Next-generation strategy for treating drug resistant bacteria: Antibiotic hybrids

Resistance against nearly all antibiotics used clinically have been documented in bacteria. There is an ever-increasing danger caused by multidrug-resistant Gram-negative bacteria in both hospital and community settings. In Gram-negative bacteria, intrinsic resistance to currently available antibiotics is mainly due to overexpressed efflux pumps which are constitutively present and also presence of protective outer membrane. Combination therapy, i.e., use of two or more antibiotics, was thought to be an effective strategy because it took advantage of the additive effects of multiple antimicrobial mechanisms, lower risk of resistance development and lower mortality and improved clinical outcome. However, none of the benefits were seen in in vivo studies. Antibiotic hybrids are being used to challenge the growing drug resistance threat and increase the usefulness of current antibiotic arsenal. Antibiotic hybrids are synthetic constructs of two molecules which are covalently linked. These could be two antibiotics or antibiotic with an adjuvant (efflux pump inhibitor, siderophore, etc.) which increases the access of the antibiotics to the target. The concepts, developments and challenges in the future use of antibiotic hybrids are discussed here. Majority of the studies have been conducted on fluoroquinolones and aminoglycosides molecules. The antibiotic tobramycin has the property to enhance the action of antimicrobial agents against which the multidrug-resistant Gram-negative bacteria were earlier resistant, and thus potentiating the action of legacy antibiotics. Antibiotic hybrids may have a role as the silver bullet in Gram-negative bacteria to overcome drug resistance as well as extend the spectrum of existing antibiotics

Screening--a unique way of better health care delivery for ENT patients.

A few Ear Camps were carried out amongst 25 schools and madrashas of Dhaka City having 10,102 pupils, to see the prevalence of ENT diseases and hearing impairment. A primary screening was done by the Bangladesh Council for Child Welfare (BCCW) with the possibilities of suffering from ear, nose & throat diseases with the help of questionnaire and clinical examination by qualified doctor. The word "Screening" is used in this paper not in the epidemiological sense but to imply primary selection. 1,403 (13.89%) were issued registration card for ENT consultation. Five otolaryngologist, one audiometrician, two ancillary staffs, BCCW workers, local volunteers and school teachers conducted the 3 days long camp. Secondary screening by the otolaryngologists revealed pathology in 1,101 students (10.89%). 26 children (0.26%) were attending schools with severe hearing loss. ENT diseases appeared to be common in urban school children and screened proved to be an efficient method for health care delivery.

Designing of peptides with immuno-modulatory properties using protein A as a probe.

A series of reports from our laboratory have described the multifarious properties of protein A of Staphylococcus aureus Cowan I, apart from its IgG binding affinity. Original reports regarding its anti-tumor, anti-toxic, anti-carcinogenic and immunomodulatory properties published earlier by the authors have implicated some uniqueness of this bacterial protein. It was conceived that such diversified properties must lie in its specific peptide sequences, rendering it to act and behave as a multipotent "Biological Response Modifier" (BRM). The high resolution X-ray structure of protein A-Fc complex has been delineated earlier, and has been the foundation of many protein engineering studies. This structure along with the amino acid sequence data of its four repetitive domains provided us the basis for designing an octapeptide. This octapeptide was synthesized by solid phase peptide synthesis considering it as the probable site through which PA binds IgG. This octapeptide (NH2-Gln-Asn-Ala-Phe-Tyr-Glu-Ile-Leu-COOH) is present in the first helical segment of B-domain of protein A, and also is a part of domain D, A and C. This octapeptide has been shown to bind IgG by the immunoblotting technique. The binding affinity of the octapeptide appears to be significantly higher than that of intact protein A, as was revealed by calculation of Ka (association constant) and Kd (dissociation constant) values. This octapeptide might serve as a good immunoadsorbant for IgG and/or immune complexes.

Long term follow-up of HIV-1 exposed children in Nairobi

Transmission of HIV-1 from an infected mother to her infant is the major route of transmission of this infection for children. In sub-saharan Africa where heterosexual transmission of HIV is the commonest mode of spread; high prevalence of HIV infection in women of child bearing age is bound to lead to increased paediatric AIDS as a result of vertical transmission. In recognising these epidemiological factors; the University of Nairobi HIV-1 Perinatal Transmission and Paediatric AIDS Project was initiated in 1986. Antenatal mothers attending Pumwani Maternity Hospital were enrolled during labour and screened for HIV-1 infection by ELISA. Those reacting positive were recruited to participate in the study. An equal number of negative controls were also recruited. The mothers and babies of both groups were followed for varying periods over the next five years. A total of 360 babies born to HIV infected mothers and 360 babies born to HIV negative mothers were examined. The mortality rate observed in the HIV-1 exposed was substantially higher than that observed in controls (RR2.8; 95CI1.3-6.1). Common causes of death among infected infants were pneumonia; measles; malaria; gastroenteritis; tuberculosis and spticaemia. The five year survival was 85 among HIV infected children. Maternal risk factors associated with transmission were marital status; duration of sexual activity and age at first intercourse

Ewing's sarcoma of maxilla--a case report.

This paper reports the case of an adolescent girl who was admitted in the ENT ward, IPGMR in February '88 with the complaints of nasal obstruction, nasal discharge associated with progressive swelling of the right side of her face for 1 year. She had an operation at Chittagong Medical College Hospital 1 year back for some problem in the right side of the nose. No history of pain, nasal bleeding or visual disturbance were present. The nasal mass was mobile, insensitive and did not bleed on touch, but the facial swelling was red, soft and cystic. Clinically diagnosed as an Antral growth with Ethmoidal involvement. Radiologically revealed soft tissue swelling, obliteration of nasal fossa and opacification of sinuses. After surgical resection the facial mass was diagnosed as Ewing's sarcoma histopathologically. The patient needed radiotherapy but did not follow it.

Effect of protein rich diet during acute phase of dysentery.

Ninety six children upto the age of five years suffering from uncomplicated acute dysentery of less than 3 days' duration were studied to find out the impact of feeding of extra-protein rich diet during their acute phase of illness. These children were randomly allocated to either control group (receiving only hospital diet) and study group (receiving hospital diet and extra milk which constituted 30% of ideal total calorie requirement of patients. Patients in the two groups were comparable on admission. Forty percent reduced food intake was observed among the children of both the groups due to severe anorexia which was reflected by no significant differences in clinical outcome, anthropometrical measurements and haematological parameters between the two groups on day 7 of hospitalisation and on day 15 after discharge.

Outbreak of dysentery due to nalidixic acid resistant S. dysenteriae 1 at Agartala, Tripura: a hospital based study.

During the epidemic of bacillary dysentery at Agartala, Tripura, a total of 62 hospitalized patients suffering from diarrhoeal diseases were studied during the later part (11-16 June, 1988) of the epidemic. Principal features of Shigellosis cases were discussed. Of these 62 cases investigated, 19(30.6%) cases had the mucoid diarrhoea. From them S.dysenteriae type 1 and S.flexneri had been recovered from 31.6% and 10.5% cases, respectively. All the strains of S.dysenteriae type 1 isolated during the period of investigation were resistant to nalidixic acid.