A comparative study of the efficacy of intravenous benzylpenicillin and intravenous augmentin in the empirical management of Ludwig's angina.

Background: Ludwig's angina is a potentially life-threatening condition characterized by bilateral cellulitis of the submandibular, submental, and sublingual spaces. Intravenous (I.V) penicillin G or amoxicillin-clavulanate (Augmentin) has been recommended for use as empirical management before obtaining culture and sensitivity results. Aim: The aim of this study was to compare the therapeutic efficacies and clinical outcomes of I.V benzylpenicillin with I.V Augmentin in the empirical management of Ludwig's angina.
Methods: This was a prospective randomized clinical study carried out to measure the rate of swelling reduction (using the lobar rate, Adam's rate, and interincisal distance) and other clinical parameters among the two drug groups (I.V penicillin G and Augmentin). Descriptive summaries of variables were generated, and Student's t-test was used to compare the mean outcomes of the two groups.
Results: A total of 26 individuals participated in the study, consisting of 46% (12) males and 54% (14) females. The participants ranged from 13 to 61 years with mean and median of 34.4 (±12.7) and 35 years, respectively. Only 8% of the cases of Ludwig's angina were not attributable to odontogenic factors, compared to 92% resulting from odontogenic causes. There was no significant difference in the efficacy of the two antibiotics used in this study.
Conclusion: The efficacies and the clinical outcomes of the two antibiotics were similar. Benzylpenicillin is probably a suitable empirical alternative where Augmentin cannot be afforded, to reduce the mortality associated with the condition.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Ludwig's angina, a condition which gained notoriety for its high mortality rate in the preantibiotic era,[1] is characterized by rapidly spreading infection resulting from severe diffuse cellulitis, bilaterally affecting the submandibular, sublingual, and submental spaces.[23] The condition is named after the German Physician Wilhelm Friedrich von Ludwig, who first described it in 1836. The condition is generally considered to be reducing in mortality with the advent of antimicrobial agents but still of clinical significance in some parts of the world.[4] Although Ludwig's angina often results as a complication of severe odontogenic infection, several other etiological and risk factors have also been implicated. These include diabetes mellitus,[45] HIV infection,[4] pregnancy,[6] puerperium,[7] alcoholism,[3] chronic malnutrition,[8] and low socioeconomic status.[9] The peculiarity of Ludwig's angina among odontogenic infections is its propensity for rapid spread, capable of leading to airway obstruction, carotid arterial rupture or sheath abscess, thrombophlebitis of the internal jugular vein, mediastinitis, empyema, necrotizing fasciitis, pericardial effusion, osteomyelitis, and septicemia.[2]

Management may, therefore, consist of a multidisciplinary approach depending on its presentation and associated comorbidities. With several implicated organisms including Peptostreptococcus, Bacteroides, Streptococcus viridans, Staphylococcus aureus, and Staphylococcus epidermis, several regimens have been recommended.[310] However, the empirical choice and administration of antimicrobial agents at its presentation before culture and sensitivity analyses may be crucial to the survival of a patient. The use of antibiotics for such infections requires updated protocols based not only on the existing scientific evidence but also on the epidemiological reality of each center and region,[10] such as availability of medication and cost, among other variables. Another area of concern is the rising incidence of antimicrobial resistance in severe orofacial infections associated with the second-line antimicrobials which could, in part, be accounted for by their inconsistency in administration.[11]

Intravenous (I.V) penicillin G or amoxicillin-clavulanate (Augmentin), clindamycin, or metronidazole has over time been recommended for use in severe odontogenic infections before obtaining culture and sensitivity results.[3] While this regimen seems to account for most inhospital empirical antibiotic choice for the management of Ludwig's angina,[10] some authors have noted the superiority of Augmentin.[12]

