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Systematic review and meta-analysis on efficacy of cefixime for treating gonococcal infections.

Background: Neisseria gonorrhea is known to have developed a high level of resistance against different classes of antimicrobials. Patients with coagulation disorders where intramuscular injections are contraindicated, oral cefixime in combination therapy can be utilized as an alternative regimen. Cefixime in combination with another macrolide might be considered as an alternative treatment option. The aim of this systematic review is to assess the efficacy of 400 mg cefixime against a range of comparator drugs. Methodology: Extensive literature search for randomized controlled trials was performed using Medline, Cochrane Registry of Controlled Trials, Embase, and Clinical trials registers. The trials assessed the efficacy of cefixime against a range of comparator drugs. Primary outcome of the study was the clinical resolution of signs and symptoms and negative culture at the end of follow-up period. Results: After screening for a total of 1184, only 8 studies were eligible for a meta-analysis. Risk ratio random effects model was used with a 95% confidence interval (CI). The pooled efficacy of Cefixime was at 97% at 95 CI 1.01 (0.98, 1.05). No statistically significant difference was found between oral cefixime and comparator drugs. Conclusion: A total of 11 studies were included following a review of 1184 publications. 8 randomized controlled trials for 400 mg oral cefixime were included in meta-analysis. Despite a high grade of evidence, a high risk of bias was found among studies. Hence, more high quality randomized controlled trials on cefixime needs to be performed in future to guide the treatment of gonococcal infections.


Introduction
Gonorrhea is reported to be the second most commonly reported communicable disease. [1] In 2008, a survey conducted by the World Health Organization (WHO) estimated that there were around 106 million new cases of gonorrhea worldwide. Targeted microbiologic diagnosis of this infection with Neisseria gonorrhea (N.G.) should be conducted in all individuals at risk or susceptible to acquire N.G. A specific and prompt diagnosis could possibly reduce the percentage of complications, transmissions, or reinfections. Due to the specificity and sensitivity, a Gram Strain of urethral secretions that show polymorphonuclear leukocytes with intracellular Gram-negative diplococci can be considered as diagnostic for infection with N.G in symptomatic individuals. [2] The treatment of N.G is further complicated due to the tendency of N.G to develop resistance to antimicrobials. [3] The evolution of resistance to antimicrobials agents in N.G.
isolates is a global burden in the treatment toward gonococcal infections. The ability of this specific disease to resist significant levels of penicillins, tetracycline, and fluoroquinolones and oral cephalosporins [4][5][6][7] have recently escalated in far East Asia. [8] In the 1990s, it was internationally recommended to use the third generation cephalosporins. However, investigations conducted in the past have reported on the treatment failures with cefixime. Nevertheless, it is still recommended as the drug of choice for N.G infections in certain countries. [9] Hence, a regimen of parenteral cephalosporin such as ceftriaxone is generally prescribed as the first line of treatment for uncomplicated gonococcal infections. Cefixime in combination with another macrolide, such as azithromycin might be considered as an alternative oral treatment option. [2] The recommendations made by the Clinical and Laboratory Standards Institute the minimum inhibitory concentration breakpoint for oral cephalosporins cefixime and cefpodoxime susceptibility were <0.25 mg/L and 0.5 mg/L. [10]

Inclusion criteria
The following criteria were included in this study: 1. Healthy male and female patients above 15 years of age. 2. Patients with a history of exposure to infected individuals. 3. Patients who were diagnosed with a gonorrhea infection microbiologically by culture and microscopy or nucleic acid amplification test (NAAT). 4. AND 5. Patients who were diagnosed with gonococcal infection on clinical grounds 6. Patients who went through a proper procedure of informed consent, before they enrolled in the randomized the controlled trial. 7. Test of cure was performed after follow-up period, either by the culture of NAAT.

Primary outcome measures
Primary outcome measures were defined as: 1. Microbiological cure (negative culture/microscopy) at the end of the treatment and follow-up. 2. Clinical resolution of signs and symptoms such as abdominal pain, genital pain, discharge from urethra and dysuria at the end of the follow-up period.

Secondary outcome measure
Secondary outcome measures were defined as: 1. Adverse reaction related to drug intakes such as diarrhea, loose stools, abdominal pain, headaches, nausea, rashes, or pseudomembranous colitis. 2. Patients requiring further symptomatic or antimicrobial therapy.

