INTRODUCTION:

Traditionally severe infections caused by aerobic gram-negative bacilli continue to be a major cause of morbidity and mortality^1-2. The majority of current infectious diseases are almost untreatable by antibiotic monotherapy therapy given the advent of multidrug resistant bacteria; moreover, the degree of severity even though the persistence of infections are worsened when epidemiology of severe infection occur³.

Therefore, efforts are being applied to develop new drugs not as vulnerable as the current ones to treat serious bacterial infection. Antibiotics, especially those belong to aminoglycoside family, have clinically proven to be outstanding compounds with unique properties, making them perfect candidates for these much needed therapeutics. Aminoglycoside antibiotics remain an important group of antimicrobial agents particularly netilmicin for the treatment of serious infections by gram-negative organisms, because it possess many desirable properties that not exhibited by other classes of antibiotics^4-6.

At least 5 to 15% of patients receiving netilmicin, tobramycin, or amikacin will develop impairment in the glomerular function but most often reversible even the percentage may be higher among those receiving gentamicin. Over the past several years, much has been learned about the efficacy and toxicities of the individual use of netilmicin and other antibiotics, a new strategy emerged for epidemiology serious infection. Patients with serious systemic infection generally require antibiotics in combination^7-8. Frequently in such instances, netilmicin is combined with a variety of other antibiotics viz imipenem, pipericillin, ciprofloxacin, minocycline, ceftazidime, cefotaxime, cefoxitin, vancomycin, ceftriaxone and clindamycin to broadens the antibacterial spectrum of the empirical therapy in term of synergy even also ensures that at least one agent will cover the infecting organism. Although these combinations are seems to be effective but their utilization has been limited due to concerns about synergistic effect, nephrotoxicity and the subsequent need for frequent monitoring⁹.

It is well known that elevated levels of netilmicin increase the incidence of nephrotoxicity due to increased drug accumulation thus current use of combination of other antibiotics with netilmicin needs to prove drug interaction in order to justify interference of other antibiotics in the clearance of netilmicin or vice-versa to evaluate either nephrotoxicity can be delayed, avoided or increased. For the patients with systemic infection, either is it recommended to use combination therapy with netilmicin or netilmicin monotherapy is adequate to encounter the infection^10-11. Combined antimicrobials should be given only after a careful clinical diagnosis has been made and in doses that would be optimal for each drug if used alone. In the combination therapy with netilmicin, it is necessary to evaluate the possible interference of one antibiotic in the performance of another in contrast to efficacy and nephrotoxicity^12-14. This systematic review presents the current knowledge on the potentialities through comparing the efficacy and safety of netilmicin monotherapy or given in combination with other antibiotics for the treatment of SIF. It was assessed using an evidence-based review of the literature followed by meat-analysis with the aim to formulate treatment guidelines.

MATERIALS AND METHODS:

Literature search and eligibility of trials:

A systematic review of the literature was performed in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines¹⁵. We carried out a literature search of the Medline and Embase databases for pertinent Randomized controlled trials (RCTs) of all and both sex including pediatric subjects published from 1978 up to April 2017. We used the text word and the medical subject heading term (Mesh term) ‘netilmicin’, ‘netilmicin and nephrotoxicity’, ‘netilmicin combination therapy’, ‘netilmicin combination therapy and nephrotoxicity’. References from the retrieved articles were also analyzed for the inclusion of any missed studies relevant to our review. Inclusion criteria for the studies had to be randomized in which clinical response and nephrotoxicity clearly specified. All age participants were included with the clinical diagnosis of SSF with minimum 5 days of duration of therapy. A primary inclusion criterion comprises one basic requirement: individual experimental study performed for clinical efficacy (failure) for SSF and associated nephrotoxicity. We accepted clinical reports published in English and other languages were considered. Exclusion criteria included: review articles, editorials, non randomized, observational, single patient case reports, case reports, animal or biochemical studies, and studies lacking measurable outcomes or impertinent to NL and NLC and studies with inextricable pediatric data. Clinical research on antibiotics is a field where some trials may remain unpublished. Nevertheless, it is unclear whether such unpublished studies may affect the comparisons of this meta- analysis, as biases may operate in favor of NL or in favor of the comparators NLC depending on sponsorship or other factors but we excluded them. The inclusion criteria and validity of the studies were independently determined by two investigators followed by third.

