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Farewell, Chloramphenicol? Is this True?: A Review

Madhavan HN*, and Bagyalakshmi R

Larsen and Toubro Microbiology Research Centre, Kamal Nayan Bajaj Research Centre, Vision Research Foundation, No.41, College Road, Chennai - 600006, Tamil Nadu, India

*Corresponding Author:
Madhavan HN
Larsen and Toubro Microbiology Research Centre, Kamal Nayan Bajaj Research Centre, Vision Research Foundation, No.41, College Road, Chennai - 600006, Tamil Nadu, India
Tel: +91-44- 28220709
Fax: +91- 44- 2825 4180

Received date: 12/12/2013; Accepted date: 31/12/2013

Visit for more related articles at Research & Reviews: Journal of Microbiology and Biotechnology

Abstract

Chloramphenicol has remained as a potent broad spectrum antibiotic over decades and due to its side effects its usage has been limited. In an era of increasing resistance to many antibacterial agents, chloramphenicol might have a role in the treatment of intra abdominal infections and respiratory tract infections caused by multi drug-resistant pathogens. This review article focuses on the spectrum of activity of chloramphenicol, mechanism of action , side effects , its parentral and oral use, its resistance mechanisms, toxicity elucidated by enteric pathogens against it and also on the possibility of its therapeutic use in treatment of multi - drug resistant bacterial infections.

Keywords

Chloramphenicol, Mechanism of action of chloramphenicol, Possible uses of chloramphenicol

Introduction

During the last decade the emergence of highly resistant pathogens has aroused renewed interest in older drugs that have fallen into disuse because of several factors including toxic side effects. One important antibiotic agent is chloramphenicol, which was released for use in the United States in 1949, but due to reports linking its use with the development of aplastic anemia it has long been put aside and is not used as standard therapy in the developed world, though it is still considered first-line treatment for enteric fever and other infections in many developing countries.[1]

Chloramphenicol, a potent inhibitor of protein synthesis, is extremely active against a variety of organisms including bacteria, spirochetes, rickettsiae, chlamydiae and mycoplasmas. It has bacteriostatic activity against most pathogens but is bactericidal for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitides.[2]

Respiratory pathogens such as H .influenzae and S. pneumoniae have also retained high susceptibility rates, with 99.2% and 99.4%. [3,4] The high susceptibility rates noted for chloramphenicol might be due to the very limited use of this drug for many years in the developed world. However, the use of chloramphenicol has reduced over a period of time due to the adverse effects like bone marrow depression or in some cases severe aplastic anaemia. [5]

Despite the constantly increasing need for new antimicrobial agents, their discovery and development appear to have greatly reduced in recent years. Presented with the significant problem of advancing antimicrobial resistance, the global scientific community has attempted to find alternative solutions; one of the most promising ones is the evaluation and use of old antibiotic compounds which have been placed under orphan drugs. Due to the low-level use of many of the older antibiotic compounds, these have remained active against a large number of currently prevalent bacterial isolates. Thus, clinicians are beginning to re-evaluate their use in various patient populations and infections, despite the fact that they were previously thought to be less effective and/or more toxic than newer agents. A number of older antibiotic compounds, such as polymyxins, fosfomycin, fusidic acid, sulphonamides, aminoglycosides and chloramphenicol, are re-emerging as valuable alternatives for the treatment of difficult-to-treat infections. The availability of novel genetic and molecular modification methods provides hope that the toxicity and efficacy drawbacks presented by some of these agents can be surpassed in the future. In an era of increasing resistance to many antibacterial agents, chloramphenicol might have an important role in the treatment of intra abdominal infections and respiratory tract infections caused by multi drug-resistant pathogens. This review article focuses on the spectrum of activity of chloramphenicol, mechanism of action , side effects , its parentral and oral use, its resistance mechanisms, toxicity elucidated by enteric pathogens against it and also on the possibility of its therapeutic use in treatment of multi - drug resistant bacterial infections.

