Does strep require antibiotics: Don’t Stress Over Strep – Associates in Family Medicine
Don’t Stress Over Strep – Associates in Family Medicine
Oh, the wonders of winter. Snowball fights, skiing, hot cocoa, and… strep throat?
Yes, the season of fun-filled pastimes and sparkling snow can also be marked by sickness. And this winter, our providers at Associates in Family Medicine are seeing higher-than-usual cases of strep throat.
While this bacterial bane on the winter season is familiar to most of us, our team of providers has noticed a number of misconceptions around strep throat. We talked to AFM physician and urgent care director Dr. Shelley Moore to get clarity on common strep throat symptoms, treatment options, spread, and more.
What are the most common strep throat symptoms?
The telltale signs of strep throat are – you guessed it – a very sore throat that is most often paired with a fever. “In general, people with strep don’t exhibit generic cold symptoms like coughs, runny noses, nasal congestion, or sneezing,” says Moore. “If you are experiencing these types of symptoms with the absence of a fever, chances are you have a viral infection, and you don’t need to be tested for strep. ”
While throat pain and fever are the most common and notable symptoms of strep throat, other signs of this bacterial infection may include:
- Body aches
- Red, swollen tonsils (possibly with white patches or streaks of pus)
- Tiny red spots on the back portion of the roof of the mouth
- Swollen, tender lymph nodes in the neck
- Nausea or vomiting (particularly in younger children)
When should I get tested for strep throat?
If you have a sore throat that’s accompanied by a fever and/or some of the other symptoms described above (especially if these symptoms persist longer than 48 hours), it’s a good idea to see a doctor.
“With strep throat, it’s better to be seen earlier rather than later,” says Moore. “The quicker you get treated, the quicker you can be sure you don’t spread the infection to others. Also, if you get to the point where your pain is not well controlled and you have trouble drinking fluids, you run the risk of getting dehydrated and weak. ”
Does strep throat require antibiotic treatment?
The short answer is yes. “Unlike ear infections, which can be bacterial or viral in nature, strep throat is always caused by bacteria (group A streptococcus),” Moore clarifies. “Therefore, best practice is to prescribe antibiotics to prevent future problems and stop the spread of the infection.
“While there are times when strep could go away without antibiotics, the problem is that some of those cases could have negative outcomes, especially for very young or elderly patients,” says Moore. “Complications can include abscesses inside the throat or on the tonsils, rheumatic fever, and even post-streptococcal glomerulonephritis, which is a rare inflammation of the kidneys.”
How can I avoid getting (or spreading) strep throat?
To steer clear of strep throat and its unpleasant symptoms, follow a couple of simple yet effective practices in your day-to-day life. First and foremost, wash your hands regularly. “It doesn’t need to be antibacterial soap,” says Moore. “Regular soap and water can wash away all the potential germs responsible for spreading strep throat.” Moore also encourages people to avoid sharing drinks or foods with one another, even among family members.
If you already have strep throat symptoms or have been diagnosed with strep throat, keep in mind that you are typically most contagious when you have a fever. “Once you have started taking antibiotics, the general rule of thumb is 24 hours – or two doses of antibiotics for most prescriptions – before you are no longer contagious,” says Moore. As is the case when trying to escape strep throat, handwashing and avoiding close contact with other people are key to be sure you don’t spread your strep infection.
Where can I go for convenient, affordable strep throat treatment and care?
Because an official strep throat diagnosis cannot be made over the phone, Moore encourages people with strep symptoms to visit their primary care provider if they are able to be seen within 24 hours.
“If you can’t get in to your primary provider in a timely manner, the next step would definitely be to visit one of our urgent care locations, especially on the weekends,” says Moore. “We have access to rapid strep tests – which are easy, fast, and painless and take less than 10 minutes in the clinic setting.”
But what about the costs? “Thankfully, a rapid strep test is one of the least expensive point-of-care tests,” confirms Moore. “At several of our AFM urgent care and primary care locations, we also have most antibiotics available onsite – making the prescriptions much more affordable to patients with and without insurance.” Additionally, a visit to one of AFM’s urgent care locations will save you big bucks over an unnecessary trip to the ER. But it’s always a good idea to check with your insurance about what is and isn’t covered in your plan.