Data collection and analysis
Two authors Syed Bilal Tanvir and Syed Saad bin Qasim independently reviewed the studies for eligibility. Study selection was based on abstracts and titles of research articles. Any conflict regarding inclusion or exclusion was mainly resolved by consensus.

Data sources, studies sections, and data extraction
A customized form was developed and tested for data extraction for the included studies. The form was derived from the template provided by the Cochrane data extraction tool. The form was customized to extract the following data from the research articles Author name. •

Data analysis
Risk ratio (RR) random effects model was used with a 95% confidence interval (CI). Cochrane Revman 5.0 software was used for this purpose. Studies were grouped according to the class of the drugs used to treat uncomplicated gonococcal infections. The pooled efficacy of cefixime was calculated against a range of comparator drugs at 95 CI 1.01). Studies were assessed for the statistically significant difference between oral cefixime and comparator drugs. Heterogeneity was also assessed among different studies.

Quality assessment of randomized and nonrandomized observational studies
A modified downs WW and black method checklist were used for this purpose. The checklist has 27 questions for assessing the quality of the studies and for the assessment of the risk of bias. Confounding, Selection bias, External validity, and reporting bias were included. The last question in the checklist was adapted from another study and assessed the power of the study.

Results
The results concluded that there was a lack of high quality of evidence on the use of oral cefixime for the treatment of both complicated and uncomplicated gonorrhea. A comprehensive literature search was done despite that only 8 RCTs were identified, where patients were treated for both complicated and uncomplicated gonorrhea treated with oral cefixime. Figure 1. Table 1 After screening for a total of 1184 studies, using different databases, 230 relevant abstracts were screened for inclusion, in the systematic review and meta-analysis. A total of 255 studies from PubMed, 28 studies from Cochrane Central Register of Controlled Trials, and 851 results were obtained for EMBASE.

Study selection and characteristics of the included studies are mentioned in
Out of the relevant 255 abstracts that were screened for eligibility, only 11 studies were included in the narrative review while only 8 studies were eligible for a meta-analysis.
Out of the 230 abstracts screened for this review, 219 abstracts were excluded from the review because of the following reasons.
• Studies where the diagnosis of uncomplicated and complicated gonorrhea, were not made microbiologically by performing, pharyngeal, rectal or urethral swab, or NAAT.

• Studies involving patients with hematological malignancies
and immunocompromised conditions such as diabetes, HIV, and other systemic diseases. • Studies where cefixime was not being assessed for its efficacy/effectiveness but after pharmacokinetic or pharmacodynamics activity. • Study where the primary outcome of the study was adverse effects of cefixime or comparator drug. • A total of 11 studies were included in this review for final narrative and qualitative review. Out of the 11 studies, 2 studies were excluded. Finally, only 8 studies were included in the meta-analysis as they were randomized controlled trials [ Figure 1].

Study selection and characteristics of the included studies
Of the 8 studies included in the review of meta-analysis, 3 studies compared the effectiveness of cefixime versus fluoroquinolone (ciprofloxacin and grepafloxacin) [11][12][13] while 5 studies compared the efficacy of cefixime versus ceftriaxone. [13][14][15][16][17] While 2 studies were noncomparative in study design, assessing the efficacy of cefixime in a patient with complicated gonorrhea; [13,18] finally, one study compared the effectiveness of cefixime versus amoxicillin and probenecid. [19] Data analysis of individual studies [ Figure 2] In trials comparing the cure rate of cefixime versus fluoroquinolone.
In trials comparing the cure rate of cefixime versus ceftriaxone • Cure rate (4 studies There was a high heterogeneity in this analysis P = 0.12 I 2 = 0%.
Trial comparing the cure rate of cefixime versus ceftriaxone: • Cure rate (1 study). The cure rate was 98% (90/97 patients in cefixime 800 mg orally) compared with 95.6% (amoxicillin and probenecid group). RR (Random effects model) 95% CI (1.01, 1.10) P = 0.48. Hence, the comparison was statistically significant. Hence, the statistically significant difference was found between the efficacy of cefixime and amoxicillin and probenecid. Test for heterogeneity was not applicable in this group.