The potency of an antibiotic lies in its ability to inhibit a number of bacterial enzymes essential for the synthesis of peptidoglycan, a major cell wall content of Gram-positive bacteria. The penicillins, in general, are a group of natural and semisynthetic antibiotics containing the chemical nucleus, 6-amino penicillanic acid, which consists of a β-lactam ring fused to a thiazolidine ring, with benzylpenicillin (penicillin G) being a relatively cheaper naturally occurring form.[13] Subsequently, 50–60 years after the discovery of benzylpenicillin in 1981, amoxicillin/clavulanate was launched with the successful addition of clavulanic acid to improve its efficacy.[10]

The most common determinant of empirical antibiotic choice in a hospital setting, typically in Sub-Saharan Africa, is cost and availability. The aim of this study was to compare the therapeutic efficacies and clinical outcome of I.V benzylpenicillin and I.V Augmentin in the management of Ludwig's angina, with the null hypothesis being that there is no significant difference in the treatment outcome of Ludwig's angina patients who are on either I.V benzylpenicillin or I.V Augmentin.

METHODS

This study was a prospective clinical study carried out at Korle-Bu Teaching Hospital, Accra, Ghana, from January 2011 to January 2013. Patients who were clinically diagnosed with Ludwig's angina were consecutively selected to participate in the study. Participants were patients with bilateral swelling of submandibular, submental, and sublingual regions, who consented to be part of the study. Patients with diabetes, renal disease, and liver disease and those allergic to penicillins were excluded from the study.

A thorough history, clinical examinations, and preliminary investigations were done for all patients, and the management was carried out in accordance with the standard operating procedures and treatment guidelines of the Department of Oral and Maxillofacial Surgery of the hospital, which involved immediate admission, administration of I.V fluids and antibiotics, incision and drainage, extraction of offending teeth, and management of comorbid conditions.

Independent variables for the study were parameters routinely done for all patients, which were body temperature, pulse, blood pressure, full blood count, blood electrolytes and creatinine, random blood sugar, and HIV tests.

The severity of the swelling was ascertained by a measure of distance between the two earlobes across the submandibular regions (interlobar distance),[14] a second measurement was taken from the laryngeal cartilage to the Vermillion border of the lower lip at rest (Adam's distance), and a third, the interincisal distance at maximum mouth opening was measured with a pair of linear calipers. The variables taken at presentation were repeated daily and recorded in a computerized questionnaire, until patients were discharged.

All patients were managed empirically with full adult doses of I.V metronidazole 500 mg 8 hourly and either Augmentin (GlaxoSmithKline, UK) 1.2 g 12 hourly or benzylpenicillin (Troge Medical, Germany) 4 mu stat, then 2 mu 6 hourly. Patients were also managed on I.V paracetamol and I.V fluids. Participants were randomly assigned to “Group A” or “Group B” on presentation, to receive Augmentin and penicillin G, respectively.

The outcome variables were (1) lobar rate – which was a ratio of the difference in interlobar distance and the number of days on admission; (2) Adam's rate – which is a ratio of the difference in Adam's distance and the number of days on admission; and (3) interincisal rate – which was a ratio of the difference in interincisal distance and the number of days on admission.

All variables were entered into Microsoft Excel 2007 and analyzed using IBM SPSS Statistics for Windows version 20 (IBM Corp., Armonk, NY, USA). Descriptive summaries of variables were generated, and Student's t-test was used to compare the mean outcomes of the two groups. Fisher's exact test was used to compare categorical variables with consequent test of association, assuming an alpha level of 0.05. Signed consent was obtained from all patients. The null hypothesis for this study was that there is no significant difference in the treatment outcome of Ludwig's angina patients who were managed with either I.V benzylpenicillin or I.V Augmentin.

RESULTS

A total of 26 patients participated in the study comprising 12 (46%) males and 14 (54%) females. The patients' ages ranged from 13 to 61 years with mean and median of 34.4 ± 12.7 and 35 years, respectively. The peak age group was between 30 and 39 years representing 34.6%, followed by participants between 20 and 29 years [Figure 1].

