivity test requested. No reason was given for not requesting. Only 16% (n=4) of the respondents had culture and sensitivity testing requests. One of the tests was not done due to financial constraint on the part of the patient. The isolates from 3 of those requests were Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus (Table 5).

Table 5: Culture and sensitivity findings

Symptoms Resolution

About 72% (n=18) of the respondents had a resolution in their presenting symptoms but this was not the case in 24% (n=6) of the respondents.

Table 6: Symptoms Resolution

With the exception of infections such as necrotizing fasciitis (where an anti-toxin effect is needed) and Clostridium difficile infections where double anaerobic coverage may be needed, the use of multiple drugs against anaerobes has no additional benefit and puts patients at risk of drug toxicities (Njoku, 2010). The study showed that cellulitis (32%) accounted for the majority of the double anaerobic coverage with clindamycin and metronidazole at TTH even though the condition does not require double anaerobic coverage. Similarly, all the conditions in this study did not warrant double anaerobic coverage per treatment guidelines (Sciarra et al., 2018). Empiric treatment of the conditions required the use of either metronidazole or clindamycin for anaerobic coverage and not concurrently (Njoku, 2010). In the case of intra-abdominal abscess, metronidazole is the anaerobic agent of choice per (Sciarra et al., 2018). Also, in pelvic inflammatory disease (PID), double anaerobic coverage is not indicated as no evidence exists to show better clinical or microbiological cure rates per Centres for Disease Control and Prevention guidelines (CDC, 2019). Treatment of PID usually targets pathogens like Neisseria gonorrhoeae and Chlamydia trachomatis, though the anaerobes may be associated with the disease, especially when tubo-ovarian abscess is present. The double anaerobic coverage using clindamycin and metronidazole was, therefore, inconsistent with the optimal use of antimicrobial agents (WHO, 2017; CDC, 2019). 

Empirical anaerobic coverage is key in certain infections and where Bacteroides fragilis are implicated, either clindamycin or metronidazole may be considered but not double anaerobic coverage. A single anaerobic agent may be added to antibiotics such as cephalosporins, penicillins, fluoroquinolones and tetracyclines when a broad-spectrum coverage is indicated (Njoku, 2010; Standard Treatment Guidelines, 2017; British National Formulary, 2022). In this study, cephalosporins (i.e. cefuroxime, ceftriaxone, cefotaxime) were predominantly added for empiric therapy and this could be due to their wider spectrum of activity, accessibility, relatively cheaper cost and effectiveness when compared to other antibiotic classes (Ebimieowei and Ibemologi, 2016; Pwint, 2017). In instances where penicillin/β-lactamase-inhibitor combinations (amoxicillin/clavulanic acid or piperacillin/tazobactam), tigecycline, carbapenems (meropenem, imipenem or ertapenem) are prescribed, the addition of metronidazole and/or clindamycin is not necessary since all these agents have anaerobic coverage (Njoku, 2010, Sweetman, 2014).

With only 12% (n=3) of the patients who had culture and susceptibility testing done, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were isolated and their susceptibilities done. Their antibiotic therapies were subsequently de-escalated from double anaerobic coverage to a single susceptible antibiotic, emphasizing the need for culture and susceptibility testing in the use of antibiotics. Clinicians must be trained on the value of performing cultures to guide treatment.

It was found that most of the prescriptions for concurrent clindamycin and metronidazole use were made by medical house officers (80%) who are considered to be under training. The lack of adequate exposure to, and training on, appropriate antimicrobial prescribing and the absence of an antimicrobial prescribing and use policy in TTH may be responsible for the double anaerobic coverage. This is particularly relevant in the choice of empirical antimicrobial agents. This practice can be reduced drastically by developing an antimicrobial prescribing and use policy for clinicians on antimicrobial selection in terms of their coverage and also making guidelines readily available to help reduce the burden of antimicrobial resistance. Also, clinicians must be trained on the value of performing cultures to guide treatment (Amponsah et al., 2021). 

Due to its ability to penetrate tissues, clindamycin is preferred over metronidazole in the treatment of gangrene, cellulitis, and foot ulcers (Njoku, 2010; Sweetman, 2014). Clindamycin has also been noted for its Gram-positive antibacterial activity making it the agent of choice for monotherapy in instances where both gram-positive and anaerobic organisms are suspected or implicated (Dalhoff, 2021). Physicians in TTH claim that, since clindamycin use may result in Clostridium difficile-associated pseudomembranous colitis, there was the need to add metronidazole to prevent it. Clindamycin may cause pseudomembranous colitis in about 20% of patients usually with a duration of use between 5-10 days (Hogenauuer, 1998). Irrational use of metronidazole has also been noted to cause the elimination of gut anaerobes leading to the growth of nosocomial pathogens such as vancomycin-resistant Enterococcus infections (Edmond, 1995; Donskey, 2000). The Ghana Standard Treatment Guidelines and the British National Formulary do not recommend dual anaerobic coverage unless unavoidable (Standard Treatment Guidelines, 2017; British National Formulary, 2022). When there is a need for anaerobic coverage, a single agent is adequate for such purpose using any of the following: clindamycin, metronidazole, amoxicillin/clavulanic acid, ampicillin/sulbactam, meropenem, piperacillin/tazobactam, cefoxitin, ertapenem, moxifloxacin and tigecycline, among others (Njoku, 2010).

A patient’s care was compromised due to financial constraints in accessing microbiological investigations. It is therefore appropriate for health insurance to cover culture investigations as suggested by Amponsah et al. (2021). 

Majority (84%) of the prescriptions with double anaerobic coverage, were not based on culture and sensitivity testing findings. Requesting and conducting this test could have helped identify the pathogens and their susceptibility to the available antimicrobial agents. This could have reduced the number of antimicrobial agents used by patients, improve adherence, reduce the cost of therapy, and also improve antimicrobial stewardship (Ijeoma et al., 2020).  However, TTH and almost all laboratories in Ghana lack of capacity for anaerobic culture (Opintan et al., 2015).

It is worth noting that no bacteriological screening was done to confirm bacteriological elimination following symptom resolution in all 25 patients even though 72% of the patients had symptoms resolved after the double anaerobic coverage. Since symptom resolution does not always imply bacteriological elimination, laboratory confirmation of bacteriological status should be part of the monitoring parameters with antibiotic therapy.

The use of clindamycin and metronidazole concurrently should be reviewed since no susceptibility testing and clinical guidelines support this practice. An antimicrobial stewardship programme should therefore be established to oversee the development of antimicrobial prescribing and use policy and the training of all clinicians on its use as well as its implementation at the TTH. In addition, treatment guidelines on antimicrobial usage for empirical treatment and surgical prophylaxis should be established to standardize antimicrobial use and optimize therapeutic benefits.

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We are grateful to Tamale Teaching Hospital's Research and Development Unit for approving of using data from the facility.