Primary outcome:

The primary outcome was the clinical failure rate in the group of patients treated with NL versus the comparator NLC and incidence of associated nephrotoxicity. We selected as time for evaluation of the clinical outcome the day closest to day 5, as all studies carried out primary outcome evaluations between days 5 and 14 even one study performed for longer duration 70 days. Day 10 is the time-point used by the majority of trials. Relapses at the time of clinical evaluation were included with failures and incidence of nephrotoxicity.

Data extraction:

From each trial report, we extracted information on the year, language of publication, number of centers and their location, company sponsorship of the study, inclusion and exclusion criteria, definition of the conditions of interest, NL monotherapy and other antibiotics used in combination (class, dose and duration) NLC, patient demo-graphics (mean age and gender), number of patients allocated per treatment arm, number of patients eligible for the efficacy analysis, clinical failure rates, associated nephrotoxicity and the day(s) of outcome evaluation. Finally, we also extracted information about the study design (method of random allocation, adequacy of allocation concealment and masking).

Statistical analysis:

We calculated odds ratios and their 95% confidence intervals (CI) for clinical failures for efficacy, and nephrotoxicity (separately for NL and NLC). Within and between study variance and heterogeneity was precisely assessed by RR, Q, P and I². We used DerSimonian–Laird random effects models for meta-analysis¹⁶. In the main analysis, study specific rates were weighted simply by the sample size of each study. Subgroup analyses were carried out to evaluate differences in comparative efficacy when different comparator antibiotics were used. Bias diagnostics were also employed using inverse funnel plots, to evaluate whether the treatment effect depends on the trial sample size (suggestive of publication bias). Two tailed P value was calculated.

RESULTS:

Literature search, eligible and excluded studies:

We carried out a literature search of the Medline and Embase databases from 1978 to April 2017. During the systematic review, 36 studies that met the maximum eligibility criteria specified for this analysis were identified. After peer review in the form of an assessment of the quality of the full text, 17 clinical trials for both NL^17-27 and NLC^28-33 were selected for inclusion in the meta-analysis. The flowchart for systematic literature review comprises of the inclusion and exclusion criteria for the studies are presented in Figure 1. The selected articles have been analyzed by subgroups according to the presentation of data from the original study and divided in two groups: studies for NL and NLC. Characteristics and results of the included studies are shown in Table 1 and 2. The total number of participants in all the meta-analysis was 976 (489-NL and 487-NLC); duration of treatment was 5 to 14 days even longer up to 70 days; moreover, only interventions with clinical efficacy (failure) and nephrotoxicity for NL and NLC were evaluated. Usually, dose range in NL monotherapy was 2.0 mg/kg to 6 mg/kg divided into one, two or three daily doses, whereas 2.0 mg/kg to 7 mg/kg in two or three daily doses used for NLC. 11 studies for NL constituting total sample size population 489 (Highest number of population in one study was 144, median 34 and lowest 15) of all age group patients having SSF. For NLC, we select combination of netilmicin as netilmicin plus pipericillin, netilmicin plus ciprofloxacin, netilmicin plus minocycline, netilmicin plus ceftazidime, netilmicin plus cefotaxime. The studies constituting the total 487 (Highest number of population in one study was 138, median 93 and lowest 18) randomized SSF patients of all age group. In case of mean age range was 1.61 to 69 years for NL and 38-54 years for NLC. The studies in NL further distributed in three groups according to dose frequency (4 studies in once, 2 in twice and 7 in thrice in a day) to evaluate efficacy and nephrotoxicity associated with dose frequency.

Table 1 Outcomes extracted for clinical efficacy (rate of failure) and nephrotoxicity of netilmicin monotherapy from included studies.

S. No	Author	Age	Dose	Dose Frequency	Duration of Therapy (Days)	Rate of failure %	Nephro toxicity %
1	Allessandra V et al 1992	2.01	Netilmicin-5mg/kg	Once a day	10	1.42	2.77
1	Allessandra V et al 1992	1.61	Netilmicin-2mg/kg	Three times a day	10	1.42	2.77
2	Auewra P et al 1991	66	Netilmicin-6mg/kg	Once a day	7	20.0	10.0
2	Auewra P et al 1991	62	Netilmicin-6mg/kg	Three times a day	7	20.0	10.0
3	Prat V et al 1990	50	Netilmicin-6mg/kg	Once a day	70	25.0	21.42
4	Donald K et al 1978	48	Netilmicin-2mg/kg	Three times a day	10	17.39	21.73
5	Richard M et al 1980	62	Netilmicin-2mg/kg	Three times a day	11	11.76	38.23
6	Michael B et al 1980	60	Netilmicin-2.5mg/kg	Three times a day	10	5.40	8.10
7	Tange RA et al 1995	52	Netilmicin-5.5mg/kg	Once a day	8.8	7.61	19.23
8	Hellum KB et al 1980	69	Netilmicin-2.9mg/kg	Three times a day	10	20.0	5.71
9	Perera MR at al 1980	63	Netilmicin-3.15mg/kg	Two times a day	7	6.66	6.66
10	Jahre JA et al 1979	60	Netilmicin-2mg/kg	Three times a day	10	13.33	6.66
11	Zao C et al 2000	42	Netilmicin-2.3mg/kg	Two times a day	10	16.12	9.67
	Mean	57.96			14.8 Days	13.09	13.80