The top things to remember about strep throat
While there’s a lot of information out there on strep throat, here are the important things to keep in mind at this time of year and always:
- If you have generic cold symptoms with a sore throat, you probably don’t need a strep test – a virus is the more likely culprit.
- If you have throat pain, a fever, and not much else, go ahead and get tested.
- Strep tests are easy, fast, inexpensive, and painless.
- Strep throat is easily treated with affordable antibiotics.
- Keep washing those hands!
- Don’t depend on the internet for your diagnosis – count on experienced urgent care and primary care providers for a convenient, personalized diagnosis you can trust.
Do I need antibiotics to treat strep throat?
Strep throat signs and symptoms
Viral infections cause about 80% of sore throats, but strep throat is caused by bacteria called group A streptococcus or group A strep. Strep throat only accounts for about 15% of all sore throats in adults and 30% of sore throats in children.
“Patients often confuse strep throat with other sore throat infections,” says Christie Barnes, MD, Nebraska Medicine ear, nose and throat specialist. “A viral sore throat is usually accompanied by a cough, sneeze, runny nose or hoarse voice. Bacterial strep can make it painful to swallow and often comes with a high fever.”
Signs and symptoms of strep throat include:
- Throat pain or painful swallowing
- Red and swollen tonsils, sometimes with white patches or pus
- Tiny red spots on the roof of the mouth
- Swollen, tender lymph nodes in your neck
- Nausea or vomiting
- Body aches
Strep throat treatment
Most doctors can diagnose and treat strep throat. If you have a sore throat, your doctor will likely take a swab of your throat to see if you have an infection.
- If the results are negative, your doctor may recommend pain medication and general fluids to manage your symptoms
- If the swab is positive for streptococcus, your doctor will likely recommend antibiotics to ensure the infection doesn’t turn into something more serious
Left untreated, strep throat can cause:
- Kidney damage – caused by the immune system’s response to fight off strep throat
- Scarlet fever – symptoms include bright red rash, sore throat and high fever
- Rheumatic fever – a condition that causes painful joints, rash and heart problems
- Pneumonia – symptoms vary from mild fever and cough to difficulty breathing and sepsis
If you’re experiencing one or more of the below symptoms, your doctor may refer you to an ear, nose and throat specialist, or ENT doctor, for additional testing.
- Severe throat pain
- White spots on your tonsils
- Painful or difficulty swallowing
- Swollen or tender lymph nodes in your neck
Depending on your condition, the ENT doctor may recommend a tonsillectomy to remove your tonsils. Often considered a rite of passage for many children, tonsil removal can also be helpful for adults with reoccurring throat and tonsil issues.
How to prevent strep throat from spreading
Strep throat can spread through direct contact, such as kissing or sharing utensils. You usually aren’t contagious 48 hours after starting antibiotics. If you choose not to take antibiotics, you may be contagious for up to three weeks.
While there is no vaccine to prevent strep throat, there are steps you can take to protect yourself and others:
- Frequently washing your hands
- Covering your mouth when you cough or sneeze
- Avoiding sharing utensils and drinking glasses while you are sick
- Avoiding kissing anyone while you are contagious
If you or your child has a sore throat, it’s a good idea to consult a doctor in person or through a telehealth visit. For more information, call 800.922.0000.
Strep throat, tonsillitis, and other throat conditions: How to know if tonsil removal is right for you
Often considered a rite of passage for many children, tonsil removal can also be helpful for adults with reoccurring throat and tonsil issues. Read on to find out if it’s right for you.
7 tips for safe antibiotic use
The overuse and misuse of antibiotics over the years have led to one of today’s most pressing health care problems – antibiotic resistance. Read about these tips to become a more responsible user of antibiotics.
Antibiotic and other medication shortages: What to do if you can’t get your prescription
Whether you need a prescription or are looking for an over-the-counter pain reliever or fever reducer, not being able to get your medications can be worrisome. Due to specific shortages, some pharmacies even limit the amount of over-the-counter medications a person can purchase at one time. “These shortages are occurring with medications that we’re not used to seeing in short supply, which can create some challenges,” says Nebraska Medicine pharmacist Christopher Zaleski, PharmD. “Especially with OTC medications, we tend to take for granted that they’ll be there when we need them.”