Discovery and Synthesis

Chloramphenicol was originally derived from the bacterium Streptomyces venezuelae, isolated by David Gottlieb, and introduced into clinical practice in 1949, under the trade name chloromycetin and was widely used in the 1950s. It was the first antibiotic to be manufactured synthetically on a large scale and is a potent broad spectrum antibiotic. Contributing substantially to its biological activity is a dichloroacetyl substituent, the biochemical derivation of which remains obscure.[6] The pathway for chloramphenicol biosynthesis was initially deduced from the patterns of isotope incorporation into chloramphenicol produced when cultures were fed with labeled substrates, and from the structures of metabolites accumulated by blocked mutants.[7,8] The results indicated a plausible series of biosynthetic reactions that generated chloramphenicol by dichloroacetylation of an aromatic intermediate.

Spectrum of action

Chloramphenicol acts on the protein synthesizing system of bacteria (the cell's ribosomes) yet does not affect mammalian, reptilian, or avian ribosomes. Due to its pH, it has the ability to penetrate into infected tissues and tissues with biological barriers. Chloramphenicol can easily pass deeply through cell membranes to inactivate bacteria living within, and into organs where other antibiotics cannot. Highly susceptible bacteria are killed outright while others are merely rendered unable to divide and the host's immune system then destroys them upon discovery.

Because it functions by inhibiting bacterial protein synthesis, chloramphenicol has a very broad spectrum of activity: it is active against Gram-positive bacteria (including the dreaded strains of MRSA), Gram-negative bacteria and anaerobes. It is not active against Pseudomonas aeruginosa, Chlamydiae, or Enterobacter species. It has some activity against Burkholderia pseudomallei, but is no longer routinely used to treat infections caused by this organism (it has been superseded by ceftazidime and meropenem).

Because of its excellent blood brain barrier penetration (far superior to any of the cephalosporins), chloramphenicol remains the first choice treatment for staphylococcal brain abscesses. It is also useful in the treatment of brain abscesses due to mixed organisms or when the causative organism is not known. Chloramphenicol is active against the three main bacterial causes of meningitis: Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. Chloramphenicol has been used in the initial empirical treatment of children with fever and a petechial rash, when the differential diagnosis includes both Neisseria meningitidis septicaemia as well as Rocky Mountain spotted fever, pending the results of diagnostic investigations. Chloramphenicol is also effective against Enterococcus faecium, which is being considered for treatment of vancomycin-resistant enterococcus. [9]

Mechanism of action

Chloramphenicol binds to the 50S ribosomal subunit and blocks fundamental ribosomal functions, such as peptidyltransferase (PTase) activity, binding and movement of ribosomal substrates through the PTase center and translation termination.

Experiments from more than several years ago have demonstrated that both monovalent and Mg2+ ions at optimal concentrations 2 are essential components for the PTase activity and the interaction of chloramphenicol with ribosomes. [10] Vogel et al,[11] have explained about the rationale for the interdependence of monovalent/ Mg2+ ions and chloramphenicol interaction with ribosomes. As proposed by Bayfield et al, [12] this ion is dissociated in inactive ribosomes and this dissociation might also account for the inability of inactive ribosomes to bind chloramphenicol.

Side effects

The major side effects found in patients treated with chloramphenicol include irreversible bone marrow depression, aplastic anemia, and leukemia. Epidemiologic studies indicate that 1:30,000 to 1:45,000 patients receiving chloramphenicol treatment go on to develop leukemia and based on epidemiologic studies, chloramphenicol has been strongly correlated with leukemogenesis.[13] Chloramphenicol-mediated hematotoxicity manifests as either a reversible, predictable, dose-dependent, early-onset, mild anemia characterized by reticulocytopenia with occasional leucopenia and thrombocytopenia observed during therapy or a post treatment pancytopenia that is unpredictable, irreversible, dose independent, and occasionally fatal.[14] Aplastic anemia appears to have ancillary factors such as underlying mitochondrial dysfunction, genetic polymorphisms that accentuate chloramphenicol binding to mitochondrial rRNA , or a genetic predisposition that enhances the ability of the bone marrow to nitroreduce chloramphenicol into its myelotoxic derivative. Chloramphenicol associated aplastic anaemia cannot be predicted by the monitoring of blood cell counts.[15] The percent mortality of chloramphenicol associated aplastic anaemia is around 50% and in neonates it 40 %.[16] Prognosis is poor, if aplastic aneamia develops after a long time of treatment. Only orally administered chloramphenicol leads to aplastic anaemia. This has made chloramphenicol to be prescribed parenterally by many physicians. It is not known whether this lowers the incidence of aplastic anemia or not but the risk is obviously lowered.[17]