Figure 1

Age distribution of patients with Ludwig's angina

Table 1 shows the employment status of the patients. Only 8% of the cases of Ludwig's were not attributable to odontogenic factors, compared to 92%, i.e., majority of which had implicated teeth as a source of the severe infection, as shown in Figure 2.

Table 1

Employment categories of patients with Ludwig’s angina

Category	n (%)
Unemployed	5 (19.2)
Employed in the informal sector	18 (69.2)
Employed in the formal sector	3 (11.6)
Total	26 (100)

Figure 2

Causes of Ludwig's angina

The most implicated tooth as a source of infection in Ludwig's angina was the right mandibular third molar (28.6%) followed by the left mandibular second molar (25.7%) as indicated in Figure 3. The least involved teeth were the second premolars on either side.

Figure 3

Implicated teeth in patients with Ludwig's angina

Table 2 compares the mean values of vital signs in patients with Ludwig's angina among the two drug groups. There were no statistically significant differences in all vital signs recorded for the two groups.

Table 2

Vital signs in patients with Ludwig’s angina

Variable	Mean±SD			P
	Augmentin (drug A)	Penicillin G (drug B)	Total
Temperature	37.0 (0.8)	37.1 (1.1)	37.0 (1.0)	0.636
Pulse	98.8 (17.2)	95.6 (17.8)	97.2 (17.3)	0.643
Systolic BP	127.9 (11.0)	120.4 (23.1)	124.1 (18.1)	0.304
Diastolic BP	78.8 (17.4)	76.0 (12.4)	77.4 (14.9)	0.645
Respiratory rate	24.9 (4.1)	24.3 (5.7)	24.6 (4.9)	0.754

SD=Standard deviation, BP=Blood pressure

Furthermore, there was no statistically significant difference in serum electrolytes, urea, and creatinine between the two drug groups. Similar observations were made for the fasting blood sugar and blood hemoglobin as shown in Table 3.

Table 3

Laboratory investigations of Ludwig’s angina patients

	Mean±SD			P
	Augmentin (drug A)	Penicillin G (drug B)	Total
FBS	6.1 (1.0)	6.6 (2.1)	6.4 (1.7)	0.463
Hb	11.3 (2.5)	10.6 (3.2)	11.0 (2.8)	0.537
WBC	14.7 (6.1)	15.2 (6.2)	14.9 (6.2)	0.327
Platelets	267.5 (149.9)	308.0 (136.9)	287.8 (142.2)	0.479
Na	141.6 (6.4)	141.2 (2.6)	141.4 (4.8)	0.859
K	4.1 (0.7)	4.3 (0.5)	4.2 (0.6)	0.509
Cl	104.6 (4.2)	102.8 (4.0)	103.7 (4.1)	0.257
Urea	9.6 (14.8)	5.8 (2.5)	7.7 (10.6)	0.363
Creatinine	83.6 (30.2)	93.1 (41.1)	88.3 (35.7)	0.510

FBS=Fasting blood sugar, Hb=Hemoglobin, WBC=White blood cell count, Na=Serum sodium, K=Serum potassium, Cl=Serum chlorine, SD=Standard deviation

Only two patients tested positive for retroviral screening which represents 7.7% of those who were included in the study and 4% of the total number seen within the period.

The mean rate of change in the conditions was comparable between the two groups, and there was no significant difference between them P > 0.05. The mean number of days spent on admission is also similar for the two groups, P = 0.829.

DISCUSSION

Ludwig's angina seems to be relatively common in Ghana as in some other developing countries.[45] It is a condition well known to be associated with high morbidity and mortality.[7] The relatively high frequency of the condition and associated mortality could, in part, be attributed to low socioeconomic status.[515] This study showed that there was no statistically significant difference in swelling reduction, trismus, and length of hospital stay among the patients treated with the two drugs, thus making the cheaper and more readily available benzylpenicillin a suitable empirical alternative, where Augmentin cannot be afforded or unavailable to reduce mortality associated with the condition.