Problems of choosing antibiotic therapy for streptococcal tonsillopharyngitis in children | #01/14
A sore throat complaint is one of the most common reasons for seeking medical help from a pediatrician. The main cause of sore throat is inflammation of the palatine tonsils and the mucous membrane of the pharynx – tonsillopharyngitis. This term is widely used in the scientific literature, despite the fact that according to the International Classification of Diseases, tonsillitis and pharyngitis are separate nosologies.
The key problem of antibiotic therapy for tonsillopharyngitis in children is the definition of indications for its appointment. It has been established that most often acute tonsillopharyngitis is a manifestation of an acute viral infection (ARVI) and, accordingly, does not require antibiotic therapy. Among the bacterial pathogens of tonsillopharyngitis in children, the undisputed leader is group A β-hemolytic streptococcus (GABHS, Streptococcus pyogenes), which accounts for 15–36% of cases of acute tonsillopharyngitis [1–3]. In 2012–2013 we examined 119children with acute tonsillopharyngitis using a rapid test for GABHS with high diagnostic accuracy (Streptatest), a positive result was obtained in 19% of patients.
The need for mandatory prescription of antibiotic therapy for streptococcal tonsillopharyngitis is beyond doubt. In a systematic review of the Cochrane Collaboration (2013), which included dozens of studies (since 1951), it was shown that the use of antibiotics for sore throat significantly reduces the likelihood of complications – both late non-suppurative (acute rheumatic fever) and early purulent (otitis media, sinusitis, paratonsillar abscess) .
The solution to this problem lies in the timely verification of streptococcal tonsillopharyngitis. Numerous studies have shown that the introduction of express diagnostic methods with high sensitivity and specificity makes it possible to identify the disease caused by GABHS directly during examination in just a few minutes of the patient, makes it possible, on the one hand, to prescribe antibiotic therapy for streptococcal tonsillopharyngitis in a timely manner, and on the other hand on the other hand, to significantly reduce the frequency of unreasonable prescription of antibiotics [5–6].
At the same time, there are still a number of topical problems of antibiotic therapy for tonsillopharyngitis in children that require discussion. These are problems associated with the choice of an antibacterial drug and the mode of its use.
Bacteria of the genus Streptococcus, including GABHS, are not capable of producing β-lactamases. In addition, this pathogen does not have other mechanisms of resistance to β-lactam antibiotics. So far, not a single GABHS strain resistant to penicillins, cephalosporins and carbapenems has been isolated in the world. Also, the pathogen in 100% of cases remains sensitive to glycopeptides and oxazolidinones. At the same time, GABHS resistance to macrolides, lincosamides, fenicols, tetracyclines, fluoroquinolones, and sulfonamides is observed .
In the course of multicenter Russian studies conducted in 2001–2005, the resistance of more than 1000 GABHS strains was assessed (Table 1): a very high level of GABHS resistance to tetracyclines, a high level of resistance to chloramphenicol, and a low level of resistance to 14- and 15-mer macrolides (less than 10%), minimal resistance to 16-mer macrolides and lincosamides (less than 2%), and no resistance to fluoroquinolones .
Given the high stable activity of penicillin against GABHS, this antibiotic (phenoxymethylpenicillin orally, as well as benzathinepenicillin intramuscularly) has been considered for many years as the drug of choice for the treatment of streptococcal tonsillopharyngitis in both domestic and foreign guidelines [9-12]. A number of guidelines also consider amoxicillin as the drug of choice [10-11].
However, in the 80s of the XX century, a serious problem was identified – the increasing frequency of clinical and microbiological inefficiency of penicillin in streptococcal tonsillopharyngitis, according to separate studies, GABHS eradication could not be achieved in every fourth patient . At the same time, it was found that other antibiotics are superior to penicillin in terms of effectiveness, in particular, if the frequency of formation of GABHS carriage in children after streptococcal tonsillopharyngitis in the treatment with penicillin was 11.3%, then when using macrolides and cephalosporins, it was significantly less – 7.1 % and 4.3%, respectively .
The study of the discrepancy between the effectiveness of penicillin in vitro and in vivo in streptococcal tonsillopharyngitis made it possible to determine the key reason for this phenomenon – the presence of co-pathogenic bacteria (Bacteroides spp. , Staphylococcus aureus, etc.) in the tonsils of patients, which produce β-lactamases and, accordingly, destroy natural penicillins and aminopenicillins [15–16]. Therefore, in patients who have recently received β-lactam antibiotics, as well as in the case of recurrence of tonsillopharyngitis, current guidelines recommend the appointment of drugs that are resistant to the action of β-lactamases, such as inhibitor-protected aminopenicillins and cephalosporins, and in some cases, lincosamides [9-12].