Another side effect of chloramphenicol is the grey baby syndrome which is a rare condition almost exclusively seen in neonates and very young infants. Toxic blood levels of chloramphenicol secondary to neonatal hepatic enzyme immaturity leads to circulatory collapse and the signs of cardiac shock. The infant is cyanosed, is acidotic, has cold peripheries and has the signs of all of marked hyponia, poor feeding, vomiting, loose stools and a distended abdomen. Because of this, it is recommended that chloramphenicol not been to be given to neonates or to young infants, but if given should be administered in low doses (25 mg/kg/day in four divided doses). [18] The adverse side effects of chloramphenicol are tabulated in Table 1. These adverse effects have led to dramatic reductions in the use of chloramphenicol in developed country settings. Use of chloramphenicol has been replaced by other antibiotics with a better side effect profile, although it remains a useful agent. In resource poor settings, its use has continued because of its availability and low cost.

microbiology-biotechnology-Dose-related-adverse

Table 1: Dose related adverse effects of chloramphenicol

Phramacokinetics

Three preparations of chloramphenicol are most commonly used in clinical practice: a crystalline powder for oral administration, a palmitate ester for oral administration as a suspension, and a succinate ester for parenteral administration. Both esters are inactive, requiring hydrolysis to chloramphenicol for anti-bacterial activity. The palmitate ester is hydrolysed in the small intestine to active chloramphenicol prior to absorption. The bioavailability of oral crystalline chloramphenicol and chloramphenicol palmitate is approximately 80%. The time for peak plasma concentrations is dependent on particle size and correlates with in vitro dissolution and deaggregation rates. The bioavailability of chloramphenicol after intravenous administration of the succinate ester averages approximately 70%, but the range is quite variable. Incomplete bioavailability is the result of renal excretion of unchanged chloramphenicol succinate prior to it being hydrolysed to active chloramphenicol. Plasma protein binding of chloramphenicol is approximately 60% in healthy adults. The drug is extensively distributed to many tissues and body fluids, including cerebrospinal fluid and breast milk, and it crosses the placenta. Reported mean values for the apparent volume of distribution range from 0.6 to 1.0 L/kg. Most of a chloramphenicol dose is metabolised by the liver to inactive products, the chief metabolite being a glucuronide conjugate; only 5 to 15% of chloramphenicol is excreted unchanged in the urine. The elimination half-life is approximately 4 hours. Inaccurate determinations of the pharmacokinetic parameters may result by incorrectly assuming rapid and complete hydrolysis of chloramphenicol succinate.[19]

Parenteral vs oral administration of chloramphenicol

Chloramphenicol can be given orally or parenterally but the bioavailability of oral formulations is better than that achieved after intramuscular or intravenous injection of the succinate ester pro-drug. [20] Nevertheless, parenteral dosing is indicated in patients with nausea, vomiting and/or altered consciousness. Although an inadequate therapeutic response has been reported after intramuscular administration,[21] more studies in enteric fever have suggested that peak plasma chloramphenicol concentrations are not influenced significantly by the route of parenteral administration.[22]After intravenous or intramuscular chloramphenicol succinate injection, approximately one-third of the dose is excreted unchanged in the urine while the remainder is hydrolysed to free drug and either excreted in the urine or conjugated in the liver.[23]

In order to characterize the factors affecting chloramphenicol pharmacokinetics after its parenteral administration as treatment for enteric fever, Acharya et al, [24] studied the disposition of chloramphenicol after intravenous or intramuscular injection of the succinate ester, together with simultaneous estimates GFR (iothalamate clearance), hepatocellular function (antipyrine clearance) and liver blood flow (ICG clearance).The findings of the study revealed that intravenous chloramphenicol produced peak plasma concentrations which are on average twice those after intramuscular injection of the same dose.