Table 2 Outcomes extracted for clinical efficacy (rate of failure) and nephrotoxicity of netilmicin combination therapy from included studies.

S.No	Author	Netilmicin Combination Therapy	Age	Dose	Dose Frequency	Duration of Therapy (Days)	Rate of failure %	Nephro toxicity %
1	Cometta A et al 1994	Netilmicin+Imipenem	54	Imipenem - 500 mg	Four times a day	12.5	13.66	10.14
				Netilmicin - 2.7 mg /kg	Two times a day
2	Chek CC et al 1989	Netilmicin+Piperacillin	44	Piperacillin-4gm	Four times a day	5.0	31.31	8.0
				Netilmicin-7mg/kg	Three times a day
3	Nasu M et al 1994	Netilmicin+Minocycline	38	Minocycline- 6.4mg/kg	Two times a day	14	26.92	11.5
				Netilmicin-2.64 mg	Two times a day
4	Hoffken G et al 1999	Netilmicin+Ceftazidime	50	Ceftazidime-1gm	Three times a day	14	28.42	9.47
				Netilmicin-2mg/kg	Three times a day
		Netilmicin+Cefotaxime	49	Cefotaxime-2gm	Three times a day		43.95	4.39
				Netilmicin-2mg/kg	Three times a day
5	Bubrick MP et al 1983	Netilmicin+Cefoxitin	54	Cefoxitin-2gm	Three times a day	10	5.0	15
				Netilmicin-2mg/kg	Three times a day
6	Kahalley S et al 1985	Netilmicin+Clindamycin	46	Clindamycin-600 mg	Three times a day	10	11.11	22
				Netilmicin-2mg/kg	Three times a day
		Mean	47.8			10.91 Days	20.91%	10.09%

DISCUSSION:

The meta-analysis indicates that for serious infections, the rate of failure for NL monotherapy was 7.82% but 3.71% more incidence of nephrotoxicity than competitor NLC. The paucity of data favors NL monotherapy, if the more chances of nephrotoxicity neglected. The favorable NL monotherapy than again resolved for dose frequency and found that NL monotherapy became most favorable when the patients with epidemiology of SSF treated with therapeutic dose range 5-6 mg/kg once in a day. In this meta-analysis, the largest difference in odds ratio was only 0.42 and none of the 95% CIs extended beyond a difference of 2% and there was no overt evidence of publication bias. Before discussing the results in more detail it is important to note that the greatest strength of the study lies in the inherent design features. The fact that it was done through a systematic review and also included the use of statistical methods such as meta-analysis, allows us to say that until April 2017. This is the synthesis of the evidence regarding the treatment of SSF with NL and NLC. The overall results need to be interpreted with caution, as biases cannot be excluded. We found no evidence of overt publication bias, or changes in the pooled treatment effect over time. Lack of allocation concealment may also cause bias in this setting. Moreover, it is difficult to interpret comparisons of NL with specific antibiotic combination NLC because of the limited number of studies in each subgroup. Small trials are difficult to interpret in isolation. Although isolated studies of NL and NLC are undertaken with the aim of showing equivalence rather than superiority, the sample size in some individual study of NL and NLC is typically too small for equivalence testing, while more than 20 studies with more than 1000 patients were excluded because they contain either efficacy or nephrotoxicity, even most relevant studies that match complete inclusion criteria were excluded because of unavailability of full text, that might be cause a clinically meaningful differences in efficacy and nephrotoxicity, if included. Thus, meta-analysis provides an opportunity to establish or refute equivalence. To our knowledge, this is the first meta-analysis that is done on both efficacy and safety of NL and NLC with dose frequency, based on published clinical trials. However, it is important to highlight some limitations of this analysis: 1) although all studies underwent a quality assessment to control the overall technical standardization, they are individually exposed to methodological weaknesses, 2) not all studies have a standard dose, although most studies use the recommended doses for each drug. Regarding the results of the clinical efficacy of this meta-analysis, the literature findings were confirmed, i.e., NL monotherapy is a good alternative for those using NLC in SSF cases.

