|Year : 2014 | Volume
| Issue : 1 | Page : 17-19
Editorial on Penicillin-sensitive bacteria
Professor of Microbiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
|Date of Web Publication||13-Jun-2014|
Professor of Microbiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Raja K. Editorial on Penicillin-sensitive bacteria. J Acad Clin Microbiol 2014;16:17-9
Penicillin, a serendipitous discovery by Alexander Fleming published by him in the British Journal of Experimental Pathology in June 1929, was regarded at first as a compound that can be used for selecting bacteria from mixed cultures. Ten years later in 1939, Howard Florey, Ernst Chain and their colleagues at the Sir William Dunn School of Pathology at Oxford University worked on different strains of the fungus, penicillium and could finally isolate it in the pure form. In 1941, Albert Alexander, a policeman became the first to be treated with Penicillin for a skin infection that spread to his lungs also, with dramatic relief. For mass production, Florey and his colleagues had to take the help of an American mycologist, Robert Thom of the Department of Agriculture and the department's Northern Regional Research Laboratory in Illinois. The main pharmaceuticals that were involved in the initial production of Penicillin were Merck, Squibb, Lilly and Pfizer who were approached by Florey himself. 
The magic of Penicillin is its β-lactam chain structure and the fact that very small quantities of Penicillin are enough to kill major pathogens like streptococci, pneumococci and staphylococci [See [Table 1].  Natural Penicillins are active against non β-lactamase-producing Gram-positive cocci (Pneumococci, Staphylococci and Streptococci), few Gram-negative cocci (meningococci and gonococci), Gram-positive bacilli (Bacillus anthracis), anaerobes (Clostridum perfringens, C. tetani) and spirochetes (Treponema pallidum, T. pertenue and Leptospira).
|Table 1: MICs of Penicillin compared among different species of Bacteria according to EUCAST in mg/L|
Click here to view
Resistance mechanisms include:
- Production of β-lactamase that opens the β-lactam ring in Haemophilus influenzae and Moraxella More Details. This can be neutralised by a β-lactamase inhibitor like clavulanic acid.
- Alteration of Penicillin binding proteins (PBPs) in Gram-positive cocci like staphylococci and enterococci. Hence, β-lactamase inhibitors have no role here.
- Uptake inhibition and efflux mechanisms which are related to the cell membrane are active in Gram-negative bacteria.
This editorial will concentrate on the use of natural Penicillin in the modern era of multidrug resistant bacteria. It is intended as an eye-opener for clinicians who feel that the oldest antibiotic is now redundant. Let us with the help of current literature, look at the situations where Penicillin in its natural form, i.e. Penicillin G and ampicillin - a modification to increase its spectrum, is still active and serves as a life-saver.
Staphylococcus aureus was the major pus-forming pathogen to be destroyed very effectively in the early days of Penicillin discovery. Today, approximately 5-10% of community-acquired staphylococcal infections remain sensitive to Penicillin. Staphylococcal infections are distinctively pus-forming and easy to recognise. Hence, it is the tendency of the treating physician to blindly start drugs like cephalosporins, quinolones or if severe, vancomycin or clindamycin, as empirical therapy. In case of a Penicillin-sensitive staphylococcus, Penicillin with its low minimum inhibitory concentration (MIC) of 0.12 mg/L is the drug of choice, penetrating better to sites of inflammation and acting faster at lower concentrations. In an interesting study by Nissen JL et al. in Denmark, they concluded that in case of staphylococcal bacteraemia, 'Definitive therapy with cefuroxime was associated with an increased risk of 30 day mortality compared with Penicillin (cefuroxime treatment (39%) versus Penicillin treatment (20%), P0 = 0.037)'.  Thus, Penicillin is the drug of choice if the isolate is a sensitive one.
Lancefield groups A, B, C, F and G remain sensitive to Penicillin. Alpha haemolytic streptococci, commensals of the oral cavity, exhibit varied sensitivity patterns. They may appear sensitive, but certain infections like infective endocarditis due to slow growing strains may not respond as the basic mechanism of action needs active multiplication.
As per Clinical and Laboratory Standards Institute (CLSI) document M100-S21, isolates of pneumococci with Oxacillin zone sizes of ≥20 mm are susceptible (MIC ≤ 0.06 mg/ml) to Penicillin. MICs for Penicillin, Cefotaxime, Ceftriaxone or Meropenem should be determined for those isolates with Oxacillin zone diameters of ≤19 mm, because zones of ≤19 mm occur with Penicillin-resistant, intermediate or certain susceptible strains. For isolates with Oxacillin zones ≤19 mm, a Penicillin MIC test was performed.  In India, laboratory resources are still limited, especially access to sheep blood, which is essential for isolation of pneumococci and its sensitivity testing. MIC testing is done only in a few reference labs. On searching literature, it was observed that isolation rates are very low but sensitivity to Penicillin remains almost 100%. In case of resistant strains, it is not mentioned whether MIC was performed for confirmation. 