The recommended route of administration of chloramphenicol is usually oral for the treatment of typhoid fever. The intravenous route is used with severely ill patients, in whom absorption may be poor. In adults, chloramphenicol can be given as the base orally, and absorption is rapid and complete. The intravenous preparation is chloramphenicol succinate, an inactive precursor, which is hydrolyzed to chloramphenicol in the body. In a study on healthy volunteers given equivalent doses of chloramphenicol, Glazko et al.,[20] reported that the area under the plasma concentration-time curve of chloramphenicol given intravenously as chloramphenicol succinate was only 60 to 70% of that obtained with oral chloramphenicol. Teow –Yee et al.,[25] conducted a study to measure the serum chloramphenicol and chloramphenicol succinate concentrations in patients with typhoid fever who were being treated with either oral chloramphenicol or intravenous chloramphenicol succinate and to assess the clinical outcome of the treatment. In this study, the authors assessed serum chloramphenicol and chloramphenicol succinate concentrations in patients given equivalent doses of chloramphenicol base either intravenously or orally for typhoid fever by high-performance liquid chromatography. The mean serum chloramphenicol concentrations were significantly lower in the patients treated with intravenous chloramphenicol succinate than in the patients treated with oral chloramphenicol capsules. The study emphasizes that where ever facilities are available, it may be prudent to measure serum chloramphenicol concentrations, especially in patients who are treated with intravenous chloramphenicol succinate, to ensure that failure to respond is not due to low serum drug concentrations. The significant findings, revealing the outcomes of orally administered chloramphenicol is given in Table 2.

microbiology-biotechnology-Significant-revealing-orally

Table 2: Significant findings revealing the outcomes of orally administered chloramphenicol

Ophthalmic chloramphenicol

Topical chloramphenicol remains popular partly because of its wide spectrum of action, being highly effective against most Gram positive and Gram negative pathogens as well as most anaerobes (including all obligate anaerobes). It has a high reported efficacy of 91% to 93% in ocular infections [32] and is active against up to 94% ocular pathogens.[33] Chloramphenicol also has a high differential solubility giving high intraocular penetration (10 000 times more fat soluble than penicillin), making it superior to most other antibiotics for prophylaxis in ocular surgery, with penetration of ointment noted to be superior to eyedrop preparations (single application of 1% ointment as effective as 13 applications of eyedrop preparation every 15 minutes).[34]

Adverse reactions

Topical chloramphenicol is generally very well tolerated with uncommon local adverse effects of hypersensitivity and transient burning/stinging. [35] A study conducted by Wallerstein et al [36] revealed that marrow toxicity may not manifest until the second or third course of treatment. The usual adult systemic dose of chloramphenicol is 3 to 5 g per day in divided 4 hourly doses while one drop (0 05 ml) of guttae chloramphenicol 0-5% contains 0-25 mg of chloramphenicol meaning that a typical course of topical treatment would provide a total of less than 10 mg delivered to .the eye, with only a fraction of this amount being absorbed systemically. There are several studies revealing the ophthalmic use of chloramphenicol in the management of ocular infections .The key findings of these studies are given in Table 3:

microbiology-biotechnology-Ophthalmic-use-chloramphenicol

Table 3: Ophthalmic use of chloramphenicol

The debate over the safety of topical chloramphenicol has caused a widespread response in the ophthalmic literature. The article by McGhee and Anastas,[44] has reviewed the knowledge and concluded that there is a theoretical but not conclusively proved risk of aplastic anaemia in the use of topical ophthalmic chloramphenicol.