After the well diagnosis if the combination therapy with netilmicin required, this meta-analysis recommended for netilmicin plus imipenem or netilmicin plus cefoxitin may be advantageous as compared to other combination included in this study. The most frequent adverse effects found were nephrotoxicity associated with NL and NLC therapy which lead to its limited use in present time but found to be most favorable as compared to other available aminoglycoside. As for the duration of treatment, no difference between the shortened and the standard therapy (5-14 days) was observed.

CONCLUSION:

Considering the results of this evidence based systematic review and meta-analysis, NL monotherapy is a good therapeutic option compared to NLC with once in a day dosing frequency.

The recommendations are summarized and detailed below.

(1) Is netilmicin monotherapy as efficacious as a combination of a netilmicin plus other antibiotics for serious infection?

Answer: Yes,

Comments: Available evidence shows that monotherapy is more efficacious as netilmicin plus other antibiotics combination therapy with regard to overall survival, overall response defined as a resolution of serious infection without modification of the initial antibiotic regimen, response of documented Gram-negative infections, and infection-related mortality.

(2) Is a combination of a netilmicin plus other antibiotics more nephrotoxic than netilmicin monotherapy?

Answer: No

Comments: Nephrotoxicity was evaluated in several trials comparing monotherapy with combination therapy. The combination: netilmicin plus imipenem, netilmicin plus pipericillin, netilmicin plus ciprofloxacin, netilmicin and minocycline, netilmicin plus ceftazidime, netilmicin plus cefotaxime, netilmicin plus cefoxitin and netilmicin plus clindamycin used in these trials. Reversible nephrotoxicity occurred as side effect but in same extent, no significantly difference found among patients treated with combination therapy than in those treated with monotherapy, even at an average combination therapy found less nephrotoxic than monotherapy.

3) Is there evidence that once-daily administration of netilmicin is as efficacious as and potentially less toxic than multiple-dose administration for SIF patients?

Answer: Yes.

Comments: As unexpected, on the basis of evidence in the entire study, favors once in day dose regimen compared to multiple (thrice) doses. The rate of failure and nephrotoxicity was less than multiple doses.

4) Is any individual combination found batter and safer as netilmicin monotherapy and that could be used in future according to demand of treatment?

Answer: Yes

The rationale for combination therapy included broad-spectrum coverage, possible synergistic activity against Gram-negative bacteria and the prevention of emergence of antibiotic resistance. The paucity of comparative data suggested that efficacy of netilmicin plus imipenem or netilmicin plus cefoxitin is batter then average efficacy of netilmicin monotherapy but slightly more prone to nephrotoxicity. This combination therapy recommended but after well diagnosis and extreme need of therapy.

ACKNOWLEDGMENT:

Authors are thankful to M/S Surgycare Lifescience to provide facility and right to publish the study. None of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper.

REFERENCE:

1. Matthieu L, Adeline M, Benoit S et al. The strategy of antibiotic use in critically ill neutropenic patients. Ann Intensive Care. 2012; 2:1-9.

2. Kibe S, Adams K, Barlow G et al. Diagnostic and prognostic biomarkers of sepsis in critical care. J Antimicrob Chemother. 2011; 66:33-40.

3. Chesney RW, McCarren DM, Haddad JG, et al. Pathogenic mechanisms of the hypocalcaemia of the staphylococcal toxic shock syndrome. J Lab Clin Med. 1983; 101:576-85.

4. Charles VP. Current status of combined antibiotic therapy. J Pediatrics. 1958; 21:1000-09

5. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev. 2012; 25:450–70.

6. Lubos D, Giampaolo B, Thierry C et al. The need for aminoglycosides in combination with β-lactams for high-risk, febrile neutropaenic patients with leukaemia. Eu J Canc Supp. 2007; 5:13-22

7. Turnidge J. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin N Am. 2003; 17:503-28.

8. Dana Maglio, Extended interval aminoglycoside dosing: from concept to clinic. Int J Antimicrob Agents. 2002; 19:341-8.

9. Kim Ming Wong, Chan YH, Cheung CY et al. Cefepime versus vancomycin plus netilmicin therapy for continuous ambulatory peritoneal dialysis associated peritonitis. Am J Kidney Dis. 2001;38: 127-31

10. Endre L et al. Efficacy and safety of ceftriaxone plus netilmicin once daily versus ceftazidime plus netilmicin twice daily in severe nosocomial infections. Cur Therap Research. 1993; 53:687-92.