An additional factor limiting the use of penicillin in tonsillopharyngitis is a possible allergic reaction to this drug, which, according to various studies, ranges from 1% to 20% of cases . In case of allergy to penicillin, the use of macrolides or lincosamides is recommended [9–11].
The summarized recommendations on antibiotic therapy for streptococcal tonsillopharyngitis in modern guidelines can be presented in the form of an algorithm (Table 2).
This algorithm is based on two main factors that determine the choice of antibiotic. However, the scientific literature provides data on a number of factors that affect the effectiveness of antibiotic therapy for streptococcal tonsillopharyngitis. In particular, it has been shown that the effectiveness of antibiotic therapy depends on the frequency of carriage of β-lactamase-producing bacterial strains in the general population, and not only in patients with tonsillopharyngitis. In a year-long study, the effectiveness of amoxicillin in streptococcal tonsillopharyngitis in children and the frequency of detection of β-lactamase-producing bacterial strains in the oropharynx in healthy children were analyzed by months. The failure rate for the use of amoxicillin during the year ranged from 8% to 32%, and there was an obvious correlation with the frequency of carriage of bacterial strains producing β-lactamase (Fig. 1) .
As one of the possible reasons for the ineffectiveness of penicillin in streptococcal tonsillopharyngitis, the suppression of α-hemolytic streptococci by penicillins, which are representatives of the normal microflora of the oropharynx and prevent GABHS colonization, is considered .
An important factor determining the choice of antibiotic therapy for tonsillopharyngitis is the difficulty of differential diagnosis according to clinical data between streptococcal tonsillopharyngitis and infectious mononucleosis. The use of aminopenicillins in infectious mononucleosis leads in the vast majority of patients (75-100%) to the development of a toxic maculopapular rash (the so-called “ampicillin rash”) . In a study of adverse reactions to antibacterial drugs, which included an analysis of about 20 thousand cases of antibiotic use, it was found that the use of amoxicillin in infectious mononucleosis increases the likelihood of a rash by 58 times .
Given these additional factors affecting the choice of antibacterial drug, the use of cephalosporins in the treatment of streptococcal tonsillopharyngitis in children is of great interest. The drugs of this group are resistant to the action of many β-lactamases , they have a lesser effect on α-hemolytic streptococci compared to penicillins, which contributes to more effective GABHS eradication [22, 23].
Data from 35 evidence-based clinical trials (more than 7000 patients) evaluating the efficacy of various cephalosporins in streptococcal tonsillopharyngitis in children were summarized in a meta-analysis. The studies analyzed compared a 10-day course of 1-3 generation oral cephalosporin with oral penicillin. Meta-analysis data showed that cephalosporins are significantly superior to penicillin in terms of clinical and microbiological efficacy (p < 0.00001) (Fig. 2) .
One of the drugs that have shown significantly greater efficacy than penicillin is the third-generation oral cephalosporin cefixime. A multicenter randomized controlled trial compared the efficacy and safety of 10-day courses of cefixime and penicillin in 154 children aged 2 to 12 years with streptococcal tonsillopharyngitis. The clinical effect was achieved in all patients. Microbiological efficacy was 83% for the group of children treated with cefixime, and 77% for the group of children treated with penicillin. Adverse events in both groups were isolated . In a similar randomized study that included 110 children with streptococcal tonsillopharyngitis, the microbiological efficacy of cefixime was significantly higher than that of penicillin – 94% versus 77% (p < 0.05) .