The age group of the patients studied compares favorably with Botha et al.[4] and Ibiyemi et al.,[5] who found mean ages of 40.2 and 33.0 years, respectively, in patients with such severe odontogenic infections. Previous studies[14] have documented unskilled group and lesser educated individuals as more likely to bear most of the burden of this condition.[16] Our study, similarly, found that most (69.2%) of the participants were in the informal sector.

We found that 92% of cases in this study had Ludwig's angina being accounted for by dental caries. This is consistent with several studies and reports.[259] The molars were the more common source of dentoalveolar infection and five of the cases had bilateral gross caries. The tooth most commonly implicated was the lower right wisdom tooth followed by the lower left second molar. The molars are more prone to caries due to the multiple fissures and grooves, which tend to retain viable substrate, a known factor for caries development.[1718] The relationship of the roots to the attachment of the mylohyoid muscle also plays a role in the direction of spread of the abscess.[19]

The outcome variables used to measure swelling reduction; the interincisal distance and interlobar distance had been employed by Bamgbose et al.,[12] to assess the effect of dexamethasone on postoperative swelling in third molar surgery. The third variable, the distance from the laryngeal cartilage (Adam's apple) to the Vermillion border of the lower lip at rest, “Adam's distance” was used in this study to ascertain the extent of swelling in the sagittal plane. Comparison of the rate of decrease in the size of swelling in the two drug groups revealed no statistically significant difference [Table 4]. Similarly, there was no significant difference in the interincisal rate for the two groups. The clinical efficacies of the two different regimens in the empirical management of Ludwig's angina were thus comparable when used with full adult doses of metronidazole and paracetamol with incision and drainage and extraction of offending teeth.

Table 4

Measurements of swelling, mouth opening, and number of days of hospitalization

Outcome	Drug	n	Mean±SD	P
Lobar rate (cm/day)	Augmentin (drug A)	13	0.38±0.23	0.966
	Penicillin G (drug B)	13	0.38±0.20
	Total	26	0.38±0.21
Adam’s rate (cm/day)	Augmentin (drug A)	13	0.73±3.37	0.286
	Penicillin G (drug B)	13	0.29±0.12
	Total	26	0.22±2.39
Interincisal rate (mm/day)	Augmentin (drug A)	13	0.14±0.11	0.764
	Penicillin G (drug B)	13	0.16±0.14
	Total	26	0.15±0.12
Number of days	Augmentin (drug A)	13	7.15±2.23	0.829
	Penicillin G (drug B)	13	7.38±3.10
	Total	26	7.30±2.65

There was no significant difference between the two groups regarding the number of days spent in the hospital, and the mean number of days for both groups was 7.3 days. This finding is comparable to that of Zamiri et al.,[19] who reported 6.6 and 5.5 days for those with systemic condition and those without, respectively. The reason for this similarity could be due to adherence to prompt, aggressive, and appropriate management protocol in this life-threatening condition.

There seems to be no consensus in the management of Ludwig's angina patients as evidenced by the wide variety of protocols both surgically and medically.[1011] The choice of management regimens seems to vary among different centers. It is evident from our study that I.V penicillin G or Augmentin with metronidazole is the adequate antibiotic regimen to start the empirical medical management of Ludwig's angina.

Ludwig's angina is mostly seen in previously healthy individuals; however, patients with immunosuppressive conditions such as retroviral infection and diabetes mellitus may have increased susceptibility to developing the condition.[4] Only two patients, however, tested positive for HIV screening which represented 8% of those studied. This is comparable to a study by Har-El et al.,[20] who reported 5% of their patients to be positive for HIV.

CONCLUSION

There was no significant difference in the efficacy of the two antibiotics used in this study. All the patients recovered fully, suggesting that the therapeutic efficacy of both antibiotics when combined with incision and drainage was adequate for the management of Ludwig's angina. The use of existing empirical antibiotics is therefore still effective and should be initiated early upon admission of these patients while awaiting culture and sensitivity report.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.