The authors quoted an idiopathic aplastic anaemia incidence of 1 in 524 000, or 2 per million in the USA. The use of chloramphenicol in Europe is 40 times the amount of that in the USA and reflects the different prescribing habits between the two communities. If topical ocular chloramphenicol was to have a relation to aplastic anaemia the incidence in Europe will be expected to be higher than in the USA. This issue was addressed by Gardner, 1991 who quoted an incidence of 1.5 per million cases of aplastic anaemia in France, a similar figure to that of the USA. These data suggest that there is no difference in the incidence of aplastic anaemia when topical ocular chloramphenicol is prescribed compared with when it is not. Practitioners should continue to use this effective drug until there is firm evidence that it is not safe.[45]

Clinical usage of chloramphenicol

Chloramphenicol is of undoubted value for the treatment of typhoid fever and bacterial meningitis. With the exception of neonatal forms of meningitis, a combination of penicillin G and chloramphenicol is the best 'antibiotic cover' before the causative organism is identified. Chloramphenicol is very effective for the treatment of meningitis due to Haemophilus influenzae type b. [44,45,46,47] Parenterally administered ampicillin, previously regarded by many as equally effective to chloramphenicol for this infection, is no longer dependable. Chloramphenicol may be preferable for the treatment of other severe H. influenzae type b infections such as epiglottitis, osteomyelitis, cellulitis and pneumonia.

The best substitute drug for the treatment of meningococcal, pneumococcal or Listeria monocytogenes meningitis in penicillin-allergic patients is chloramphenicol.[48] This may also apply to meningitis caused by Group B streptococci. Chloramphenicol together with penicillin G is often the preferred chemotherapy for the treatment of cerebral abscess. Chloramphenicol is especially useful for temporal lobe abscesses of otitic origin which usually yield a mixed bacterial flora including anaerobes such as Bacteroides fragilis .[49] Metronidazole or clindamycin may prove to be acceptable alternative drugs for this clinical situation. By comparison to ampicillin and cotrimoxazole, chloramphenicol appears superior for the treatment of typhoid fever.[50] For the treatment of paratyphoid fever and septicaemia caused by other Salmonella spp., chloramphenicol is also probably the most effective drug; alternative drugs for these diseases are the same as for typhoid. One of these alternatives must be used when chloramphenicol-resistant Salmonella species strains are involved. Strains of Salmonella typhi resistant to chloramphenicol caused a typhoid epidemic in Mexico during the early 1970's, but whenthe epidemic subsided endemic strains reverted to chloramphenicol sensitivity. [51] Chloramphenicol resistant S. typhi and other salmonella, strains appear to be prevalent in South-East Asia. [52]

Chloramphenicol in treatment of bacterial meningitis

Bacterial meningitis is still a major public health problem in developing countries. Three species of bacteria Haemophilus influenzae type b (Hib), Neisseria meningitidis (Mnc), and Streptococcus pneumoniae (Pnc) cause more than three-quarters of all cases of acute bacterial meningitis in such countries. Schauf et al.,[53] have conducted a study to determine the bactericidal effects of chloramphenicol and three, β-lactams (ampicillin, cefamandole, and penicillin G) on 27 strains of Haemophilus influenzae type b isolated from the blood or cerebrospinal fluid of infected infants. Of the ampicillin-susceptible strains, 75% were killed by < 2.0 ug of each antibiotic per ml; however, the concentration of the β -lactam agents required for bactericidal activity was higher than that required for inhibitory activity. Chloramphenicol was the only agent which had no marked discrepancy between inhibitory and bactericidal concentrations regardless of β -lactamase production.