With streptococcal tonsillopharyngitis, it is important not only to ensure the patient’s recovery from an infectious disease, but also to prevent the development of late complications and the spread of infection. Therefore, the goal of antibiotic therapy is the eradication of the pathogen. Studies have shown that a high level of eradication is achieved using a 10-day course of treatment with penicillin. The same duration of treatment is recommended for most other antibiotics [10, 27]. It has been established that in case of violation of the duration of the course of treatment with penicillin prescribed by the doctor, the effectiveness of therapy for streptococcal tonsillopharyngitis decreases by an average of 20% . Even more than 50 years ago, studies were conducted that showed that the prescribed 10-day course of treatment is not fulfilled by the vast majority of patients. One study showed that only 46% of children with tonsillopharyngitis continued to receive penicillin on day 3 of therapy, 31% on day 6, and 8% on day 9.day . In a similar study, the performance was better: 81% of patients took penicillin on the 5th day of treatment and 56% on the 9th day. The authors studied the factors that affect the implementation of the doctor’s recommendations. It was shown that the duration of the course of therapy did not depend on the age and sex of the child, the severity of the disease assessed by the doctor, and the duration of the symptoms. At the same time, it was found that the duration of treatment was influenced by the mother’s assessment of the severity of the child’s condition, the appointment of therapy by a doctor who observed the child for a long time, or by another doctor, as well as the attitude of the mother to the doctor .
Given the low compliance with a 10-day course of antibiotic therapy for tonsillopharyngitis, as well as the unequal effectiveness of various antibiotics, clinical studies of the effectiveness of shortened courses of treatment for streptococcal tonsillopharyngitis are of great interest. A number of studies have shown that a 6-day course of amoxicillin, a 4–5-day course of cephalosporins, and a 5-day course of azithromycin are comparable in effectiveness to a 10-day course of penicillin. At the same time, a number of advantages of short courses were noted: higher compliance, lower incidence of adverse effects, better attitude of the patient’s parents to treatment, and lower treatment costs . In 2009A systematic review of the Cochrane Collaboration was published comparing efficacy in acute streptococcal tonsillopharyngitis in children with short courses of antibiotic therapy compared with a 10-day course of penicillin. The review analyzed 20 studies involving more than 13,000 patients. Short courses of more effective antibiotics were characterized by faster resolution of fever and sore throat. There were no significant differences between a 10-day course of penicillin and a short course of other studied antibacterial drugs in terms of the frequency of tonsillopharyngitis recurrence .
One of the drugs, the effectiveness of a short course of which has been proven in streptococcal pharyngitis, is also cefixime. A randomized trial of 160 children with strep throat compared the efficacy of a 5-day course of cefixime with a 10-day course of penicillin. Clinical efficacy was achieved in 96% of patients treated with cefixime, and in 97.4% of patients treated with penicillin, eradication of GABHS was achieved in 82.8% and 88.2% of children, respectively. Within 4 weeks after the end of treatment, relapses were observed in 6 patients treated with cefixime and in 8 patients treated with penicillin. In general, there were no significant differences in the results of treatment in the studied groups, which allowed the authors to conclude that the effectiveness of a short course of cefixime and a standard course of penicillin is comparable . An important pharmacokinetic feature of cefixime is a relatively long half-life, which allows the drug to be taken once a day , which contributes to increased adherence to treatment.
In our clinic, the experience of using cefixime (Supraks®) was summarized with an assessment of clinical efficacy and safety as an empirical therapy for respiratory tract infections in children aged 1 to 12 years, including patients with acute tonsillitis and exacerbation of chronic tonsillitis. All children with tonsillitis showed rapid positive dynamics. In general, the study showed good tolerability of cefixime — 8.3% of patients had adverse events in the form of mild diarrhea, which did not require discontinuation of the drug .
The 3rd generation oral cephalosporin cefixime is highly active against many clinically significant Gram-positive and Gram-negative bacteria. Good bioavailability of the drug after oral administration (about 50%) allows you to create a high serum concentration and effective concentrations in tissues. The conducted studies indicate the high efficiency of cefixime in tonsillopharyngitis, the drug is included in the Standard of the Ministry of Health of the Russian Federation for the provision of primary health care for acute tonsillitis in children and adults on an outpatient basis . The original cefixime preparation Suprax® is presented on the Russian pharmaceutical market, which is available in the form of granules for suspension, dispersible tablets and capsules, which makes it possible to use it in children from an early age.
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I. A. Dronov 1 , Candidate of Medical Sciences
N. A. Geppe, Doctor of Medical Sciences, Professor 62 Candidate of Medical Sciences
First Moscow State Medical University. I. M. Sechenov, Moscow
1 Contact information: [email protected]
abstract. Tonsillitis-pharyngitis is a frequent childish disease. Among pathogenic bacteria the main role plays A group of β-hemolytic streptococcus (GAS). Effectiveness of short courses of treatment with antibiotics may be compared with 10-days course of treatment with penicillin. Clinical trial showed that oral intake of III generation cephalosporin – cefixime is highly efficient with children with streptococcus tonsillitis-pharyngitis including treatment by short courses.