11. Perazella MA. Toxic Nephropathies: Core Curriculum 2010. Am J Kidney Dis. 2010; 55:399-09.

12. Broe ME, Giuliano RA, Verpooten GA. Choice of drug and dosage regimen. Two important risk factors for aminoglycoside nephrotoxicity. Am J Med. 1986; 80:115-8.

13. Gonzalez US, Spencer JP. Aminoglycosides: a practical review. Am Fam Physician. 1998; 58:1811-20.

14. Richard A, Krieger JN. Gentamicin for the practicing urologist: review of efficacy, single daily dosing and "switch" therapy. J Urology. 2000; 163: 1076-84

15. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009; 6:1000-10.

16. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials.1986; 7: 177–88.

17. Alessandra V Nicolia P, Luca B et al. Comparison of 5 Milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children, J Antimicrob agents and chemother. 1992; 36: 1499-03

18. Auwera P, Meunier F, Ibrahim S et al. Pharmacodynamic parameters and toxicity of netilmicin (6Milligrams/Kilogram/Day) given once daily or in three divided doses to cancer patients with urinary tract infection. J Antimicrob agents and chemother. 1991; 35: 640-7.

19. Prat V, Horcicková M, Hatala M et al. Long-term effect of the administration of repeated single doses of netilmicin in urinary tract infections, Cas Lek Cesk. 1990;129:306-8.

20. Donald K, Irwin T, James P et al. Pharmacology and efficacy of netilmicin. J Antimicrob agents and chemother. 1978; 13: 832-6.

21. Richard DM, Bonnie VB, Paul HE et al. Prospective comparative study of efficacy and toxicity of netilmicin and amikacin. J Antimicrob agents and chemother. 1980; 17:217-25.

22. Michael B, Michael WL, Francis PT et al. Prospective randomized trial of netilmicin and amikacin, with emphasis on eighth nerve toxicity. J Antimicrob agents and chemother. 1980; 17:707-14.

23. Tange RA, Dreschler WA, Prins JM et al. Ototoxicity and nephrotoxicity of gentamicin vs netilmicin in patients with serious infections. A randomized clinical trial. Clin Otolaryngol Allied Sci. 1995; 20:118-23.

24. Hellum KB, Madsen ST, Digranes A et al. High dose netilmicin therapy of severe or chronic infections. Scand J Infect Dis Suppl. 1980; 23:189-94.

25. Perera MR, Amirak ID, Noone P. Netilmicin 200 mg twice a day for adult patients with life-threatening infections. A preliminary report. Scand J Infect Dis Suppl. 1980; 23:186-8.

26. Jahre JA, Fu KP , Neu HC. Clinical evaluation of netilmicin therapy in serious infections. AM J Med 1979; 66:67-73.

27. Zhao CA, Li J, Hou J, Guo M et al. Randomized controlled clinical trial on etimicin, a new aminoglycoside antibiotic, versus netilmicin in the treatment of bacterial infections. J Chin Med. 2000; 113:1026-30.

28. Cometta A, Baumgartner JD, Lew D et al. Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patientst. J Antimicrob agents and chemother. 1994; 38: 1309-13.

29. CHEK CC, Beryl AP, Heather A et al. Randomized trial comparing ciprofloxacin plus netilmicin versus piperacillin plus netilmicin for empiric treatment of fever in neutropenic patients. J Antimicrob agents and chemother. 1989; 33: 87-91.

30. Nasu M, Goto Y, Yamasaki T et al. Clinical studies on the time-difference combination therapy with netilmicin and minocycline in methicillin resistant staphylococcus aureus infections Jpn J Antibiot. 1994; 47:1305-17.

31. Hoffken G, Pasold R, Pfluger KH et al. An open, randomized, multicentre study comparing the use of low-dose ceftazidime or cefotaxime, both in combination with netilmicin, in febrile neutropenic patients J Antimicr Chemo. 1999; 44: 367–76.

32. Bubrick MP, Howard RJ , Pancorbo S et al. A comparative study of netilmicin-cefoxitin and gentamicin-cefoxitin in surgical patients with serious systemic infection. Clin Therapeutics. 1983; 5:515-24.

33. Kahalley S, Chandler J , Hawkins J et al. Prospective, randomized comparison of the efficacy and safety of netilmicin-clindamycin and tobramycin-clindamycin in the treatment of serious systemic infections. Clin Therapeutics. 1985; 7:497-06.

Received on 23.07.2017 Modified on 19.08.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(3): 101-108.

DOI: 10.5958/0975-4377.2017.00018.0