Pecoul et al [54] have conducted a clinical trial to compare the efficacy at day 4 of a double intramuscular injection of long-acting chloramphenicol 100 mg/kg with that of ampicillin administered intravenously for 8 days at 200 mg/kg (4 times a day). The results did not demonstrate any statistically significant difference between long-acting chloramphenicol and ampicillin with respect to case fatality rates and failure rates at day 4. The authors have concluded that long-acting chloramphenicol is cheap and easy to administer, advantages that are of particular importance where medical resources are scarce, and it is now admitted that adverse effects are unusual. The use of a single injection of an oily suspension of chloramphenicol to patients of all ages with meningococcal meningitis has been recommended.[55] In most field conditions, the bacteriological diagnosis of meningitis is not feasible. Starting antibiotic treatment as early as possible for all suspected cases of bacterial meningitis is the only means of preventing death and secondary morbidity. For such a strategy, an oily suspension of chloramphenicol appears to be the best antibiotic to use as a first-line treatment; a second injection of oily chloramphenicol has to be given no more than 48 hours later. After 3 or 4 days, depending on clinical or biological criteria, the treatment can be modified or continued with oral chloramphenicol.

Rahal et al [56] have studied the bacteriostatic and bactericidal effects of chloramphenicol, ampicillin, tetracycline, and sulfisoxazole and compared it against several potential meningeal pathogens. Chloramphenicol is bactericidal at clinically achievable concentrations against Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. It is bacteriostatic against gram-negative bacilli of the family Enterobacteriaceae and against Staphylococcus aureus. Chloramphenicol has proven highly efficacious in the treatment of bacterial meningitis caused by those organisms against which it is bactericidal at low concentrations. The authors concluded that because leukocytic phagocytosis in the subarachnoid space is inefficient, the bactericidal activity in cerebrospinal fluid is important for optimal therapy of bacterial meningitis. Chloramphenicol does not provide such activity in meningitis caused by enteric gram-negative bacilli. The significant findings of various studies conducted with regard to the use of chloramphenicol in the treatment of bacterial meningitis is provided in Table 4

microbiology-biotechnology-Chloramphenicol-bacterial-meningitis

Table 4: Chloramphenicol in the treatment of bacterial meningitis

Typhoid fever (caused by S. typhi) remains a significant problem and is estimated to have caused 21·6 million illnesses and 216,500 deaths globally, affecting all ages. Chloramphenicol no longer has a place as first line treatment of Salmonella typhi (S typhi) as much of it in the developing world is now resistant to chloramphenicol. Multiple resistance (to chloramphenicol, ampicillin and cotrimoxazole) has been reported in up to 90% of cases of Salmonella typhi in Vietnam and almost 70% in Pakistan. [66] It has been suggested that almost all countries now have a significant proportion of multiple resistance of this bacteria. The current drugs of choice are fluoroquinolones and third-generation cephalosporins, but decreased susceptibility to these antimicrobials has also been reported.[67]

After sporadic outbreaks of chloramphenicol resistant typhoid between 1970 and 1985, many strains of S typhi developed plasmid mediated multidrug resistance to the three primary antimicrobials used (ampicillin, chloramphenicol, and co-trimoxazole). This was countered by the advent of oral quinolones, but chromosomally acquired quinolone resistance in S typhi and S paratyphi has been described in various parts of Asia, possibly related to the widespread and indiscriminate use of quinolones.

Appropriate antibiotic treatment (the right drug, dose, and duration) is critical to curing typhoid with minimal complications. The emergence of multidrug resistant typhoid in the 1990s led to widespread use of fluoroquinolones as the treatment of choice for suspected typhoid, especially in South Asia and South East Asia where the disease was endemic.[68]

In the past few years, however, the emergence of resistance to quinolones has placed tremendous pressure on public health systems in developing countries as treatment options are limited.[69] The review of the use of chloramphenicol in treatment of typhoid fever is provided in Table 5

microbiology-biotechnology-Chloramphenicol-treatment-typhoid

Table 5: Chloramphenicol in the treatment of typhoid fever

Chloramphenicol resistance

Resistance to chloramphenicol is mainly due to the production of inactivating enzymes, the chloramphenicol acetyl transferases (CAT). Three types of CAT (types I–III) have been described in gram-negative bacteria, but resistance due to the production of CAT of type I has been encountered most frequently in Enterobacteriaceae and is generally plasmid-encoded. However, there are also reports on other mechanisms of chloramphenicol resistance, such as efflux systems inactivation by phosphotransferases mutations of the target site and permeability barriers.