Adverse events
Meta-analysis of adverse events was not performed in this systematic review. The major reason was improper reporting methods for adverse events or absence of data for adverse events.

Patient characteristics
1577 patients were included in this systematic review, of which 1151 patients were included in meta-analysis. The male to female ratio was 1/1.40.

Risk of bias
A modified downs and black method checklist were used to determine the risk of bias. Primarily four parameters were assessed to determine the risk of bias among studies.
Confounding, Selection bias, External validity, and reporting bias were included. The last question in the checklist was adapted from another study and assessed the power of the study. Risk of bias is expressed in the form of percentages in Table 2. Questions number 1-10 is related to reporting; number 11-13 related to external validity; 14-20 related to internal validity bias and 21-26 selection; and 27 related to the power of the study.

Summary of main findings
This systematic review found out that there is insufficient evidence data to prove or disprove the benefits of cefixime for the treatment of gonorrhea on adult patients. A total of 8 studies of single-dose oral cefixime were identified and included in the meta-analysis. The success rate of the treatment ranged from 92% to 99 %. This systematic review compared the success rate of the treatment at the end of the follow-up period between cefixime and comparator antibiotics. Previously a systematic review and metaanalysis have been conducted to determine the efficacy of intramuscular (IM) ceftriaxone. This systematic review found out ceftriaxone to have better efficacy than cefixime which had a pooled percentage cure rate of 78.1%. All of these studies mentioned in this systematic have met out inclusion criteria. [11,[13][14][15][16][17]19] Furthermore, the efficacy of cefixime was also compared with fluoroquinolones such as grepafloxacin and ciprofloxacin and found a pooled cure rate of 97.5% 95% CI 1.02 (1.00, 1.04) [12] while the pool cure rate of cefixime was found to be 99% 95% CI 1.02 (1.00, 1.04). [13,[15][16][17] This systematic review also found out the cure rate of cefixime to be at 98% 95 CI 1.01(0.97, 1.10) when compared with amoxicillin and probenecid, having a cure rate of 95% 95% CI(0.97, 1.10). [19] According to the WHO guidelines and BASHH treatment guidelines, fluoroquinolones are no longer recommended as the mainstay for treating gonococcal infections due to high amounts of resistance. [2] A single dose of 400 mg cefixime orally taken once coupled with 2 g of azithromycin is recommended as an alternative treatment option for uncomplicated gonorrhea. [7] However, in patients where IM injection are contraindicated in conditions such as hemophilia, or patients under therapy with anticoagulants, it might prove as a useful alternative to IM ceftriaxone. Furthermore, in resource poor settings where IM ceftriaxone is not available, it might prove as a useful substitute. Although a steady increase in the prevalence of high cefixime MIC suggests that in future the effectiveness of these drugs might slowly decline. Despite this fact, another oral cephalosporin such as cefuroxime and cefpodoxime cannot be recommended as an adequate substitute to cefixime

Additional information
Aplasca et al. [11] RCT 400 mg Orally single dose 500 mg ciprofloxacin orally single dose

Additional information
Ramus [17] RCT 400 mg orally single dose   1 Is the Hypothesis/aim objective of the study clearly described?
Are the main outcomes to be measured clearly described in the Introduction or Methods section?     and ceftriaxone as they possess low efficacy and inadequate pharmacodynamics. [10] Limitations Most of the studies included in this systematic review are more than a decade old. Hence, these studies cannot be conclusively relied on by the academics and clinicians for the treatment of patients. Another major limitation of the study is that the adverse effects of different drugs were either not reported or appropriate methods were not used to separately report them. There was a very high level of heterogeneity among studies as well.

Conclusion
Data collected in this systematic review suggest that cefixime might prove to be a useful option for the treatment of gonorrhea infection with a success rate of over 98%. This systematic review and meta-analysis suggest cefixime to be clinically more effective when compared with a fluoroquinolone. However, the efficacy of ceftriaxone is still superior when compared with cefixime, which is in line with the current guidelines of WHO and BASHH. Hence, more high quality randomized controlled trials for cefixime in combination with another macrolide needs to be conducted in future to guide the clinicians in treating uncomplicated gonococcal infections in patients where IM injections are contraindicated.