Most of the isolates from an outbreak in New Delhi in 2005-2006 were susceptible to Penicillin, ampicillin, rifampicin and Ceftriaxone. All the isolates were found resistant to cotrimoxazole (MIC >16 mg/mL) and two-thirds were resistant to ciprofloxacin. There is a dearth of information about susceptibility rates in India; however, in the above outbreak, one isolate was resistant to ampicillin. 
Treating gonococcal urethritis became relatively easy after the discovery of Penicillin. However, response to Penicillin was seen to be reduced first in 1954, and the first article reporting resistance appeared in 1956 by Thayer et al. In India, Chacko and Yogeshwari from Chennai reported 45.6% resistance in 1966, while later in 1971, Moses et al. from Mumbai reported 56% resistance.  In 1981, the cause of resistance was attributed to β-lactamase enzymes. Later on, Penicillin-binding protein alterations were also noticed. By 1990, Penicillin was no longer a treatment option for gonorrhoea and the era of fluoroquinolones began. As soon as Penicillin was withdrawn, sensitivity rates slowly increased but lack of quality laboratory support has been the major cause for empiric single high-dose therapy in gonorrhoea, and this in turn has led to gonococci acquiring newer modes of resistance. 
Ampicillin is the drug of choice. Penicillin shows MICs that are 2-4-fold higher than ampicillin in case of Enterococcus faecalis. Though monotherapy may be enough for urinary tract infections (UTI) and skin infections, combination with aminoglycosides is necessary in case of infective endocarditis, osteomyelitis and meningitis in neonates. At present, vancomycin is the alternative therapy recommended in ampicillin-resistant enterococcal infections.
Isolating this fastidious bacterium and doing its susceptibility testing is beyond the capacity of the average laboratory in India. A large study involving approximately 8523 strains, in 1999-2000, found that ampicillin sensitivity has shown a slow decline with a rate of 81.9% in the study. However, sensitivity to Ceftriaxone has remained 100%, and 99.6% remain susceptible to amoxycillin-clavulanate even now. The mechanism of resistance is popularly thought to be due to β-lactamase production but there is a group of strains called β-lactamase negative ampicillin-resistant (BLNAR) strains that are also slowly increasing in number. 
Benzyl Penicillin is the treatment of choice in anthrax. For lung infection, fluoroquinolones and tetracyclines are effective alternatives.
Gram-positive anaerobes like peptostreptococci, Clostridium tetani and C. perfringens remain sensitive to Penicillin. However, adequate anti-toxin and supportive measures are essential for cure in case of toxin-mediated diseases.
It is fortunate that Penicillin retains its potency with respect to agents like Treponema pallidum and Leptospira. Leptospirosis outbreaks are responsible for keeping the medical community aware of the activity of the oldest antibiotic even now.
The special article in this issue deals with Penicillin-sensitive bacteria in a few centres in India. 
This may not be representative of the whole Indian scenario; however, this exercise was intended to increase the awareness of the readers to the continuing usefulness of Penicillin so that it is not dropped from the antibiotic sensitivity testing panels in the laboratories that they serve as clinical microbiologists.
It is our ardent appeal that more laboratories join this simple and interesting exercise of comparing data from different parts of India in a free and open manner so as to increase co-operation, knowledge and understanding in microbiology. Simply contributing retrospective laboratory data need not compromise any publishing or allied activities.
| References|| |
|1.||Aldridge S, Parascandola J, Sturchio JL. The discovery and development of Penicillin-928-1945-a booklet. Am Chem Soc Royal Soc Chem 1999;3-5. |
|2.||Penicillins: EUCAST clinical MIC breakpoints 2009-04-19 (version 1.3). |
|3.||Nissen JL, Skov R, Knudsen JD, Østergaard C, Schønheyder HC, Frimodt-Møller N, et al. Effectiveness of Penicillin, dicloxacillin and cefuroxime for Penicillin-susceptible Staphylococcus aureus bacteraemia: A retrospective, propensity-score-adjusted case-control and cohort analysis. J Antimicrob Chemother 2013;68:1894-900. |
|4.||CLSI document M100-S21; 2011. p. 96-9. |
|5.||Deva A, Prasad SR, Madappa BP, Junjegowda K, Bachu RP. Pneumococcal infections at a rural tertiary care hospital: A seven year study on isolation rate, clinical spectrum and antibiogram. J Clin Diagn Res 2014;8:50-2. |
|6.||Jhamb U, Chawla V, Khanna S. Clinical profile of group a meningococcal outbreak in Delhi. Indian Pediatr 2009;46:794-6. |
|7.||Moses JM, Desai MS, Bhosle CB, Trasi MS. Present pattern of antibiotic sensitivity of gonococcal strains isolated in Bombay. Br J Vener Dis 1971;47:273-8. |
|8.||Patel AL, Chaudhry U, Sachdev D, Sachdeva PN, Bala M, Saluja D. An insight into the drug resistance profile & mechanism of drug resistance in Neisseria gonorrhoeae. Indian J Med Res 2011;134:419-31. |
|9.||Tristram S, Jacobs MR, Appelbaum PC. Antimicrobial resistance in Haemophilus influenza. Clin Microbiol Rev 2007;368-89. |
|10.||Special article on Penicillin sensitive bacteria. J Acad Clin Microbiol 2014. |