Chloramphenicol acetyltransferases (CATs) are able to inactivate chloramphenicol as well as thiamphenicol and azidamfenicol. Due to the replacement of the hydroxyl group at C-3 by a fluor residue, the acceptor site for acetyl groups was structurally altered in Ff. This modification rendered Ff resistant to inactivation by CAT enzymes, and consequently, chloramphenicol-resistant strains, in which resistance is exclusively based on the activity of CAT, are susceptible to Ff . There are two defined types of CATs which distinctly differ in their structure: the classical CATs, referred as type A CATs and the novel CATs, also known as xenobiotic CATs and referred as type B CATs.

Apart from enzymatic inactivation, which confers chlomphenicol resistance transposon based chloramphenicol resistance was first detected in 1979 in P. aeruginosa and later on shown to be based on the presence of the transposon Tn1696.[ 83]

Emergence of chloramphenicol resistance

Until the mid-1970s chloramphenicol was the undisputed drug for treatment of typhoid fever, and in developed countries the use of this antibiotic resulted in a reduction in mortality from 10% to <2% . Although before 1970 a few sporadic isolations of chloramphenicol-resistant Salmonella typhi had been reported from chloramphenicol-resistant strain was that which occurred in Mexico in 1972. At about the same time, there was a second substantial outbreak in Kerala, India [84] and in both outbreaks mortality was high. In the succeeding 5 years outbreaks occurred in several other countries, notably, Vietnam, Indonesia, Korea, Chile, and Bangladesh.[85] A notable feature of all chloramphenicol-resistant strains from outbreaks in Mexico, the Indian subcontinent, and Southeast Asia was that although the strains belonged to different Vi phage types, resistance to chloramphenicol was encoded by a plasmid of the H 1 incompatibility group, often in combination with resistance to streptomycin, sulfonamides, and tetracyclines. [86]

In India, the incidence of MDR Salmonella typhi isolates has been reported to be as high as 60% in Pune ,[87] in 1999, but then declining to 22% in Nagpur.[88] The resurgence of resistant isolates in Ludhiana, India, in 2002 has, however, been a cause for concern [89,90]. A US-based study of imported strains [ 91] noted an increase in the number of MDR and Nalidixic acid resistant Salmonella typhi globally, although all isolates remained sensitive to ciprofloxacin and ceftriaxone. In Bangladesh[92] there has been a reported decrease in MDR isolates with no corresponding increase in sensitive strains. For ciprofloxacin there has been an increase in minimum inhibitory concentration in strains imported into the UK,[93] in Bangladesh,[94] as well as in India. [95]

Discussion

Chloramphenicol has been efficient in treating not only enteric fever and meningitis but also pulmonary infections. In assessing the role of chloramphenicol in treatment of acute respiratory tract infection, Ioannidis et al [96] have evaluated the efficacy of chloramphenicol in treatment of acute respiratory tract infection of mixed bacterial origin and reported that a clinical improvement was encountered in 96.25% patients. In an other study by Kemmerich et al [97] the authors evaluated the use of enoxin, ofloxacin, ampicillin and chlormaphenicol for treatment of experimental Haemophilus influenzae pneumonia and reported a survival rate as 48% with chlormaphenicol as against 78% with ampicillin. Howard et al [98] have reported that 1.9% strains of Haemophilus influenzae type b as resistant to both ampicillin and chlormaphenicol which in turn suggests that cefotaxime to be used as the first line empirical treatment for Haemophilus influenzae type b pulmonary infection. In yet another study by Deivanayagam et al [99] the authors evaluated the effectiveness of ampicillin and combination of penicillin and chlormaphenicol in treatment of pneumonia and reported that there is no significant difference observed in the primary outcome, cure rate or secondary outcome among the two groups. With regard to community acquired pneumonia, Asghar et al [100] have reported that there is treatment failure with chloramphenicol in children aged between 2 -59 months .Aspa et al [101] have reported that 18% of Streptococcus pneumoniae causing pneumonia in adults in Europe exhibited resistance to chlormaphenicol . Campos et al [102] 2003 have reported that 14.3% of Haemophilus influenzae type f were resistant to chloramphenicol. Duke at al [103] have emphasized the fact that WHO recommends the use of chloramphenicol in neonates who fail to respond to first line antibiotics