Cochrane Review of Antibiotic Comparison for Streptococcal Infection Published. Patients usually go to the doctor complaining of a sore throat. Most cases of sore throat are caused by viruses, but some infections are associated with group A beta-hemolytic streptococcus (GABHS), the authors of a Cochrane systematic review point out. GABHS infections can have serious consequences, including rheumatic fever and kidney disease.
Most throat infections resolve spontaneously and the risk of complications is extremely low, but antibiotics are needed in some cases. For many years, the drug of choice has been penicillin, an inexpensive antibiotic used to treat GABHS infections. According to the authors, GABHS resistance to penicillin is rare, international guidelines for GABHS pharyngitis recommend the use of penicillin in the first place.
In a Cochrane systematic review, a team of researchers from Australia and Belgium wanted to find out which antibiotic is most effective for GABHS pharyngitis. Among the criteria for the effectiveness of antibiotics, the following were evaluated: relief of symptoms (pain, fever), reduction in the duration of the disease, prevention of clinical recurrence, prevention of complications (purulent complications, acute rheumatic fever, poststreptococcal glomerulonephritis). In addition, we compared data on the frequency of side effects of drugs and the risk-benefit ratio of antibiotic treatment for streptococcal pharyngitis.
Only data from randomized, double-blind trials comparing different antibiotics and reporting at least one of the following outcomes were selected for review: clinical cure, clinical relapse or complications, and/or adverse events.
The review included 19 RCTs with a total of 5839 patients.
Most studies (16 of 19) compared penicillin with other antibiotics: six with cephalosporins, six with macrolides, three with carbacephem, and one with sulfonamides. In other studies: clindamycin with ampicillin, azithromycin with amoxicillin in children.
Acute tonsillopharyngitis caused by GABHS was confirmed in all participants. Age of participants: from one month to 80 years; nine studies included children only, and 10 included children over 12 years of age and adults.
Cephalosporins versus penicillin
There was a small difference in symptom resolution in favor of cephalosporins versus penicillin, but the difference was not statistically significant in the ITT (intention to treat) analysis.
Clinical relapses were lower for cephalosporins compared with penicillin, but this relationship was found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33, N = 2, n = 770). There were no differences in the number of adverse events.
Macrolides versus penicillin
There were no differences between macrolides and penicillin for any outcome.
Thus, there was no difference between macrolides and penicillin in symptom resolution (OR 1.11, 95% CI 0.92 to 1.35; 6 trials; n=1728), effect on relapse (RR 1.21, 95% CI 0.48–3.03; 6 trials; n= 802 participants). Children had more adverse events with macrolides compared with penicillin (RR 2.33, 95% CI 1.06 to 5.15; N = 1, n = 489).
Carbacefem versus penicillin
Carbacefem versus penicillin showed better resolution of symptoms after treatment in adults and children (ITT OR analysis 0.70, 95% CI 0.49 to 0.99; NNTB 14, N = 3, n=795), in subgroup analysis of children (OR 0. 57, 95% CI 0.33 to 0.99; NNTB 8, N = 1, n = 233), but not in subgroup analysis of adults (OR 0.75, 95% CI 0.46–1.22, N=2, n=562). Limited data in children suggest that carbacefem is more effective than penicillin in resolving symptoms.
Azithromycin versus amoxicillin
One unpublished study in children showed a higher cure rate with azithromycin compared with amoxicillin given for 10 days (OR 0.29, 95% CI 0.11–0.73; NNTB 18, N=1, n=482), but there were no differences between groups in ITT analysis or long-term follow-up. Children had more side effects with azithromycin compared with amoxicillin (OR 2.67, 95% CI 1.78 to 3.99; N = 1, n = 673).
Clindamycin versus ampicillin
The only reported clinical outcome was gastrointestinal side effects (nausea or vomiting and loose stools) and rash or urticaria.
Sulfanilamide versus penicillin
One adult study was included in this comparison.
Only side effects were reported, there was no difference between sulfanilamide and penicillin (RR 1.