The role of chloramphenicol in the treatment of Vancomycin resistant enterococcus blood stream infection is well documented. and mortality rate was lowered inpatients treated with chloramphenicol.. Hartmann et al.,[104] have reported the first paediatric case of ventriculitis due to VRE (in a 2-month-old infant) to be successfully treated with combined intravenous (i.v.) and intraventricular chloramphenicol after failure of i.v. linezolid and intraventricular gentamicin. Sood et al.,[105] have reported a case of prosthetic valve endocarditis and persistent bacteremia due to vancomycin-resistant Enterococcus faecium. The combination of parenteral chloramphenicol plus minocycline therapy was administered for 8 weeks and resulted in cure after treatment with quinupristin-dalfopristin had failed. Chloramphenicol proved to be effective in initiating a clinical response in multi drug resistant bacterial infections

Loss of R-plasmid would lead emergence of chloramphenicol-sensitive strains showing very low MICs. High degree of chloramphenicol susceptibility to S. enterica serovar typhi isolates has also been reported from India Over period of years several Indian studies have documented a 90-95% re-emergence of chloramphenicol susceptibility. This has also been reported even from neighboring countries. Since its Introduction in1948, chloramphenicol has remained the drug of choice for typhoid fever and remains the standard against which the newer antimicrobials are compared. Treatment with chloramphenicol in typhoid fever reduces the mortality from 20 to 1% and the duration of fever from 14-28 to 3 to 5 days. Chloramphenicol has re-emerged as valuable drug of choice for treatment of enteric fever in India.

Recently, the New Delhi metallo-beta-lactamase (NDM-1), a novel type of metallo-beta-lactamase (MBL) conferring resistance to almost all beta-lactam antibiotics, including carbapenems that are used in treatment of antibiotic-resistant bacterial infections, has emerged and, therefore, has alarmed the world. This has become a significant threat to human health due to its extensive drug resistance, leaving few or no therapeutic options and, therefore, becoming a major public health problem throughout the world, particularly in India. Chloramphenicol has the potential to induce a good clinical response even in bacterial infections caused by microbes harbouring blaNDM-1 in the future.

Conclusion

The reduced use of chloramphenicol appears to increase the sensitivity of chloramphenicol. The reversal may be due to loss of plasmids encoding resistance to chloramphenicol and other first line drugs like ampicillin, co-trimoxazole or may be due to emergence of susceptible strains. Chloramphenicol can be administered orally and its clinical efficacy is well established.Where drug sensitivity tests are not available, chloramphenicol can be given in uncomplicated typhoid fever and the response monitored carefully. In fact investigators have suggested using chloramphenicol, along with the third-generation cephalosporins, in typhoid fever due to ciprofloxacin-resistant S. enterica serovar typhi infection. In view of Re-emergence of sensitivity and reduced resistance to chloramphenicol in S. typhi isolates in many studies, chloramphenicol may be reconsidered for the treatment as the antibiotic of choice for the treatment typhoid fever.

In an era of increasing resistance to many antibiotics, chloramphenicol might have a role in the treatment of intraabdominal infections and respiratory tract infections caused by multidrug-resistant pathogens. Thus, it represents a great comeback in clinical practice.

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